Grants

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Melanoma is the most lethal type of skin cancer. About 50% of patients with metastatic melanoma have a meaningful response to treatment with immunotherapy, of which some develop a durable response. Many patients with the best response to immunotherapy develop immunotherapy-induced melanoma-associated vitiligo (MAV), an autoimmune cutaneous side effect. Previous mouse work has revealed that tissue-resident memory T cells (TRM) in vitiligo-skin with specificity for melanoma antigens were required for long-lived protection against melanoma. By examining human specimens, our recent studies revealed that long-term melanoma survivors with MAV maintain tissue-resident memory T cells (TRM) which were long-lived and functional. TRM have recently been recognized by our group and others as critical participants in anti-tumor immune responses. We identified a TRM subset characterized by high interferon gamma expression (TRM-IFNG) that is highly prognostic for improved survival in melanoma patients. Strikingly, TRM-IFNG cells had precursors in the patient’s primary melanoma up to 6 years prior, showing durability of the patient’s natural immune memory response. While there have been many studies focusing on metastatic melanoma, there is a gap of knowledge in understanding how the immune response to primary melanoma affects the recurrence and overall survival of melanoma patients. The goal of this proposal is to investigate the TRM response at the time of primary melanoma diagnosis and test its requirement for immunotherapy response. Our hypothesis is TRM-IFNG cells are established at the time of primary melanoma and are recalled and expanded in order to mediate responses to immunotherapy (IT). We will test this using melanoma mouse models as well as prospectively collected patient specimens to determine how TRM-IFNG formed in skin and tumor at the time of initial melanoma occurrence mediate responses to immunotherapy in the metastatic setting. In a preclinical model, we will utilize a topical immunotherapy to increase the TRM repertoire in primary and metastatic melanomas in order to set the stage for a future clinical trial aimed at treating primary melanoma as a way of inducing durable cancer-fighting TRM cells in patients. Successful completion of this proposal will advance our knowledge of the contribution of early disease TRM establishment to long-lived memory. Our long-term goal is to advance the understanding of durable immunity to cancer and provide new avenues for immunotherapy development and improved patient survival.

Up to $661K

2031-03-31

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Durability of Yoga for Treating Veterans with Chronic Low Back Pain

NIH

Significance to VA: Chronic low back pain (cLBP) is a highly prevalent condition for veterans. In addition to chronic pain, cLBP leads to significant amounts of disability, reduced health-related quality of life (QOL), and increased health care utilization. Our previous results and other studies of yoga for Veterans with cLBP show that yoga participants had reduced pain and disability at follow-up assessments at 6-month follow-up. There is also some evidence indicating that self-care treatments like yoga, especially those provided in group format, may be less expensive and may reduce health care costs, conserving limited resources for other conditions and services. Since persons with cLBP usually live with this chronic condition for the rest of their lives, understanding and facilitating long-term yoga practice for VA patients is an important step for the provision of high-quality VA healthcare. Innovation and Impact: If funded, this will be the first study to examine a durability intervention for promoting long-term yoga practice. It uses text messaging for both behavioral reminders, and for ecological momentary assessment of the durability outcome. The study tracks 18 months of follow-up data. Specific Aims: The primary aims of the proposed project are to examine the effectiveness of a coaching intervention plus text reminders for promoting long-term maintenance of yoga practice and function among Veterans with cLBP. We will also examine intervention costs and subsequent health care costs. Methodology: We will recruit and randomize 176 Veterans with cLBP to either standard yoga or the durability-enhanced yoga intervention. Participants will complete health outcome assessments at baseline, 3 months, 6 months, 12 months, and 18 months. The standard yoga intervention includes weekly in-person yoga sessions for 12 weeks. The enhanced yoga arm will receive weekly behavioral coaching sessions from weeks 10-15 and will receive ongoing text reminders. The co-primary outcomes will be the mean days and minutes per week of yoga practice and the mean change in back pain-related disability at 12 months. We will measure yoga practice and other health outcomes including pain severity, QOL, and fatigue through 18 months. We will measure attendance and home practice. We will monitor and assess adverse events and instructor fidelity. Path to Translation/Implementation: If the durability intervention can increase long-term yoga practice and associated health benefits, this will provide very strong evidence for wider implementation of yoga as a specific treatment for chronic low back pain.

2031-12-31

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

Durable and broad airway immunity through next-generation intranasal boosters

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Intramuscular SARS-CoV-2 mRNA-LNP do not reliably nor durably elicit respiratory mucosal IgA. Moreover, vaccinated individuals who become infected are more durably protected and this is thought to be mediated by respiratory mucosal IgA. Currently, there are no mucosal respiratory vaccines for human use. We identified a mucosal booster vaccine admixed with a mast cell agonist adjuvant, mastoparan-7, and a toll-like receptor 9 agonist adjuvant, CpG, that elicits durable mucosal IgA. Importantly, mice intranasally boosted with a multivalent nanoparticle vaccine adjuvanted with mastoparan-7 and CpG are protected from bat SARS-like virus challenge. We propose to study the mechanism of mast cell and antigen-presenting cell signaling modulated by this novel mucosal adjuvant combination. We will pursue our central objective which is to understand how mucosal IgA is elicited and maintained following respiratory mucosal vaccination with our exciting universal vaccines to ultimately achieve durable and broadly protective immunity against zoonotic coronaviruses. To achieve this objective, we will complete these aims: Aim 1: Test the hypothesis that mast cells and antigen-presenting cells elicit specific cytokines and chemokines that modulate durable IgA. We propose to study the impact of intranasal boost dose and interval on IgA kinetics and durability. We will also define if the mastoparan-7 and CpG adjuvant combination requires mast cell and antigen presenting cells that signal through CpG via the TLR-9 pathway. We will then define gene expression profiles from respiratory tract mast cells and antigen presenting cells that are activated by mastoparan-7 and CpG and modulate durable mucosal IgA responses. Aim 2: Test the hypothesis that M7/CpG nanoparticle vaccine elicits durable IgA secreting cells and IgA memory B cells in the respiratory tract using lineage-tracing, fluorescent reporter mice pre- immune with common-cold CoV. We will determine how intranasal boosting modulates IgA-secreting plasma cells and IgA memory B cells that home back to the respiratory mucosa in SARS-CoV-2 immune mice and in mice immune against common-cold coronaviruses. We will use cre-lox inducible, IgA-secreting cell and IgA memory B cell fluorescent reporter mice to define how intranasal boosting modulates mucosal IgA immunity. We will also test adjuvant and intranasal safety using a human lymph node organoid model from upper- respiratory tract draining lymph tissue from humans. Aim 3: Test the hypothesis that durable mucosal IgA can protect against transmissible SARS-CoV-2 variants in hamster transmission models and protect against SARS-related coronaviruses. We will determine if the mastoparan-7 and CpG adjuvanted nanoparticle intranasal booster reduces transmission of SARS-CoV-2 variants in hamster models. We will also use IgA knockout mice to determine if IgA is required for protection against SARS-like viruses.

Up to $662K

2031-01-31

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

Durham

State of Connecticut

Durham

Up to $4.4M

Rolling

general

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

Durham

State of Connecticut

Durham

Up to $4.3M

Rolling

general

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

Dyer s Woad Control in Siskiyou Mariposa Lily and Yreka Phlox Habitat

Fish and Wildlife Service

This project will fund Siskiyou County Dept. of Agriculture to chemically treat 55 acres of invasive weeds at Yreka phlox populations and 38 acres at Siskiyou mariposa lily populations. Due to the nearly year-round germination of dyer s woad from the seedbed and the threat of encroachment from adjacent lands, long-term treatment is necessary to protect the habitats of these protected plants. This agreement will provide funding for weed surveys and treatment on private lands in and around know populations of these plants. At each population area, private lands will be worked or surveyed at least twice each year for the presence of dyer s woad. Identified plants will be controlled by chemical spot treatment, or hand pulling if within the designated buffer zone adjacent to the known populations, two to three times per year.

$40K

natural resources

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

Dynamic Functional Network Biomarkers of Emotion Regulation Flexibility in Internalizing Disorders

NIMH - National Institute of Mental Health

Project Summary/Abstract. Close to 20% of Americans suffer from internalizing disorders like depression, anxiety, and posttraumatic stress in their lifetime (National Center for Health Statistics, 2023). These conditions disproportionally affect young adults, and prevalence rates have risen 30% in the past five years (Santomauro et al., 2021). Moreover, there is considerable comorbidity across internalizing disorders and heterogeneity within disorders (Price et al., 2019; Spinhoven et al., 2014), highlighting the need to identify transdiagnostic biomarkers for effective screening and treatment. Deficits in emotion regulation (ER) is a hallmark risk factor for internalizing disorders (Aldao et al., 2010, 2016). Specifically, low flexibility in ER strategy use – the inability to use a large and varied repertoire of strategies flexibility according to contextual demands – has been linked to internalizing disorders transdiagnostically (Wen et al., 2021, 2024, 2025). However, the neurobiological mechanisms by which flexibility in ER influences internalizing disorders remain largely unclear. Elucidating such mechanisms is a critical step to advancing effective, targeted clinical interventions. In this K99/R00, three aims are proposed to examine the mechanism of ER flexibility in internalizing disorder etiology. In the K99 phase, a large-scale longitudinal dataset (PI: Craske) containing resting state fMRI data and self-reported ER from young adults with varying levels of internalizing disorder severity will be analyzed. Dynamic co-activation pattern analysis will be used to identify functional brain network dynamics (e.g., transitions between the salience, default mode, and central executive networks), and examine associations with ER flexibility as assessed by an innovative, validated index of ER flexibility developed by the Candidate (Wen et al., 2021, 2024; Aim 1). These functional brain network dynamics will then be evaluated in relation to broad symptom dimensions underlying internalizing disorders transdiagnostically (Aim 2). In the R00 phase, new data will be collected for individuals with clinical levels of internalizing symptom severity. Variables include internalizing symptoms, ER flexibility, functional network dynamics, stress, and cognitive control that is theorized to underlie ER (LeMoult & Gotlib, 2019). Path analyses will be conducted to compare two models with hypothesized neurobiological pathways by which ER flexibility influences broad internalizing symptom dimensions (Aim 3). This proposed K99 training will be conducted with Dr. Michelle Craske (primary mentor) and Dr. Lucina Uddin (co-mentor) at UCLA, with guidance from an advisory committee of experts in neuroimaging and psychopathology research. This environment will help the Candidate achieve the career development goal of acquiring of new skillsets in functional neuroimaging and knowledge in functional brain dynamics. The proposed training will provide the Candidate with intellectual and technical training needed to launch an independent research program at a top academic institution studying the neurobiological mechanisms by which emotional processes influence the etiology for internalizing disorders broadly.

Up to $118K

2028-06-30

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Dynamic heterogeneity in the fatedecisions of early mammalian embryogenesis

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY The mammalian embryo is a self-organizing system that robustly patterns itself, forming a blastocyst with three types of cells essential for future steps of development. Formation of the blastocyst is an important and conserved milestone in this process. Two sequential fate decisions give rise to the three cell types that comprise the blastocyst: cells on the outside are first separated from those on the inside, the inner cell mass (ICM), that then differentiates into the epiblast (EPI) and primitive endoderm (PE). Identifying how and when these decisions are made has been difficult to resolve due to the highly stochastic and dynamic nature of early mammalian development. Live imaging approaches have shed light on these cell trajectories, with recent work showing that the second fate decision begins with the commitment of a single EPI lineage. This lineage itself breaks symmetry of the bipotent ICM but is also a source of intercellular signaling that induces PE fate in surrounding cells. Strikingly, this lineage can be traced back to an earlier heterogeneity in the ICM but how this difference arises is unknown. The proposed work seeks to determine the features of the early blastomeres that bias them towards the earliest EPI lineage and to characterize the functional role of this pre-patterning. Aim 1 will use live imaging of endogenous reporters that visualize blastomere volumes, divisions and cell cycles alongside transcription factor dynamics to train a statistical model that predicts gene expression from cell histories. This aim will identify the dynamic inputs that trigger symmetry breaking within the ICM. Aim 2 will precisely target the early molecular asymmetry of the ICM to disrupt the first epiblast lineage and the separation of cell fates it induces. The impact of this perturbation will be quantified by live imaging markers of the second fate decision over time. The work described in Aim 2 will show how heterogeneity in the early ICM initiates and propagates later cell fate commitment. The proposed studies, which are supported by novel fluorescent reporters and an established image analysis pipeline, will provide a deeper understanding of the decision circuits and cell signaling networks that govern this critical stage of mammalian development.

Up to $34K

2028-05-31

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Dynamic Imaging with Sparse Total-Body Positron Emission Tomography

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Abstract Total-body (TB) Positron Emission Tomography (PET) is a medical imaging technology that enables comprehensive imaging of metabolic processes across the entire body in a single bed position. It offers substantial advantages for dynamic imaging and kinetic modeling, such as high temporal resolution and multiparametric capabilities, making it invaluable for assessing cancer staging, early treatment response, and distinguishing malignancy from infection/inﬂammation. However, the widespread adoption of TB PET is limited by its high cost, primarily due to the expense of scintillator material and readout electronics. This proposal seeks to develop an affordable dynamic TB PET system through the use of sparse detector architectures, which will reduce material costs while maintaining the performance beneﬁts of full-body coverage. We hypothesize that sparse designs can produce high-quality dynamic images that allow for kinetic modeling and parametric imaging with minimal loss of quantitative accuracy compared to full-rank TB PET. Our innovative approach combines spatial down sampling of the detector matrix of the 2-m long EXPLORER TB PET scanner with advanced reconstruction algorithms. Classical and deep learning-based Kernel methods will help recover image quality in high-noise, low-count environments. This project will address three speciﬁc aims: (1) demonstrating parametric imaging using sparse TB PET, (2) comparing image quality between sparse TB PET and conventional PET scanners, and (3) optimizing reconstruction parameters and detector matrix conﬁgurations for high temporal resolution in dynamic imaging. By achieving these aims, we will develop a robust, cost- effective TB PET system with potential to revolutionize both clinical and research applications. The successful implementation of this technology will expand access to dynamic TB PET, enhance diagnostic workﬂows, and accelerate research in cancer and other diseases.

Up to $161K

2028-04-30

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

Dynamic interplay between genome organization and long noncoding RNAs in the regulation of gene expression

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY In multicellular organisms, development and homeostasis require exquisitely precise, dynamic, and coordinated deployment of complex regulatory programs. As many genes are under the control of vast regulatory regions – with some enhancers located over a million base pairs away from target genes – we and others have explored to what extent the 3D organization of the genome facilitates the establishment of specific regulatory interactions. Additionally, regulatory regions are pervasively transcribed to generate a striking diversity of long noncoding (lnc)RNAs, which are emerging as important chromatin and transcriptional regulators. However, the molecular determinants and regulatory roles of genome organization remain unclear, and only a minute fraction of known lncRNAs have been ascribed any function. My recent work used innovative single-cell live imaging approaches to show that genome organization and cis-regulatory lncRNAs both play a key role in regulating the temporal dynamics of gene expression. My findings also suggest that lncRNAs may exploit – or even regulate – genome organization to exert long-range transcriptional control. The goal of my research is to understand how genome organization and lncRNAs regulate gene expression, and to investigate their mutual interplay. My lab will use our cutting-edge approaches to measure transcriptional dynamics in Drosophila embryos to investigate how long-range interactions are established; how lncRNAs operate in the context of long-range regulation and utilize genome organization; and how in turn lncRNAs can control genome organization. In my prior work, I identified novel “tethering elements” that foster specific long-range interactions to enable fast gene activation during development. In Project I, I will investigate the role of a well-known epigenetic repressor, Polycomb Repressive Complex 1, in facilitating transcriptional activation by mediating long-range interactions between tethering elements. Through a combination of genomics and live imaging, I will identify the molecular mechanisms establishing long-range interactions and determine their impact on gene expression. My recent work also showed that both long-range enhancers and tethering elements are pervasively transcribed genome- wide. In Project II, using methods I developed to visualize the transcription of endogenous lncRNAs in living embryos in combination with complex genetic perturbations, I will begin to determine the regulatory functions of select lncRNAs associated with important developmental genes and dissect their interplay with genome organization. In particular, I will investigate how lncRNAs regulate the recruitment of architectural factors and the establishment of long-range interactions. Finally, in Project III, I will use novel single-cell live imaging approaches that I developed to investigate how lncRNAs dynamically control local regulatory microenvironments to regulate genome organization and gene expression in vivo. Collectively, these three synergistic projects will enable my future research program by identifying guiding principles that will inform our understanding of the dynamics of gene regulation and be examined in future studies in other model systems and cellular and temporal contexts.

Up to $447K

2031-01-31

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Dynamic Language Infrastructure-Doctoral Dissertation Research Improvement Grants

U.S. National Science Foundation

This program supports doctoral research focusing on building dynamic language infrastructure (DLI). Developing language infrastructure includes the documentation and preservation of languages in ways that articulate or advance linguistic theory, as well as the use of digitization techniques and novel computational methods that support and advance the study of language. Special emphasis is given to languages that are endangered, i.e., understudied and at risk of falling out of use. The program supports the development of the next generation of researchers that contribute to language data management and archiving and to the analysis of these archives to advance language infrastructure. Funding can support fieldwork and other activities relevant to the digital recording, documenting and archiving of endangered languages, including the preparation of lexicons, grammars, text samples and databases. Funding in this solicitation is in the form of doctoral dissertation research improvement grants (DDRIs) for up to 24 months and this solicitation addresses the preparation and evaluation of proposals for DDRI proposals.

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Dynamic mechanisms of human mitochondrial translation

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Human mitochondria contain a dedicated translation system that produces 13 essential proteins required for oxidative phosphorylation and ATP generation. Disruption of this process contributes to a wide range of human diseases, including cancer, metabolic syndrome, cardiovascular disorders, and neurodegenerative conditions. Because of its bacterial origin, mitochondrial translation is also inadvertently targeted by commonly used antibiotics, leading to mitochondrial toxicity. Genetic, biochemical, and structural studies have identified the key components involved in mitochondrial translation and provided structural snapshots of mitoribosomal complexes, underscoring the importance of dynamic ligand–ribosome interactions. Together with ribosome profiling and functional cellular studies, these efforts have revealed numerous unique features of mammalian mitochondrial translation. Despite this progress, the dynamic mechanisms that govern mitochondrial protein synthesis remain poorly understood, hindering interpretation of pathogenic mutations and the design of safer antibiotics. Key challenges include the difficulty of manipulating the mitochondrial genome, limited access to homogeneous mitochondrial material, and the inherent complexity of translation, which involves transient intermediates and likely parallel pathways. In my postdoctoral research, I pioneered the use of in vitro reconstitution and single-molecule spectroscopy approaches to investigate the dynamic mechanisms of yeast cytosolic translation. These approaches enable direct, real-time observation of translation by tracking individual dye-labeled ribosomal subunits, mRNAs, tRNAs, and protein factors. Building on this expertise, my independent research group has developed a unique purified human mitochondrial translation system suited for single-molecule analysis. During the ESI MIRA phase, we will integrate single-molecule spectroscopy with complementary biochemical, structural, and cellular approaches to define the dynamic mechanisms of human mitochondrial translation. In Area 1, we will determine how mitoribosomes initiate translation on leaderless mRNAs and how initiation is regulated by mRNA structures and the LRPPRC–SLIRP complex. In Area 2, we will explore how structurally atypical mitochondrial tRNAs decode the mRNA codons and how polyproline- induced ribosome stalling is rescued by the mitochondrial-specific factor TACO1. In Area 3, we will define the dynamic processes that ensure accurate and efficient translation termination and ribosome recycling at canonical and non-canonical stop codons. By providing quantitative, high-resolution models of these essential steps, our work will establish a comprehensive framework for understanding human mitochondrial translation and its regulation in health and disease, informing the development of targeted therapies and safer antibiotics.

Up to $457K

2031-04-30

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Dynamic Modeling of Dicer Function

NIGMS - National Institute of General Medical Sciences

Project Summary It has been well established that small non-coding RNAs, such as microRNA (miRNA) and small interfering RNA (siRNA), act as potent regulators in numerous biological processes. MiRNA, for instance, modulate gene expression by targeting mRNA based on sequence complementary via the RNA Induced Silencing Complex (RISC). This allows miRNA to regulate key cellular events including cell differentiation, proliferation, and apoptosis. Consequently, when expression levels of miRNAs are dysregulated or alterations to the miRNA sequence occur, individuals can become more susceptible to the development of a variety of disease types, such as cancer, immune-related and neurodegenerative diseases. In response, researchers have been using a combination of techniques to identify the mechanism(s) behind points of dysregulation to guide future RNA- targeted therapeutics. Towards this goal, extensive studies have been carried out to identify and characterize the proteins involved in the miRNA biogenesis pathway, which include the endoribonuclease III protein Dicer. Dicer performs the final cleavage reaction to remove the hairpin loop region of precursor miRNA (pre-miRNA) to produce mature miRNA strands. While in humans, Dicer’s role is centralized around miRNA maturation and regulation, exploration into Dicer proteins from other species has revealed a highly dynamic and multifunctional activity, which includes the cleavage of siRNAs, a key component in antiviral defense. Differences in substrate specify are seemingly dependent on the ATP hydrolysis activity of Dicer’s N-terminal helicase domain. To further investigate this functionality and determine its connection to substrate specificity, structural and biochemical studies have been implemented to uncover the mechanisms behind ATP-independent vs ATP-dependent helicase activity. However, these approaches have been unable to capture the conformational heterogeneity associated with this functionality. Therefore, this proposal puts forth a new approach that combines results from a series of molecular dynamics simulations used to investigate Dicer’s flexibility (Aim 1) with published experimental observations from biochemical, kinetic, and structural studies to create data-informed predictive simulations (Aim 2). These predictive simulations will be used to investigate the central hypothesis of this proposal which is that the overall flexibility of Dicer’s helicase domain is dependent on whether it can hydrolyze ATP, and that in the absence of this activity, the helicase domain is unable to maintain one stable structure and samples a variety of conformational states. Overall, with the extensive resources offered by the University of Utah and expert guidance provided to me by my mentors, I am confident that this proposal will not only generate the first comprehensive integrative dynamic model of Dicer function, but also introduce a novel workflow to explore hypotheses and predict related functional outcomes of other disease-associated RNA interactions.

Up to $76K

2028-01-31

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Dynamic OCT tracking for enhanced visualization of ophthalmic surgery

NEI - National Eye Institute

PROJECT ABSTRACT Cataracts and glaucoma are the two leading causes of blindness worldwide. Crucial ophthalmic procedures to treat cataract, glaucoma, and other vision conditions require precise visualization of anatomy and microsurgical instruments. Visualization in such surgeries has been limited to stereo optical microscopes since the early 20th century. With advancements in optical coherence tomography (OCT), we can now obtain real-time 3D visualization within the eye. Over the past decade, intraoperative OCT (iOCT) systems have become widely researched and integrated into the latest ophthalmic microscopes built by companies such as Zeiss and Leica. These iOCT systems come with the potential to revolutionize ophthalmic surgery, with an unparalleled ability to resolve key anatomic features at micron-level precision. However, there is a crucial challenge that hampers the clinical utility of iOCT. This challenge stems from the fundamental tradeoff between OCT field-of-view and imaging speed. This tradeoff constrains state-of-the-art systems to operate with a relatively small (e.g. 5x5 mm) field of view to achieve the volume update speeds (~10-15 Hz) required for surgical visualization. Consequently, a trained operator on the surgical team must manually reposition the OCT scan throughout the surgery. The current implementation of iOCT results in a “point-and-shoot” approach to imaging, i.e. using OCT as an intermittent snapshot tool, rather than as a continuous surgical visualization technology. With even small movements of the surgical instruments, the OCT image can quickly lose sight of the surgical region of interest (ROI). Manual tracking of iOCT discards a key advantage of OCT, which is real-time 3D data collection. With advances in deep learning methods for image processing and object recognition, there are new opportunities to tackle this problem. The goal of this project is to engineer a novel computational system for automatic, real- time tracking of the surgical ROI in a clinical iOCT system. Our vision is to develop a system that can be readily applied to existing clinical microscopes, and adaptable to future robotic surgical systems. As part of our preliminary work, we have created a lateral tool tracking OCT system using deep learning models applied to the microscope feed. Our current system utilizes a novel synthetic data approach, making use of 3D-rendered models of eyes and tools to accelerate deep learning model development. In the proposed project, we expand on this preliminary work by developing a system for 3D multimodal surgical ROI tracking of iOCT that can be applied to many different types of ophthalmic surgeries. We will then evaluate our platform via ex-vivo porcine and human cadaver eye studies with wet-lab benchmarking and simulated surgeries with our clinical collaborators. Our immediate application is ophthalmic surgery, but the methodology has relevance to a wide range of 3D imaging systems for microsurgical procedures. By developing this system for dynamic OCT surgical tracking, we hope to improve ophthalmic visualization in both training and surgical practice.

Up to $43K

2029-04-30

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Dynamic Regulation of Alternative Splicing in the Initiation and Progression of Islet Autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY / ABSTRACT Type 1 diabetes (T1D) is an autoimmune disease from an immune-mediated attack on the pancreatic beta cells. As ~5% of those developing T1D have a positive family history, there is little awareness of symptoms. T1D is most virulent in children, yet it affects all age and ancestry groups. The beta cell destruction in T1D is identified only through presence of islet autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma- associated protein 2 (IA-2A), and zinc transporter 8 (ZnT8A), although their prevalence can vary depending on age, sex, and ancestry. Genetic factors account for ~50% of T1D risk, and we (and others) have identified over 100 loci containing disease-associated variants. The vast majority of T1D variants reside in the non-coding genome and map to enhancer regions in immune-relevant cell types (e.g., CD4+ T cells). The mechanisms underlying the transition from an individual’s genetic risk to islet autoimmunity and development of T1D have not been resolved. The proposed research is an ancillary project of The Environmental Determinants of Diabetes in the Young (TEDDY) study. TEDDY is a longitudinal cohort study designed to discover triggers of islet autoimmunity by following newborns at high genetic risk with frequent follow-up and collection of samples for deep phenotyping and biological profiling. This project proposes to use TEDDY data and PBMC samples to examine an under-studied mechanism in T1D, the role of alternative splicing. Alternative splicing of pre-mRNA generates diversity in gene expression (regulation) and protein in a tissue-specific manner. Errors in alternative splicing can result in errors in gene regulation and has been shown to lead to human disease, including autoimmune diseases. Further, genetic variation also impacts proper splicing of mRNA, generating aberrant variants. We have shown that alternative splicing is associated with T1D in known T1D loci using short-read RNA sequencing. In addition, RNA-binding proteins (RBPs) with roles in alternative splicing can generate different mRNA and protein isoforms with change or loss of protein function. We have identified 12 genes in known T1D loci that encode RBPs of relevance to gene expression and T1D susceptibility. To gain a comprehensive understanding of the role of these RBP-regulated alternative splicing events on initiation and progression of islet autoimmunity leading to T1D, we propose to focus on a relevant cell type (CD4+ T cells) obtained from TEDDY participants at multiple time points during the transition periods of islet autoimmunity. We will obtain long-read RNA sequencing (for full isoform detection) and short-read RNA sequencing (for isoform abundance) to define differential alternative splicing events, construct RBP networks, and utilize deep learning time series models to map T1D risk over time. We will experimentally validate alternatively spliced genes, their RBPs, and biological mechanisms that lead to islet autoimmunity and T1D. Together, the outcome of the proposed research will enable better prediction of islet autoimmunity and T1D risk trajectory, the timing for monitoring, and novel therapeutic interventions in T1D.

Up to $1.4M

2029-04-30

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Dynamic Regulation of Epidermal Differentiation Genes by Cell-State-Specific PBAF Interactome

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Dynamic Regulation of Epidermal Differentiation Genes by Cell-State-Specific PBAF Interactome Epidermal homeostasis requires cell-state-specific regulation of differentiation genes, maintaining repression in progenitors while ensuring timely activation in the terminal differentiation process to establish barrier function. Dysregulation of differentiation genes contributes to prevalent skin disorders such as psoriasis, eczema, and cutaneous squamous cell carcinoma. The molecular mechanisms governing the transition between repression and activation for differentiation genes remain incompletely understood, limiting the development of new targeted therapeutic strategies. We recently discovered that the PBAF chromatin remodeling complex plays dual roles in epidermal differentiation regulation: it functions as a repressor in the progenitors, but switches to an activator in the terminal differentiation process. To begin unraveling the molecular mechanism underlying PBAF’s functional switch, we discovered that PBAF’s protein interactome, rather than its genomic binding sites, undergoes drastic changes between the progenitor and the differentiation state. Using a targeted genetic screen, we identified the E3 SUMO ligase PIAS1 as a crucial PBAF interactor for repressing differentiation. Building on these findings, we will elucidate the mechanisms underlying PBAF’s functional switch from repressor to activator in differentiation regulation, using PBAF-PIAS1 interaction as the focal point to understand the contributions from other interacting proteins. First, we will define the upstream regulatory mechanisms controlling PIAS1-PBAF association and dissociation. Second, we will determine the downstream impact of PIAS1-PBAF interaction in epidermal differentiation regulation. We hypothesize that PIAS1’s protein stability and association with PBAF is regulated by ubiquitination, and PIAS1’s SUMOylation activity directly impacts the recruitment of repressors versus activators to differentiation genes. Leveraging my lab’s expertise in functional genomics, proteomics, and epidermal tissue models, this study will dissect the molecular pathways modulating differentiation gene repression versus activation through the PBAF interactome. By elucidating both the upstream mechanisms governing the PBAF interactome and the downstream impacts on differentiation dynamics, this work will significantly advance our understanding of epidermal differentiation regulation. Specifically, it will shed light on several underexplored areas, including the identification of novel differentiation regulators and the roles of ubiquitination and SUMOylation in this process. By uncovering novel regulators and molecular mechanisms governing epidermal differentiation, our findings can inform new therapeutic strategies for treating disorders characterized by epidermal differentiation dysregulation, aligning with NIAMS’s mission to advance the understanding and treatment of skin diseases.

Up to $524K

2031-04-30

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Dynamic RNA Folding and Function

NIGMS - National Institute of General Medical Sciences

SUMMARY This research broadly seeks to reveal molecular principles that enable biological systems to sense and adapt to changing environments, and to understand how to use these principles to engineer synthetic biological systems that benefit humankind. A focal point of this work is RNA – a fundamental component of all living systems that enacts genetic, regulatory and catalytic functions by folding into intricate shapes within cells. As RNA folding can occur immediately during transcription, this raises a fundamental question as to how nascent RNA structures can influence many aspects of gene expression including transcription, translation, splicing, and polyadenylation. The overall vision for this proposed research program is to address aspects of this question through detailed structure-function studies of riboswitches and model eukaryotic systems, and development of technologies that can measure and model nascent RNA folding in broad RNA systems. Riboswitches are broadly distributed non- coding regulatory RNAs that bind to specific ligands and in response control gene expression. A critical feature of many riboswitches is that regulation occurs during transcription, making them ideal model systems to study the impacts of nascent RNA structure on gene expression. Principles of nascent RNA folding and function learned from riboswitches is beginning to be shown to hold true in other areas of biology including non-coding RNA biogenesis and eukaryotic RNA Pol III transcription termination. Our goal is to develop a molecular understanding of how cotranscriptional RNA folding regulates and coordinates cellular gene expression. Towards this goal, over the next five years we propose two research themes. The first uses diverse riboswitches, and eukaryotic RNA Pol III transcription termination, as model systems, to uncover general, quantitative relationships between RNA sequence, nascent folding, and transcription termination and translation initiation. We will combine high throughput cellular and in vitro functional characterization approaches to rapidly characterize model regulatory RNA sequence variants, with a hybrid experimental-computational approach called Reconstructing RNA Dynamics from Data (R2D2) to measure and model cotranscriptional RNA folding. Biophysical and data-driven modeling will be used to uncover quantitative relationships to address fundamental questions about how RNA folding kinetics and nascent RNA-RNA polymerase interactions govern transcription and translation regulation. Theme two will incorporate RNA folding energetics extracted from RNA structure chemical probing to improve R2D2’s accuracy and integrate new computational RNA folding algorithm developments to allow R2D2 to reconstruct RNA structure sub-populations of longer RNA systems. Detailed knowledge of how nascent RNA folding links to RNA regulatory function will contribute to a deeper understanding of gene expression processes, as well as numerous RNA biotechnologies such as diagnostics, RNA-targeting antibiotics and drugs, and nucleic acid therapeutics.

Up to $383K

2031-04-30

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Dynamic, Real World Learning, Innovative Mobility, and Versatile Exploration (DRIVE): Evaluating a dose-matched developmental powered mobility intervention for young children with Cerebral Palsy

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary Power mobility intervention for non-mobile toddlers with cerebral palsy (CP) will directly address a primary cause of developmental delays. Children with CP encounter the central problem of impaired self-initiated mobility before age 2, which disrupts typical developmental cascades and leads to detrimental downstream effects in cognition, communication, and motor development. Less than 30% of toddlers in Gross Motor Function Classification Levels II-IV have access to independent, self-initiated mobility by 4 years old, a significant developmental and experiential mobility gap. Outcomes of traditional motor-focused therapies for children with CP are variable and fail to adequately address overall development. While the promise of power mobility as a solution has existed for decades, it is not standard of care and rarely considered as an option, let alone provided, during early intervention in the United States. Do-it-yourself solutions such as ride-on cars have significant access and functionality limitations, families and clinicians may be reluctant to pursue wheeled mobility solutions, even if temporary, and fidelity monitoring in previous power mobility research is nonexistent. Developmental power mobility intervention (DPM) is an innovative, process-based approach that leverages the FDA cleared Explorer Mini to address the above gaps and engage children in tool use, exploratory perceptual motor experiences that trigger developmental cascades, and goal-directed mobility regardless of a child’s walking potential. We will conduct a 2-arm, dose-matched, randomized clinical superiority trial with an active control group and pre-post-follow up study design that will test our central hypothesis that DPM will produce greater improvements in short-term (12 weeks) and medium-term (6 months) global development and activity performance outcomes compared to usual care physical therapy focused on movement, orientation, repetition, and exercise (MORE-PT) in young children with CP, and will not impede gross motor function. We will recruit children 12-30 months expected to have both delayed onset of walking and use of hand-held or wheeled (manual or powered) devices. Both groups will receive intervention twice weekly for 12 weeks, either (A) DPM (treatment) or (B) MORE-PT (usual care active control). Our specific aims are to: (1) Quantify and compare global development outcomes; (2) Quantify and compare change in gross motor function; and (3) Quantify and compare change in activity performance. Our long-term goal is to advance scientific understanding of DPM use to support enhanced development and functional mobility for young children with CP. This work will strengthen evidence and translational support for clinicians and families navigating complex mobility-related clinical decision-making.

Up to $647K

2031-06-30

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Dynamical Systems

U.S. National Science Foundation

The DS program supports research on the theory, analysis, modeling, simulation, design, and application of dynamical systems. Examples of application areas include acoustics and vibration analysis, and noise and vibration control technologies.??Of interest are multi-scale, multi-physics, and large-scale interconnected and complex dynamical systems, nonlinear, hybrid, time-varying, multi-energy domain and distributed dynamic systems, as well as biological systems, and micro and nano-scale systems.

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

Dynamics and Encoding in Cell Signaling

NCI - National Cancer Institute

PROJECT SUMMARY Cell communication research is a growing field that is complimentary to, but distinct from, traditional signal trans- duction fields. This emerging field emphasizes the spatiotemporal aspects of cell communication and quantitative understanding of how information transmission and processing occurs. A central focus on the field is to under- stand exactly what distinguishes “normal” and “disease” cell signaling behavior in terms of spatial and temporal details. There are at least 80 labs worldwide that use live cell imaging, genetically encoded biosensors, compu- tational image analysis, and mathematical models to determine modern quantitative concepts for cell communi- cation. In 2024 we held the inaugural Signaling Dynamics and Encoding conference. The conference was cre- ated to provide scientists in the field with the opportunity for cross-fertilization of shared higher-level concepts across the many pathways studied in the field, including immune signaling, receptor-mediated signal transduc- tion, gene expression, cell cycle, and metabolic signaling pathways. The conference was a success, attracting 136 scientists from around the world, including over 60 PIs and 57 trainees. To continue the success of this conference, we are planning a 2nd Signaling Dynamics and Encoding FASEB Scientific Research Conference on June 21-25, in Nashville Tennessee. We will bring together an international community in the cell communication field. To accomplish this, we aim to (1) provide structure for an emerging research field by establishing and building relationships and collaborations between senior scientists and early career researchers through net- working opportunities and a speaker lineup including both early career researchers and established leaders. This includes 20 trainee talks over the course of the conference. Lightening talks will highlight trainee posters and encourage interactions and networking at poster sessions between trainees and established investigators. We aim to (2) provide trainees with knowledge, networks, and mentors for career opportunities through meetings and networking opportunities with established researchers in both industry and academia. This first iteration of the meeting will aim to (3) create new models by connecting researchers interested in related concepts across biologically different signaling and regulatory systems, providing opportunities for researchers to think outside the typical boundaries of their work and find new insights from colleagues in parallel fields. We will also aim to (4) promote access to new image analysis and modeling technologies by emphasizing the latest technical ad- vances in these areas. Altogether, the Dynamics and Encoding in Cell Signaling FASEB Scientific Research Conference provides a much needed and exciting forum for the cell communication field and will enable cross- disciplinary collaborations and insights into cell function and behavior that is not currently possible.

Up to $18K

2027-05-31

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

Dynamics and plasticity of the hematopoietic stem cell niche

NHLBI - National Heart Lung and Blood Institute

Project summary/Abstract Hematopoiesis is a highly regulated process fueled by hematopoietic stem cells (HSCs) and progenitors in response to physiological and pathological changes throughout life. During development, the system quickly expands to provide increasing numbers of blood cells for the growing tissues and organs. In regeneration, HSCs re-establish the hematopoietic hierarchy and supply lost blood cells to restore tissue function. In pathological conditions, dysregulated hematopoiesis drives disease progression. A detailed cellular and molecular understanding of the mechanisms of dynamic hematopoiesis is key to intervening in these processes for therapeutic benefits. Although the niche critically regulates HSCs and hematopoiesis, how the niche is dynamically regulated to adapt to the distinct demands in the ever-changing conditions is not clear. Our previous work has identified key cellular components of the niche in the bone marrow and developing liver, allowing precise studies of niche dynamics in these organs. Our recent work has also revealed surprising cell fate plasticity in the bone marrow niche. The proposed work in this application builds on these findings to 1) define niche dynamics and plasticity in development, regeneration, and hematological disease, 2) uncover the mechanisms that regulate these processes, and 3) harness the mechanisms to enhance niche function and boost blood cell production. We will use several novel mouse models generated in the lab to study the function of key pathways in regulating niche dynamics and cell fate plasticity. We will employ single-cell transcriptomics, imaging, metabolic analysis, functional studies, and other cutting-edge approaches to understand how these key pathways regulate niche dynamics and plasticity. Collectively, these experiments will uncover novel mechanisms that regulate niche cell dynamics and plasticity with broad implications for better treatment of blood diseases. They may lead to transformative strategies for boosting blood cell production by enhancing niche function.

Up to $1.1M

2033-01-31

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

Dynamics of Coupled Natural and Human Systems

U.S. National Science Foundation

The Dynamics of Coupled Natural and Human Systems (CNH) Program promotes interdisciplinary analyses of relevant human and natural system processes and complex interactions among human and natural systems at diverse scales.

$500K – $1.5M

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

Dynamics of influenza A virus infection in mallards and swine

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Influenza A virus (IAV) poses a significant burden to both human and animal health. The spillover of IAV from animals to humans can furthermore result in influenza pandemics. Mallards and swine represent two important classes of species within influenza ecology. Mallards, like other wild aquatic birds, sustain IAV diversity within nature. Swine are intermediate hosts with susceptibility to both human and avian influenza viruses. Because of this susceptibility, IAV infection in swine can result in transfer of distinct IAV lineages with pandemic potential to humans. Although both swine and mallards are susceptible to IAV, the virus shows drastically different tropism in these hosts. These differences are likely to drive distinct population dynamics of IAV within each host. I hypothesize that the genetic composition of within-host viral populations will be shaped by the spatiotemporal dynamics of infection and that changes in viral population diversity over space and time will therefore show marked differences between swine and mallards. To test this hypothesis, swine and mallards will each be infected with a barcoded virus relevant to the host species: A/swine/North Carolina/A02245294/2019 (H3N2) virus (Sw/NC/19) or A/mallard/MN/10096/99 (H3N8) virus (Ma/MN/99). These viruses will carry a genetic barcode which allows tracking of many lineages within the viral population using next generation sequencing. In Aim 1, I will determine the spatial distribution and genetic composition of virus populations within swine and mallards following infection. Using the combination of extensive tissue sampling, barcoded viruses, and next generation sequencing I will be able to track IAV populations across the anatomy of the host. In Aim 2 I will determine how influenza virus populations change over time at a given anatomical site within swine and mallards. Through repeated sampling of the same anatomical site, I will be able to determine how IAV populations are shaped over time. These findings will advance understanding of IAV dynamics within distinct host species, yielding insight into the evolutionary processes that underly the emergence of IAV pandemics.

Up to $50K

2029-05-31

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

Dynamics of Integrated Socio-Environmental Systems

U.S. National Science Foundation

The Dynamics of Coupled Natural and Human Systems (CNH) Program supports interdisciplinary research that examineshuman and natural system processes and the complex interactions among human and natural systems at diverse scales. Research projects to be supported by CNH must include analyses of four different components: (1) the dynamics of a natural system; (2) the dynamics of a human system; (3) the processes through which the natural system affects the human system; and (4) the processes through which the human system affects the natural system. CNH also supports research coordination networks (CNH-RCNs) designed to facilitate activities that promote future research by broad research communities that will include all four components necessary for CNH funding.

$150K – $1.8M