Grants

NCATS - National Center for Advancing Translational Sciences

Project Abstract Among the thousands of genetic disorders in humans, most are rare and lack effective treatments. Suppressor tRNA therapy has come a long way to become a realistic treatment option for genetic diseases. Sup-tRNAs read through premature stop codons derived from genetic mutations in translation to generate full-length proteins. Compared to gene or mRNA-based therapies that deal with one gene or one mutation at a time and require safety and efficacy assessment for each therapeutic agent, a major advantage of tRNA therapy is the potential of using the same tRNA to treat many diseases that just share a common genetic mutation in many genes. However, about 30% of human genetic disorders are from missense mutations that cannot be treated with sup- tRNAs. For those disorders, missense-correcting tRNAs are needed which are charged with one amino acid but read the codon of another amino acid in translation. PI's lab has developed a missense-correcting tRNA identification platform and applied it to identify such tRNAs charged with Arg but read Gln/His/Trp/Cys codons which correspond to most frequent missense mutations in genetic disorders. Aim 1 will develop a high-throughput engineering platform for missense-correcting tRNAs that will be more efficient, and at the same time, less toxic to cells. We will screen tens of thousands of potential missense-correcting tRNAs simultaneously in cellular models. Aim 2 will screen for missense-correcting tRNA expression with reduced toxicity to cells. Our studies will establish a foundation for using missense-correcting tRNAs as a new therapeutic modality for rare diseases.

Up to $451K

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Mobile Health Intervention to Improve Psychosocial Functioning in Veterans with Posttraumatic Stress Disorder and Depression Symptoms

NIH

Background: Veterans experience high rates of posttraumatic stress disorder (PTSD) and depression, which are frequently comorbid and result in difficulties with psychosocial functioning substantially greater than either disorder alone. Functioning difficulties in Veterans have not been adequately addressed by most existing psychotherapies for PTSD and depression because they often focus on symptom improvement and are highly resource-intensive, requiring the training and time of skilled providers. To address this gap, mobile health (mHealth) apps can serve as a widely accessible, standalone or adjunctive intervention to target psychosocial functioning among Veterans with comorbid PTSD and depression. This RR&D CDA-2 proposal involves the development of a self-guided mHealth intervention based on Skills Training in Affective and Interpersonal Regulation (STAIR), an evidence-based psychotherapy that explicitly targets functioning improvements and also alleviates PTSD and depression symptoms among trauma survivors. As part of the intervention, real-time assessment will be incorporated to support Veterans in monitoring their functioning, symptoms, and potential benefits from STAIR. Aim 1 is to adapt the existing STAIR Coach mobile app to make it optimal for self-guided use and to enhance it with real-time assessment (i.e., ecological momentary assessment of functioning and symptoms and passive sensing of location and communication patterns). A user-centered iterative design process will be used to obtain feedback on the intervention from Veterans with PTSD and depression (N = 15) and VA STAIR providers (N = 5). Aim 2 is to evaluate self-guided STAIR Coach with real-time assessment in a pilot randomized controlled trial (RCT), focusing on determining feasibility and acceptability and exploring outcomes of psychosocial functioning, PTSD symptoms, and depression symptoms. Veterans with PTSD and depression (N = 40) will be randomized to self-guided STAIR Coach with real-time assessment (intervention condition) or to real-time assessment only (active control condition) for 12 weeks. Aim 3 is to apply idiographic analysis to each Veteran’s real-time assessment data to inform the timing and personalization of a future just- in-time adaptive intervention (JITAI) based on STAIR. A JITAI embodies a precision medicine approach to deliver the right type of support to the right person at the right time and has the potential to flexibly target the PTSD or depression symptom most linked to functioning for a Veteran. The candidate is applying as a clinical psychologist at the National Center for PTSD Dissemination and Training Division located at VA Palo Alto. Research and training will take place in the rich institutional environment of VA Palo Alto and its academic affiliate Stanford School of Medicine, with the guidance of an accomplished mentorship team comprised of mHealth and STAIR experts. The training goals of the proposal are directly relevant to the specific aims and include gaining expertise in app intervention development, clinical trial methodology, and idiographic quantitative data analysis. Additionally, the candidate will train in overall mHealth innovation and VA professional development skills. The research and training in this CDA-2 will prepare the candidate to achieve her immediate goal of obtaining a VA Merit Review Award that involves building and testing a STAIR JITAI to maximize functioning among Veterans with PTSD and depression. The candidate’s long term goal is to become an mHealth expert in timely and personalized interventions, including JITAIs, for enhancing psychosocial functioning in the everyday lives of Veterans with PTSD and depression. Significance and Innovation: This CDA-2 will address a high priority area of mental health for VA and is consistent with national VA priorities (e.g., Whole Health), with the goal of helping Veterans with PTSD and depression function more fully in their lives, which may in turn decrease suicide risk. It will target the improvement of functioning through cutting-edge mHealth technology and advanced analytic techniques. It may ultimately help to position the VA as a national leader in incorporating innovative technologies into recovery-oriented mental health care.

2030-09-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Mobile Mindfulness-Based Intervention for Unhealthy Alcohol Use in People with Anxiety

NIAAA - National Institute on Alcohol Abuse and Alcoholism

PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development application (K23) will provide protected time for Dr. Natalia Van Doren to strengthen her trajectory as an independent researcher at the University of California, San Francisco (UCSF) and the Kaiser Permanente Northern California (KPNC) Division of Research. Her career goal is to become an expert in developing and testing digital health interventions to address the spectrum of unhealthy alcohol use in people with chronic mental health comorbidities, an area of critical public health importance aligned with NIAAA Strategic Plan, Goal 4. Building on her existing training in clinical psychology and health services research, the integrated training and research plans proposed in this application will provide Dr. Van Doren with advanced training in several critical areas needed to enhance her program of research. Under the mentorship of leaders in alcohol treatment and digital health, training includes: (1) tailoring evidence-based alcohol interventions for mobile platforms (Dr. Maureen Walton; Dr. Sarah Bowen), (2) qualitative methods for treatment research (Dr. Karen Osilla), (3) conducting randomized clinical trials (RCTs) (Dr. Derek Satre; Dr. Stacy Sterling), (4) advanced longitudinal data analysis (Dr. Nicholas Jacobson). These training objectives will be achieved through a combination of didactic and applied activities and through the application of these skills in a Stage 1 behavioral treatment development trial involving the adaptation and initial pilot testing of a novel mindfulness-based ecological momentary intervention (MEMI) targeting unhealthy alcohol use in people with anxiety. Target areas for learning in each training domain are directly linked to the specific aims of this research study, which include (1) iteratively tailoring and optimizing the MEMI to address unhealthy alcohol use in people with anxiety; (2) conducting a pilot RCT to (2a) assess feasibility/acceptability and (2b) generate initial effect size estimates of intervention efficacy compared to a self- monitoring placebo, in preparation for a future R01 trial; and (3) using intensively collected ecological momentary assessments (EMA) to examine within-person mechanisms of change, aligned with the NIH Science of Behavior Change (SOBC) framework. UCSF and KPNC provide ideal environments for the attainment of these training and research objectives, including an established digital health ecosystem within KPNC, seminars and courses in designated training areas, and a highly active Clinical and Translational Science Center at UCSF with a wide array of resources for career development and training. This K23 Award will provide Dr. Van Doren with a repertoire of advanced skills designed to complement her prior training and to provide an essential bridge between her prior experience and her career goal to conduct an active program of patient-oriented research as an independent scientist, toward the ultimate goal of reducing the public health burden of unhealthy alcohol use.

Up to $203K

2031-06-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Modular Biomanufacturing and Cryopreservation Platform for Scalable Production of Clinical-Grade Stem Cell Therapies

NCATS - National Center for Advancing Translational Sciences

Human induced pluripotent stem cells (hiPSCs) are a foundational technology for regenerative medicine, disease modeling, and cell-based therapies. However, the clinical translation of hiPSC-derived therapeutics is constrained by unresolved challenges in manufacturing scalability, product consistency, and long-term storage. Current production methods, such as static culture or stirred-tank bioreactors, either lack throughput or impose damaging shear forces that compromise cell viability and stemness. Additionally, existing cryopreservation strategies are not optimized for the large-volume required for centralized manufacturing and distributed clinical deployment. To address these bottlenecks, we propose to develop a modular, low-shear, perfusion-based biomanufacturing platform coupled with controlled-rate cryopreservation for scalable and reproducible expansion of hiPSCs. This R21 will establish the technical feasibility and foundational workflows for a generalizable manufacturing system suitable for diverse therapeutic applications. In Aim 1, we will engineer and optimize a multilayer, perfusion-based bioreactor system to support hiPSC expansion at clinical scales. We will define operational parameters, evaluate multiple hiPSC lines, and develop protocols for efficient harvesting and redeployment. In Aim 2, we will implement long-term culture strategies to preserve genomic stability and pluripotency across multiple passages and optimize cryopreservation workflows using cryobags and controlled-rate freezing. Post-thaw cells will be assessed for viability, genomic integrity, and differentiation potential. Successful completion of this project will yield the first integrated platform for low-shear, current Good Manufacturing Practice (cGMP)-compatible expansion and cryostorage of hiPSC-derived therapeutic products. This innovation will reduce production variability, enhance scalability, and enable rapid deployment of hiPSC-based therapies across a range of disease indications. The resulting system will serve as a flexible and translational foundation for future commercial partnerships and larger-scale studies, consistent with the high- risk, high-reward goals of the R21 mechanism.

Up to $428K

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A Modular Cross-Linker Platform for Proteome-Scale Mapping of Dynamic Protein-Protein Interactions in Cells

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Protein–protein interactions (PPIs) govern nearly every facet of cellular function and represent a key axis for therapeutic targeting. Yet, the vast majority of the ~650,000 predicted PPIs in the human proteome remain uncharacterized, largely due to limitations in technologies that can map interactions in live cells. Existing approaches rely on genetic tagging or in vitro systems and lack the resolution to detect transient, low-abundance, or state-specific interactions—especially in pharmacologically or disease-relevant contexts. This proposal aims to overcome these challenges by developing a next-generation crosslinking mass spectrometry (XL-MS) platform that enables quantitative, proteome-wide interactome mapping in live cells. Current XL-MS methods are limited by narrow residue reactivity, short and inflexible spacer geometries, inefficient enrichment strategies, and poor quantitative compatibility. Here, we will build a modular crosslinker platform that enables: (i) orthogonal residue reactivity and tunable spacer designs to access a broader spectrum of interaction interfaces; (ii) isotope-encoded handles for robust MS1-based quantitation; and (iii) cleavable enrichment handles that allow gentle, MS- compatible peptide recovery. In Aim 1, we will synthesize and benchmark a chemically diverse crosslinker library, systematically evaluating how spacer length, geometry, and residue reactivity affect proteome-wide PPI coverage in cells. In Aim 2, we will develop isotopically encoded variants and optimized workflows for quantitative PPI comparison across biological states, applying the platform to two high-impact systems: unbiased mapping of small molecule–modulated PPIs (stabilizers and disruptors) and dynamic PPI remodeling during human T cell activation. Together, these studies will establish a versatile XL-MS platform and reagents that addresses key limitations of current technologies, enabling quantitative, proteome-scale PPI discovery in native cellular contexts with unprecedented sensitivity, coverage, and versatility.

Up to $230K

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A Molecular Mechanism of Blue Light Toxicity Impacting the Visual Cycle

NEI - National Eye Institute

PROJECT SUMMARY Retinal degeneration is a leading cause of blindness, with mounting evidence implicating environmental factors such as blue light (430–470 nm) exposure in its progression. A key pathological mechanism involves the phototoxic byproduct A2E, which accumulates in retinal pigment epithelium (RPE) cells and undergoes photoactivation by blue light to generate reactive oxygen species (ROS). These ROS, in turn, drive lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs), producing electrophilic metabolites that contribute to retinal injury. Our recent studies have identified epoxyketooctadecenoic acids (EKODEs) as prominent LPO byproducts formed via A2E-induced oxidation, with the ability to covalently modify proteins via cysteine adducts. This proposal investigates the hypothesis that blue light–activated A2E promotes EKODE formation, which in turn inhibits lecithin retinol acyltransferase (LRAT), a critical enzyme in the visual cycle responsible for regenerating the light-sensitive chromophore. Disruption of LRAT function is strongly associated with severe visual dysfunction and photoreceptor degeneration. By directly linking A2E-mediated oxidation to the generation of EKODEs and their inhibitory effects on LRAT, this study will address a critical gap in our understanding of blue light–induced retinal damage at the molecular level. To test this hypothesis, Aim 1 will define the wavelength-dependent conditions under which photoactivated A2E catalyzes LPO and promotes EKODE formation. Using novel LC-MS/MS methods, we will characterize these lipid oxidation products in vitro and in biologically relevant models, such as bovine eyecups. Aim 2 will investigate the impact of EKODEs on LRAT activity, employing proteomic approaches to detect and map EKODE-protein adducts in vitro and in vivo. By elucidating how blue light exposure, in the presence of A2E, leads to electrophilic EKODE production and LRAT inhibition, this research will provide novel insights into the biochemical pathways driving retinal degeneration. The findings could inform the development of targeted interventions, such as antioxidant therapies or optical filters, to mitigate blue light–induced retinal damage and preserve visual function.

Up to $384K

2028-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

A mouse model to analyze Foxp3+ TFH cells

NIAID - National Institute of Allergy and Infectious Diseases

Protective immunity to many pathogens involves the production of pathogen-specific high-affinity antibody (Ab). Additionally, allergic immune responses often involve the production of allergen-specific high affinity IgE. A unique subset of T cells, follicular helper T (TFH) cells, are required for helping B cells make high affinity Abs. TFH cells promote and control the germinal center reaction. Germinal centers (GCs) and secondary Ab responses cannot develop in the absence of TFH cells, however excessive development of TFH cells can lead to deregulated Ab responses and autoimmunity. A related subpopulation of follicular T cells, T follicular regulatory (TFR) cells are also important for controlling TFH and germinal center responses. Conventional TFR cells develop from Foxp3+ Treg cells. TFR cells have properties of both regulatory T (Treg) cells and TFH cells. Depending on the specific type of immune response, TFR cells can either inhibit the GC and Ab responses or help promote the GC and the Ab response. How these opposite types of TFR functions are regulated is not well understood. Answering the question of how TFR cells are regulated and how they function has become more complex due to the recent discovery of a subclass of TFH cells that up-regulate Foxp3 and express the same markers used to identify TFR cells. These “Foxp3+ TFH cells” appear to be a new subset of TFR cells. However, the function of Foxp3+ TFH cells is not well understood, and their precise role in vivo has not been previously analyzed using a knockout mouse model. In this proposal, we propose to develop a novel mouse model where we will be able to genetically dissect out Foxp3+ TFH cells from the immune response for the first time. Using two different mutant mouse lines, including a newly developed mouse model we have generated, we will produce bone marrow chimeras (BMCs) where TFH and conventional (Treg-derived) TFR (cTFR) cells develop normally but Foxp3+ TFH cells cannot develop. Thus, we can use these mice to probe the development of high affinity Abs in the absence of Foxp3+ TFH cells. This model system can clarify whether Foxp3+ TFH cells have a very different function from cTFR cells in the GC and whether the helper activity of TFR cells for the Ab response in some immune responses is due to cTFR or Foxp3+ TFH cells or both types of cells. IMPACT: this study will generate an innovative mouse model of Foxp3+ TFH deficiency and will validate a new experimental system for analyzing Foxp3+ TFH cells. This work will also provide new information about the regulation of protective Abs and allergic IgE. Our data will hopefully lead to new targets for intervention in allergic and autoimmune disease and new approaches to augmenting protective Ab responses.

Up to $159K

2028-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

A multi-agent AI system for automated curation and functional annotation of enzymes in human gut microbiome

NLM - National Library of Medicine

PROJECT SUMMARY Human gut microbiomes influence health by producing metabolites and enzymes that modulate immunity, transform drugs, and digest nutrients. However, most of these enzymes remain functionally unknown. Current annotation tools rely mainly on sequence similarity searches, which can only assign meaningful functions to less than 30% of microbial proteins. Although recent approaches incorporate protein language models and structural comparison, they still rely on predefined pipelines, manual literature or database searches, and specialized expertise in microbial research. This makes the annotations time-consuming without intelligent automation for context-aware insights and limits their scalability across diverse microbial ecosystems. Large language models (LLMs) have emerged as powerful tools in scientific research by analyzing data, answering complex questions, and generating new hypotheses. Building on these strengths, Artificial Intelligence (AI) agents, which combine LLMs with external resources like databases, tools and APIs, can automate tasks and workflows, mimicking human expert decision-making. Although they are widely used in industry, their potential in bioinformatics has only recently been explored. The overall objective of our project is to develop GENZ-AI (Gut ENZyme AI), a multi-agent AI system for automated curation and functional annotation of gut microbial enzymes. GENZ-AI will leverage LLM and advanced AI agents to autonomously delegate tasks, integrate diverse data sources, and deliver enriched annotations with relevant references. We will use advanced techniques, such as prompt optimization and imitation learning, to continuously refine its performance based on real-world annotation sample workflows and user feedback. The significance of GENZ-AI lies in leveraging these cutting-edge technologies to automate and enhance the data curation and workflow organization for enhanced enzyme annotation. This achievement will also improve gut microbiome-based diagnostics and therapeutics (e.g., dietary interventions, drug enhancement, immune modulation) while substantially reducing the time and effort required. The outcome will be a set of novel computational approaches implemented as user- friendly, reusable, open-source tools, including specialized applications for CAZymes, a class of glycan- metabolism enzymes critical to gut microbiome functions. The CAZyme annotation results and software tools will be integrated into dbCAN-PUL and dbCAN-sub databases. The key innovations of this project include a structure-informed protein language model for generalized EC number prediction, the application of CrewAI framework to build a multi-agent system optimized for enzyme annotation in microbiome, and the in-depth investigation of CAZyme and its glycan substrate utilization through GENZ-AI. The broader impact extends beyond the human gut microbiome, as GENZ-AI can be applied to any microbes, providing a scalable solution for diverse microbial ecosystems and pioneering the adaptation of LLM-powered AI agents in bioinformatics.

Up to $1.3M

2030-05-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

A multi-biologic, AAV-deliverable HIV-1 functional cure

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Broadly neutralizing antibodies (bnAbs) and the antibody-like biologic eCD4-Ig (eCD4) can suppress established HIV-1 and SHIV infections when they are present at sufficient concentrations. BnAbs and eCD4 can be delivered passively or expressed from a recombinant adeno-associated virus (rAAV) vector. rAAV expression bypasses cost and compliance concerns associated with periodic antibody infusions, as well as side-effects associated with a life-time of use of conventional or long-acting antiretroviral therapy (ART). Moreover, unlike ART, long- term antibody-mediated control engages multiple effector arms of the immune system, potentially accelerating the rate of decay of the proviral reservoir. eCD4, a potency and half-life enhanced CD4-Ig fused to a coreceptor-mimetic sulfopeptide, has several advantages over bnAbs. It is exceptionally broad, neutralizing all 200-plus HIV-1 and SIV isolates assayed. rAAV-expressed eCD4 (rAAV-eCD4) can protect from multiple high-dose challenges of both SHIV and SIV. eCD4 can combine with non-neutralizing CD4-inducible antibodies common in the sera of infected persons to mediate very potent antibody-dependent cell-mediated cytotoxicity (ADCC). More recently, we have shown that more potent and bioavailable forms of eCD4, combined with the bnAb 10-1074, can fully suppress established SHIV infections in both infant and adult macaques. We are therefore close to robust functional cures in rhesus macaques. The current application seeks to bring us across the finish line and identify antibodies and eCD4-Ig variants that would best function in a human clinical trial. To do so, we will therefore in Aim 1 compare new eCD4 sulfopeptide variants, determine the Fc-domain that best limits anti-drug antibodies and enhances expression, and ensure in vivo that eCD4 poses no risk of immune interference. Aim 2 presumes that a bnAb partner of eCD4 will be useful in maintaining long term viral suppression and asks what class of antibodies works with eCD4 most effectively. Several properties are considered: their inherent bioavailablity, potency, and breadth, and how they complement eCD4 to limit potential viral escape. Aim 3 then seeks to improve the former properties by employing a novel system whereby human antibodies affinity mature in wild-type mice, starting with bnAbs modified with largely germline framework regions, and selecting in vivo those with greater potencies and longer half-lives. Aim 4 applies knowledge that we have accumulated from the previous decades and insights from the previous aims to establish and compare functional cures mediated by eCD4 paired with optimized forms of CD4-binding site bnAbs and V3-glycan antibodies. Collectively, these aims will directly inform human clinical trials designed to suppress established HIV-1 infections without ART.

Up to $890K

2031-03-31

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Multi-site Randomized Controlled Trial of Psilocybin for Treatment-Resistant Depression (TRD) in Veterans

NIH

Significance to VA: Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Also, TRD in Veterans is associated with a high risk of suicide, addiction, unemployment and medical morbidity. Innovation and Impact: Clinical studies have revealed antidepressant effects of psilocybin for depression and TRD in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of comorbid PTSD and when used in combination with serotonin reuptake inhibitor antidepressants. This state-of-art clinical trial will evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD to advance knowledge in psychedelic therapy in Veterans. Methodology: This multi-site, double-blind, randomized controlled trial will evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will be randomized (N=240) and undergo two psilocybin dosing sessions along with preparation, administration, and integration psychological support. For the 1st psilocybin administration, participants will receive either a 1mg dose (control condition) or a 25mg dose (active) under blinded conditions. At their 2nd psilocybin dosing visit 4 weeks later, all participants will receive a 25mg dose. Outcomes will be measured by a centralized independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session and over 6 months follow-up. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug after each dosing session and at follow-up. Assessments of subjective experiences of psilocybin, expectancy and blinding are included in the protocol. Specific Aim 1 (Efficacy): Evaluate the short-term antidepressant effects of 25mg psilocybin compared to 1mg psilocybin for TRD under blinded conditions by centralized evaluator. Primary Hypothesis: Participants treated with the 25mg psilocybin dose (n=120) will show a significantly greater decrease on the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week-4 post-dose compared to the 1mg psilocybin dose control group (n=120). The Hamilton Depression scale is also collected as a common data element. Specific Aim 2 (Safety): Evaluate risks in participants who took ≥ one psilocybin dose with the Swiss Psychedelic Side Effects Inventory and other reported adverse events. Exploratory Aims (E): E1 PTSD: For the subgroup with TRD+PTSD (~50% of the sample), estimate the change from baseline to week 4 on Clinician-Administered PTSD Scale-Revised (CAPS- 5-R) by group. E2 2nd Dose: Examine the antidepressant effects of one vs two 25mg dosing sessions by comparing change in MADRS from baseline to week 8 (i.e., ~4 weeks after the 2nd dose) between the group receiving the 1mg dose followed by the 25mg dose versus the group treated with two 25mg doses. E3 Response & Remission: Explore rates of response (ΔMADRS ≥50% reduction) and remission (MADRS score ≤10) at week 4, week 8 and month 6, within group and between groups. E4 Other Relevant Outcomes: Explore potential effects of treatment on patient-reported and other outcomes over time, including expectancy, depression, PTSD, suicidality, psychological flexibility, and functional outcomes. Measure altered experience during psilocybin dosing sessions and explore impact on outcomes and functional unblinding. Qualitative Aim: Participants (~10 per site; n=50) will be interviewed on topics of acceptance, satisfaction, and facilitators/barriers of treatment with psilocybin to gain a better understanding of Veteran preferences on the treatment itself, the composition/structure of the psychological support model and future implementation of clinical psychedelic treatment programs in VA. Path to Translation/Implementation: Industry-sponsored studies seeking FDA approval are already underway. The timing of FDA-approval of psilocybin should align with the conclusion of this study. VA can use these results to make decisions on offering psilocybin treatment and to guide implementation within VA mental health systems.

2031-06-30

Free to search & build · $99 one-time to unlock the application pack · No subscription

A Multi-targeted Approach for the Impaired Healing of Diabetic Foot Ulcers Through Combined Electric Field Stimulation and Nitric Oxide Therapy

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Diabetic Foot Ulcer (DFU) is a major complication of diabetes, often leading to lower extremity amputations. DFUs are characterized by a complex pathology resulting from peripheral vascular disease, neuropathy, and infections, all exacerbated by prolonged hyperglycemia, which collectively impede normal wound healing. Standard DFU treatments, such as surgical debridement, wound dressing, and infection management, primarily address individual aspects of the pathology, leading to only about 25% of cases achieving complete healing within 12 weeks. This highlights the limitations of current treatments and the need for innovative solutions that comprehensively address multiple aspects of DFU. Diabetes impairs mitochondrial activity, reducing cellular energy and hindering wound healing and closure. Our previous research showed that electric field stimulation significantly enhanced mitochondrial activity, ATP production, and the proliferation of human dermal fibroblasts. Additionally, nitric oxide (NO) has been shown to promote angiogenesis, prevents ischemia, and reduces inflammation and infection, as also demonstrated in our study with a NO releasing prohealing peptide amphiphile (PA) nanomatrix. However, in diabetic conditions, decreased endothelial NO synthase (eNOS) activity lowers NO levels. Thus, as a multi-targeted strategy, combining electric field stimulation with NO therapy may enhance DFU healing by stimulating cellular energy for wound closure and tissue regeneration, while also reducing complications, such as vascular disease, inflammation, and infection in hyperglycemic conditions. In this study, we will evaluate the therapeutic effects of electric field stimulation and NO therapy, investigating the healing mechanisms of diabetic wounds. To conduct this evaluation, we will develop a bio-engineered cell culture platform that mimics a 3D human skin extracellular matrix (ECM) environment, integrating electric stimulation and NO delivery. This platform will be designed using a peptide amphiphile (PA)-based NO-releasing nanomatrix coating on a highly porous 3D electrospun nanofiber scaffold with two-electrode arrangement (semi- capacitive coupling) for electric stimulation, as proposed in Specific Aim 1. In Specific Aim 2, we will evaluate the effects of combined treatments, particularly electric field stimulation, on behaviors related to wound healing, such as cell proliferation and ECM production, in diabetic skin cells derived from DFU patients under hyperglycemia using the platform. This evaluation will focus on the ATP binding purinergic (P2) receptor-mediated pathway. We will also test the combined treatment, particularly NO, to enhance diabetic endothelial activities, reduce inflammation, and inhibit DFU related bacterial growth under hyperglycemia using the platform in Specific Aim 3. Successful completion of this study will offer a novel DFU treatment strategy by delivering electric field stimulation and NO, validated with an innovative wound healing cell culture platform, enhancing current treatment methods. Additionally, it will enhance Rowan University's biomedical research capabilities and provide valuable hands-on research opportunities for undergraduate students, fostering their development as future scientists.

Up to $562K

2029-06-30

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A multi-tissue temporal framework for Th2 responses

NIAID - National Institute of Allergy and Infectious Diseases

The central objective of this P01 is to define a unifying framework for how Type 2 immune responses are initiated, maintained, and recalled across barrier tissues. Type 2 immunity is critical for defense against helminths and drives pathology in chronic allergic diseases such as asthma, eczema, and food allergy. Despite its clinical importance, how these responses are coordinated across diverse tissue environments remains poorly understood. Each barrier tissue—gut, skin, and lung—has unique structural and sensory elements that shape immunity, prompting the question: are there conserved principles or tissue-specific programs driving Type 2 inflammation? This program integrates four interdependent projects, each addressing a distinct tissue context and complementary biological question: Project 1 (P1, Small Intestine): Defines a neuro-epithelial-immune circuit involving tuft cells and Neuromedin U neurons and tests how this circuit regulates ILC2s and Th2s during helminth infections; Project 2 (P2, Skin): Reveals hair follicles as neuro-immune hubs shaping allergic sensitization and IgE production, with distinct roles in different skin types; Project 3 (P3, Large intestine): Explores how Notch-programmed basophils form inflammatory niches that support Th2 tissue-resident cells and memory during whipworm infection in the large intestine; and Project 4 (P4, Lung): Identifies spatially distinct Th2 tissue-resident memory populations in novel immune hubs that we hypothesize regulate their maintenance and the exacerbation of allergic lung inflammation. Together, these projects address three program-wide themes: initiation and priming of Th2 responses, neuroimmune regulation, and tissue-resident memory and recall. Harmonized methods and shared resources enable rigorous cross-tissue comparisons and mechanistic insight. Synergy and unique expertise across projects is the program’s core strength. Discoveries in one tissue rapidly inform hypotheses in others, creating an iterative feedback loop that amplifies innovation and discovery. The centralized cores; Administration, Microscopy and Mouse, provide shared infrastructure for advanced imaging, genetically engineered mouse models (>50 alleles), and data integration, enhancing efficiency and rigor. This level of coordination and resource sharing is uniquely enabled by the P01 mechanism and could not be achieved through separate grants. Our combined approach reveals conserved immune hubs and tissue-specific adaptations that redefine how Type 2 immunity is orchestrated across organs and will reveal novel targets to enhance or suppress this response. By integrating mechanistic studies with translational relevance—validated in human tissues—this P01 establishes foundational principles for manipulating Type 2 inflammation in infectious and allergic diseases, delivering transformative insights only possible through this synergistic program.

Up to $2.7M

2031-05-31

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A multidisciplinary approach to defining wildlife health: biological, ecological, and social determinants of the health of wildlife populations in the National Park System

Environmentalsustainability

National Park Service

National parks play an important role in natural resource conservation; however, it is uncertain how these activities are perceived to relate to wildlife health. The objective of this project is to explore the definition, importance, and determinants of wildlife health in national parks. This information is foundational to understanding the relevance and value of healthy wildlife and national parks to the American public and can be used to inform education, outreach, collaboration, and management activities. This project serves a public purpose by supporting development of theory and knowledge that will benefit the NPS and the broader scientific community; researchers external to NPS will gain from new knowledge provided through this research and related results dissemination.

$1 – $32K

rolling

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A Multifunctional Biologic to Regulate Transplant Rejection

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Solid organ transplantation remains the definitive treatment for end-stage organ failure, but is limited by the adverse effects of lifelong immunosuppression and the risk of chronic rejection. Blockade of the CD154/CD40 costimulatory pathway has shown unparalleled efficacy in preclinical models, but clinical translation has been hampered by complications and the need for complex multi-component interventions to achieve maximal efficacy. Separately, regulatory T cell (Treg) therapies offer promise but face challenges including high costs, complexity, and concerns about durability in inflammatory environments. This exploratory proposal addresses these limitations through an innovative high-risk, high-reward approach that integrates these two therapeutic strategies into a single recombinant biologic: β-Tol, a multifunctional fusion protein combining anti-CD154 and one or more immunomodulatory moieties. The central HYPOTHESIS is that this novel fusion protein will synergistically inhibit pathogenic effector T cell differentiation, while promoting their conversion into protective Treg. Preliminary data demonstrate that CD154 blockade synergizes with the immunomodulatory moiety to dramatically enhance mouse Treg conversion, while suppressing effector differentiation, and that initial β-Tol constructs outperform conventional anti-CD154 treatment for Treg induction in vitro. The research design employs a multidisciplinary approach combining protein engineering, immunological characterization, and preclinical validation. Specific Aim 1 will define the regulatory identity of Treg induced by different β-Tol candidates using profiling and functional suppression assays to identify optimal construct architecture. Specific Aim 2 will assess therapeutic potential using stringent mouse skin transplant models combined with fate-tracking of alloreactive T cells. Pharmacokinetic studies will inform dosing strategies, while pathological examination will assess safety profiles. By leveraging modular protein engineering and interdisciplinary collaboration, this exploratory proposal seeks to develop a next-generation immunotherapeutic platform for transplantation. Success would provide foundational proof-of-concept for a clinically translatable strategy to induce immune regulation with precision, reduced toxicity, and in the form of a streamlined monotherapy – all aligned with NIH's mission to improve health through innovative biomedical research.

Up to $255K

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A Multimethod Approach to Preventing Substance Use Among Youth

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Adolescent substance use is a significant public health issue with costly consequences. Youth exposed to household challenges (i.e., parental substance use, parental incarceration, and parental mental health challenges) are more likely to use substances compared to those who are unexposed. Youth exposed to negative neighborhood contexts (e.g., neighborhood violence and low social cohesion) are more likely to use substances compared to those who are unexposed. The nine selective substance use prevention programs have had little success changing outcomes for this group. None were informed by the lived experiences of children, who experience both household challenges and negative neighborhood contexts. Most programs have struggled to attract and retain these youth. Mechanisms such as social connections have primarily been ignored despite their relevance for substance use prevention among youth. Thus, additional selective prevention programs are needed to prevent substance use among youth at this intersection. The PI (Powell) partnered with families exposed to household and neighborhood challenges to develop the Better Together (BT) intervention. BT is an 8-session, age-appropriate intervention designed to prevent substance use among adolescents (ages 11 to 13) exposed to household and neighborhood challenges. BT is a novel and promising strategy to enhance internal and external assets and help youth abstain from substance use. Qualitative findings from a process evaluation suggest that BT is acceptable and feasible. Quantitative findings from a pilot study also provide strong preliminary evidence that our team can recruit, retain, and engage youth affected by household and neighborhood challenges. We propose a hybrid type 1 study with two aims to achieve our long-term goal of preventing drug use and its consequences among youth exposed to household and neighborhood challenges. In Aim 1, we will conduct a randomized trial to evaluate the effectiveness of the Better Together Intervention, compared to a time-matched control group, in preventing alcohol and marijuana use over 18 months. We will also examine individual and interpersonal factors that mediate the relationship between the intervention and substance use using the Karlson-Holm-Breen method for mediation. In Aim 2, we will examine contextual factors that impact effective program implementation using surveys, interviews, and geospatial data. In Aim 4, we will assess how contextual factors impact effective program implementation, youth participation, and substance use outcomes. This research addresses high-priority topics for NIDA and NIH, including personalized interventions informed by people with lived experiences as well as scaling and implementing an innovative evidence-based interventions that address poor health outcomes. This study will address key effectiveness, implementation, and cost questions critical for widescale dissemination. Study processes and findings can inform future research, practice, and policies on substance use prevention in other populations and across settings.

Up to $686K

2031-03-31

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A Multimodal Assessment Protocol for Characterizing Restricted and Repetitive Behaviors in Autism

NIMH - National Institute of Mental Health

Project Summary/Abstract The overarching aim of the proposed project is to develop and validate novel, multimodal, scalable, time- and cost-efficient assessment protocol for comprehensive characterization of key subdomains of restricted and repetitive behaviors (RRB) that can assist in the diagnostic process, facilitating etiologically oriented research, the treatment selection, and monitoring symptomatology over time. Although RRB are a core, clinically impactful feature of autism spectrum disorder (ASD), existing measures are limited by poor ability to comprehensively capture all relevant RRB subdomains and currently, there are no dedicated clinician interviews nor protocols to capture and quantify daily variations of distinct RRBs in ASD or in neurogenetic disorders. In the proposed project, we will build on the Dimensional Assessment of Restricted and Repetitive Behaviors (DARB), an informant-report questionnaire developed and validated by our group following the NIH Patient-Reported Outcome Measurement Information System framework. DARB has a comprehensive item bank developed to assess eight distinct RRB subdomains and has been shown to have a stable and replicable 8-factor structure, strong model and conditional reliability, invariance across age, sex and diagnostic status, and excellent test-retest replicability. In the current proposal, we will aim to: develop and validate the computerized adaptive test (CAT) version of the DARB (DARB-CAT) to maximize precision and reduce patient burden by individually tailored item selection and administration (Specific Aim 1), refine and validate a clinician interview version of the DARB (DARB-I) (Specific Aim 2) and develop an ecological momentary assessment (EMA) RRB protocol (DARB-EMA) to capture daily and weekly changes in specific RRB and contexts in which they occur (Specific Aim 3). We will also develop and pilot a platform that will integrate the administration, scoring and reporting of the DARB-CAT, DARB-I and DARB-EMA components (Exploratory Aim 4). Finally, we will explore mechanisms underlying RRB subdomains (Exploratory Aim 5). This project will generate the world’s first comprehensive, multimodal RRB assessment ecosystem incorporating state-of-the-art psychometric principles that will have a significant potential to enhance the pathway from screening to clinical and neurobiological characterization to treatment tailoring and tracking.

Up to $767K

2031-06-30

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A multimodal liquid biopsy assay to quantify androgen receptor’s somatic alterations in metastatic castration-resistant prostate cancer.

NCI - National Cancer Institute

PROJECT SUMMARY The high mortality rate of metastatic prostate cancer underscores the urgent need for a sensitive detection assay for androgen receptor (AR) alterations, which are primary drivers of resistance to AR-targeted therapies in metastatic castrate-resistant prostate cancer (mCRPC). AR alterations, including amplifications, mutations, and splicing variants, are present in 50-70% of mCRPC patients and are associated with worse outcomes, underscoring the importance of targeting AR alterations to optimize treatment and guide personalized therapy. Despite extensive genomic knowledge with the potential to enhance clinical care and guide future clinical trial design, the discoveries of AR alterations in mCRPC have not been translated into clinical practice due to the lack of assay development and implementation. This project aims to bridge this gap by developing and validating a plasma-based multimodal digital PCR assay for AR alterations as a Laboratory Developed Test. In Aim 1, we will determine and validate the analytical performance of the assay by quantifying AR somatic alterations, ensuring its accuracy and reproducibility. In Aim 2, we will establish the clinical utility of the assay by evaluating its prognostic and predictive capabilities in a cohort of mCRPC patients. This minimally invasive liquid biopsy approach will facilitate the monitoring of clonal evolution and treatment resistance, capture genomic heterogeneity across metastatic sites, and provide a cost-effective, sensitive tool for identifying clinically relevant AR alterations that inform personalized therapy, ultimately refining current and future clinical practice in mCRPC and improving patient outcomes.

Up to $226K

2028-02-29

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A Multiomic Single Nucleus RNA-seq and ATAC-seq Examination of Key Brainstem Respiratory Control Regions from Fentanyl Overdose Decedents with and without Xylazine Present, and Matched Controls

NIDA - National Institute on Drug Abuse

Over 81,000 individuals died of an opioid overdose (OD) in 2023, and >92% of those cases involved fentanyl. Fentanyl has very potent opioid-induced respiratory depression (OIRD) effects, the primary cause of opioid OD death. Key brainstem regions, the preBötzinger complex and ventral respiratory group (preBot/VRG) and parabrachial and pontine Kölliker-Fuse nuclei (PB/KFn), play critical roles in respiration, and have been implicated in OIRD. Therefore, it is likely that the cellular etiology of opioid OD, notably the sites of action of fentanyl, involves these understudied brain regions. Despite evidence for individual differences including heritable variation in opioid OD (e.g., our GWAS of opioid OD death), most biologically mechanistic studies have focused on addiction-centric brain regions. Consistent with the likelihood of differential cellular signatures across these brain regions, our preliminary data suggest pervasive bulk tissue expression differences in the preBot (i.e., genes distinct from those implicated in regions relevant to addiction). In addition, prior studies have primarily relied on bulk tissue or single omics approaches to characterize the cellular etiology of opioid OD death. New multiome methods allow us to deeply characterize how the partnership between chromatin accessibility and gene expression in these brain regions drives opioid OD involving fentanyl, thus offering insights into biology and implicating genes that could be therapeutically targeted. Against the backdrop of unabated fentanyl-driven OD deaths, our proposal will: (A) generate the first single-nucleus (sn) paired RNAseq and snATACseq (i.e., multiome) data from the preBot/VRG and PB/KFn, from diverse human fentanyl OD decedents (N=40) and matched controls (N=40). (B) Characterize cell populations, states and cell-type specific relationships between differential gene expression and chromatin accessibility in each brain region across groups. (C) Estimate enrichment of opioid GWAS variants and genes, yielding mechanistic insights to large-scale population-scale genetic discovery. (D) Combine existing opioid-related expression differences in the same and other brain regions to delineate a brain-wide network of transcriptional variability associated with OUD and opioid OD, and produce in-silico prioritization of gene-drug pairs that are viable for preclinical follow-up.

Up to $578K

2030-11-30

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A multiorgan microphysiological platform to discover and screen therapeutics for treating radiation induced vascular injury

OD - NIH Office of the Director

Summary In the event of a nuclear or radiological catastrophe, affected individuals are exposed to a wide range of radiation doses with the extent of injury depending on the victims' distance from the epicenter, the duration of exposure, and their inherent sensitivity/resistance to ionizing radiation, amongst other factors. While the use of Neupogen, Neulasta and Entolimod to treat hematopoietic acute radiation syndrome (H-ARS) has been approved by the FDA, therapeutic approaches to the treatment of radiation-induced vascular/endothelial injury are largely supportive. Vascular/endothelial injury is a leading cause of morbidity and mortality in radiation-induced injury through damage to vascular barrier function and increased leukocyte trafficking and there are no specific pharmacologic therapies available that protect from leukocyte- mediated tissue damage. While animal models have been used to develop therapeutics for treating radiation damage, use of emerging technologies such as organ-on-chip allows for testing of these therapeutics in biomimetic environments using primary human cells. We propose to integrate our microfluidic models of blood-brain barrier (BBB), gut, and lung into a multiorgan RadChip platform that incorporates essential features for testing radiation induced vascular injury. We will characterize the impact of radiation damage on vascular endothelial cell activation, barrier integrity, transendothelial electrical resistance (TEER) and interaction with immune cells in our RadChip composed of multiple important organ-specific cell types. The signaling pathways regulating radiation-induced vascular permeability and leukocyte migration in human EC will be determined. A novel in silico model will be used to elucidate cellular processes impacted by radiation exposure and identify/validate FDA-approved drugs/compounds as potential therapeutics for treating radiation injury. This multiorgan RadChip will be used to test the efficacy of FDA approved drugs for treating radiation induced vascular injury. The specific aims of this project are to 1) Use a multiorgan platform to model radiation-induced vascular injury in humans, 2) Determine the mechanism by which radiation injury impacts immune cell-endothelial cell interaction, 3) Use a novel in silico model to determine the signaling pathways regulating radiation-induced vascular damage to repurpose FDA approved therapeutics. These studies will not only provide important mechanistic insights into the underlying pathogenesis of acute radiation syndrome but also provide a platform to identify and screen potential FDA-approved drugs/compounds for treating radiation injury.

Up to $555K

2031-03-31

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A multiple health behavior change intervention for people with obesity who smoke cigarettes: a randomized clinical trial

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Individuals with obesity who smoke cigarettes are disproportionately at risk for disease, disability, and premature death but may be reluctant to give up smoking due to fear of subsequent weight gain and trouble managing their weight without cigarettes. Applying weight gain prevention as part of a multiple health behavior change program prior to smoking cessation, may help this population lose weight, which itself would be beneficial, and could increase confidence in ability to tackle the challenge of quitting smoking. Previous studies have provided weight loss interventions during or after smoking treatment, and mostly not among individuals with obesity. Weight loss in advance of quitting smoking could provide a buffer against future potential post-cessation weight gain and may improve mood, help increase the salience of future health outcomes, and increase self-efficacy for tackling the challenges associated with quitting smoking among individuals with obesity who smoke. Design: A 2-group randomized controlled clinical trial of 220 adults with obesity who smoke cigarettes (BMI ≥ 30) who will be randomly assigned to either weight gain prevention (an intervention based on self-regulation approaches to produce and maintain weight loss shown to be effective for weight gain prevention) or lifestyle education (control condition) before smoking cessation treatment. Method: Participants will receive 8 weeks of remotely delivered weight gain prevention or lifestyle education followed by 8 weeks of smoking cessation with counseling and combination nicotine replacement therapy. Smoking cessation treatment will include brief maintenance sessions of the weight gain prevention or lifestyle education intervention. Changes in weight and biochemically verified smoking abstinence will be measured during the intervention and through a 12-month follow-up. Aims: Primary hypothesis 1a is that the weight gain prevention group will have significantly less weight gain at the end of smoking treatment and 6, 9, and 12-months post-treatment relative to baseline compared to the lifestyle education group. Primary hypothesis 1b is that the weight gain prevention group will have significantly higher rates of abstinence from smoking at the end of smoking treatment and 6, 9, and 12-months post-treatment compared to the lifestyle education group. Significance: This project focuses on preventing weight gain and improving smoking cessation outcomes in an at-risk group during a critical period using an innovative, evidence-based, self-regulation approach to weight gain prevention. Use of a multiple health behavior change intervention can maximize anticipated health benefits of smoking cessation and reduce the potential for relapse to smoking due to post-cessation weight gain. With an effective program, more individuals with obesity who smoke cigarettes may be willing to attempt smoking cessation which could impact the two leading causes of preventable mortality in the US.

Up to $733K

2031-04-30

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A Multiple Health Behavior Change Intervention for Weight-Loss and Smoking Cessation among Pre-Bariatric Surgery Patients

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Smoking prevalence among pre-bariatric surgery patients is estimated to be as high as 40%. In addition to quitting smoking, patients are expected to lose weight before surgery, which is challenging as smoking cessation is associated with weight gain. Pre-bariatric surgery patients would significantly benefit from a tailored multiple health behavior change (MHBC) intervention targeting weight loss and smoking cessation concurrently, yet no such interventions have been examined within this patient population. This K23 aims to develop and pilot a MHBC intervention for pre-bariatric surgery patients to evaluate feasibility and acceptability, compare the intervention to a standard of care (SOC) control group in achieving weight loss and smoking cessation at post-treatment, and examine bariatric surgery completion, weight loss, and smoking cessation at 6-month follow-up. This pilot randomized control trial (RCT) will include 64 adult pre-surgical patients that have severe obesity and smoke cigarettes. Participants in the intervention arm (n=32) will complete a 4-month concurrent behavioral weight loss and smoking cessation intervention with medication (Naltrexone 50 mg/day, Bupropion 300 mg/day). Qualitative interviews will be conducted with the first 6 participants to refine the intervention prior to enrolling the pilot RCT sample. The SOC control group (n=32) will follow participants across the same 4-month period. Weight and smoking will be assessed monthly and at post-treatment. Smoking cessation will be measured using timeline follow-back interviews to assess 7-day point prevalence abstinence, and biochemically confirmed through exhaled carbon monoxide. Participants will return 6-months later to re-assess these outcomes and bariatric surgery completion. This pilot RCT is critically important to improve bariatric surgery utilization and reduce risk for smoking relapse post-surgery. This K23 will directly address the PI's training goals to: 1) Obtain training in the development/evaluation of interventions for dual risk behaviors (obesity, cigarette smoking), including mixed methods research to guide intervention development; 2) Gain training and experience in the conduct of clinical trial research using behavioral and pharmacological treatments for obesity and smoking; 3) Obtain statistical training in longitudinal mixed modeling to analyze clinical trial data; 4) Strengthen grants management skills and professional development in research ethics, leadership opportunities, and supervision of trainees. The PI will work with a knowledgeable team of mentors to support career development, and complete/attend workshops, courses, directed readings, conferences, and meetings. These activities will meet the PI's training goals by providing the necessary training to become an independent investigator. The Yale Program for Obesity, Weight, and Eating Research (POWER) is an ideal environment for the proposed K23, as POWER has the facilities and resources needed to support clinical treatment trials. Further, the Department of Psychiatry is one of the nation's leading departments in research activity and productivity and provides a supportive and stimulating environment for interdisciplinary research.

Up to $191K

2031-02-28

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A Multipotent Fibroblast Population Drives a PDGFR-beta-Dependent Immuno-Fibrotic Response in Heart Failure

NHLBI - National Heart Lung and Blood Institute

Project Summary/Abstract Cardiac fibrosis compromises left ventricular (LV) function and worsens clinical outcomes in heart failure (HF). Currently, there are no clinical therapies that target fibrosis in the failing heart. Platelet-derived growth factor (PDGF), a central mediator of fibrotic responses, acts via two receptors - PDGFRα and PDGFRβ. Our pilot studies using explant cultures, flow sorting, single cell RNA sequencing (scRNAseq), and in vivo mouse models have uncovered a novel stem cell antigen(Sca)-1-expressing PDGFRα+ multipotent cardiac fibroblast population that sources myofibroblasts, interacts with tissue macrophages, and drives fibrotic and inflammatory responses during adverse LV remodeling. During HF, these cells decrease PDGFRα expression and instead upregulate PDGFRβ. The role of PDGFRβ in cardiac fibroblast biology in HF is unknown. We propose the novel hypothesis that a heretofore unrecognized Sca-1+PDGFRβ expressing cardiac fibroblast with mesenchymal stem cell features (termed cFMSCs) are key drivers of a PDGFRβ-dependent immunofibrotic axis in HF. Three Aims will test this hypothesis. In Aim 1, using a murine coronary ligation model, in vitro studies of cell function, scRNAseq, and inducible cardiac fibroblast-specific and Sca1+ cell-specific PDGFRβ-deletion mouse models, we will comprehensively define the importance of PDGFRβ in cFMSC cell function in ischemic HF. We will isolate Sca1+PDGFRα+ cFMSCs and assess PDGFR β-dependent myofibroblast differentiation, multipotency, downstream signaling and immuno-fibrotic secretome, and cFMSC-macrophage interactions. scRNAseq of sorted cells will assess cFMSC subpopulations and changes in transcriptomic profiles. In Aim 2, we will establish the pathogenetic role of cFMSC-localized PDGFRβ in chronic HF, by using inducible cardiac fibroblast-specific PDGFRβ knockout mice, deleting cFMSC PDGFRβ during chronic HF, and assessing late effects on LV remodeling, fibrosis, tissue macrophages, and inflammatory profiles. To establish necessity of cFMSC PDGFRβ signaling, cardiac fibroblast PDGFRβ loss will be induced by tamoxifen in PDGFRβf/f-Tcf21MerCreMer mice 4 w post- MI and LV remodeling, fibrosis, and tissue macrophage and inflammatory profiles will be assessed 6 w Iater. The effects of sustained cardiac fibroblast PDGFRβ activation on LV remodeling will be assessed using PDGFRβ[S]D849V-Tcf21MerCreMer mice. To establish sufficiency of cFMSC PDGFRβ signaling, we will perform intramyocardial adoptive transfer of sorted PDGFRβ-deficient and -competent Sca1+PDGFRα+ cFMSCs from HF mice into naïve mice and assess late LV remodeling and fibrosis. In Aim 3, we will test potentially translatable therapies to antagonize cFMSC PDGFRβ signaling in chronic HF, including CP-67345, a specific small molecule PDGFRβ inhibitor, fibroblast-targeted nanoparticle delivery of PDGFRβ siRNA, and anti-PDGFRβ neutralizing antibody. We will measure the effects of these therapies on LV remodeling, fibrosis, cFMSC abundance, cardiac macrophages, and tissue inflammation. By conclusively defining the role of cFMSCs and fibroblast PDGFRβ in pathological LV remodeling, these studies will provide novel perspectives on the immunofibrotic response in HF.

Up to $765K

2030-01-31

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A Nanomaterial-Engineered Proteomic Platform to Map Curvature-Dependent Cardiac Signaling

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Membrane curvature clusters the signaling receptors and ion channels that govern cardiac excitation–contraction coupling. In cardiomyocytes, sharply curved caveolae (~60 nm), moderately curved clathrin-coated pits (~120 nm), and cylindrically curved transverse tubules (T-tubules) modulate β-adrenergic and Ca2+ pathways through their distinct protein sets. Interruptions to their shape and protein composition lead to arrhythmia, hypertrophy, or contractile failure, respectively. Current imaging and proteomic tools capture only fragments of these nanodomains, leaving a technological gap in unbiased curvature-defined proteomics and a knowledge gap in how geometry dictates cardiac signaling. The overall objective of this project is to close these gaps by developing a Nanomaterial-Engineered Proteomic (NanoPro) platform and providing a proteomic atlas for each curvature class in cardiomyocytes. NanoPro uses nanostructures to proximity-label nearby proteins on the cell membrane and produces unbiased, 20 nm-resolution proteomic atlases of each curvature class. We will reach the objective through two specific aims. Aim 1 will establish dome-NanoPro to profile the proteome of nanomaterial-engineered caveolae and clathrin-coated pits in cardiomyocytes. Aim 2 will streamline pillar-NanoPro to map the proteome of nanomaterial-engineered T-tubules in cardiomyocytes. NanoPro represents a new concept of structure-defined proteomics by integrating cell membrane engineering with deep, unbiased proximity-labeling mass spectrometry. Upon successful development, NanoPro will close the technological gap in curvature-defined proteomics and narrow the long-standing knowledge gap in cardiac cell signaling by revealing how membrane curvature orchestrates signaling networks in caveolae, clathrin-coated pits, and T-tubules with the first complete proteomic atlas of these structures. These proteomic data sets will expose curvature-encoded biomarkers for early detection of cardiac stress and uncover druggable targets that can be regulated to prevent arrhythmia, hypertrophy, and contractile failure.

Up to $712K

2030-04-30

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