Grants

marine scienceenvironmentEducation+1

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NOI to Sole Source to Imaging Service Solutions for maintenance support services

HEALTH AND HUMAN SERVICES, DEPARTMENT OF.NATIONAL INSTITUTES OF HEALTH.NATIONAL INSTITUTES OF HEALTH OLAO

NOI to Sole Source to Imaging Service Solutions for maintenance support services

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NOI to Sole Source to Precision for Medicine for repository services

HEALTH AND HUMAN SERVICES, DEPARTMENT OF.NATIONAL INSTITUTES OF HEALTH.NATIONAL INSTITUTES OF HEALTH OLAO

NOI to Sole Source to Precision for Medicine for repository services

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NOI to Sole Source to Qiagen for maintenance and service contract

HEALTH AND HUMAN SERVICES, DEPARTMENT OF.NATIONAL INSTITUTES OF HEALTH.NATIONAL INSTITUTES OF HEALTH OLAO

NOI to Sole Source to Qiagen for maintenance and service contract

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NOI- Global Project to Promote Safer and Healthier Workplaces

employmentworkforce development

Bureau of International Labor Affairs

This Notice of Intent is not a request for funding applications. The United States Department of Labor (USDOL), Bureau of International Labor Affairs (ILAB) intends to award a cooperative agreement of up to $10,000,000 to the International Labor Organization (ILO) to implement a technical assistance project to support global efforts to create safer and healthier workplaces. The project will focus on increasing the capacity of countries and social partners to improve occupational safety and health, particularly for working youth. The project will also include efforts to build and strengthen partnerships across international and regional organizations to share best practices, raise awareness, and contribute to improved legislation and enforcement. Authority: DOL Manual Series (DLMS) 2-836 (G)(3): Services are available from only one responsible source and no substitute will suffice; or the recipient has unique qualifications to perform the type of activity.

rolling

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NOI: Cities Leading through Energy Analysis and Planning (Cities-LEAP)

Golden Field Office

The Office of Energy Efficiency and Renewable Energy (EERE) intends to issue, on behalf of the Strategic Programs Office, a Funding Opportunity Announcement (FOA) entitled Cities Leading through Energy Analysis and Planning (Cities-LEAP) . As part of the Cities-LEAP project, EERE s Office of Strategic Programs, through its Policy and Analysis and Technology-to-Market Teams, intends to solicit applications to advance data-driven decision-making by local governments in support of their climate and energy goals. This anticipated funding opportunity is intended for local and tribal governments as prime applicants and strongly encourages partnerships between local and tribal governments and entities such as academic institutions, technology companies, utilities, regional planning bodies, and non-governmental organizations to develop and pilot data-driven decision frameworks that strengthen the analytical underpinning of energy-impacting actions by local governments across the United States. The purpose of this Notice is to provide potential applicants advance notice that the Office of Strategic Programs, on behalf of the DOE Office of Energy Efficiency and Renewable Energy (EERE), intends to issue a FOA titled, Cities Leading through Energy Analysis and Planning (Cities-LEAP) . NO APPLICATIONS WILL BE ACCEPTED THROUGH THIS NOTICE. Please do not submit questions or respond to this Notice of Intent. Prospective applicants to the FOA should begin developing partnerships, formulating ideas, and gathering data in anticipation of the issuance of this FOA. It is anticipated that this FOA will be posted to EERE Exchange in March 2016.

$1 – $2

rolling

energyclean energy

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Non-Addictive Analgesic Discovery from Marine Microbial Natural Products

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary: Chronic pain, widely considered the United States’ #1 public health crisis, is the most common cause of long-term disability in the world, affecting more than 25 million people in the US and nearly one third of the world’s population overall. Current pharmaceutical treatment options are broadly ineffective and often contribute severe side effects, including anxiety, heart disease, liver disease, and/or addiction. To address the enormous unmet public health challenge of peripherally-mediated chronic pain, novel phenotypic screening tools and new, non-addictive chemical entities that serve as pain therapeutics are urgently needed. Here, we propose a new collaboration that aims to discover novel, non-opioid and non-addictive analgesics from marine microbial resources and advance them to enter the Pain Therapeutics Development Program (PTDP). Our proposal exploits a recently developed phenotypic assay, developed through the HEAL Initiative, that leverages human induced pluripotent stem cell (hiPSC) sensory neurons and glia cultured on multi-well microelectrode arrays (MEAs). This allows long-term and high- content characterization of sensory neuron electrophysiology under baseline (spontaneous) and evoked (thermal and electrical stimulus) conditions. This moderate throughput, pain-physiology-relevant system for hit identification represents a unique approach to compound screening that has yet to be applied to natural product-derived analgesic discovery outside of the preliminary data provided in this proposal. We will employ this unique assay to screen an existing library of purified and structurally characterized marine microbial natural products and extract fraction libraries generated from a diverse and chemically rich culture collection of marine bacteria. We further exploit a new approach called Small Molecule In Situ Resin Capture (SMIRC) to access chemical space that is not available using culture dependent techniques. The hiPSC assay will be used to identify high-priority hits and guide the isolation of active compounds, which will be structurally characterized and tested for toxicity and addiction phenotypes to inform prioritization. A carefully planned workflow, including collaboration with a small biotech company focused on analgesic lead optimization, will maximize the discovery potential of this program.

Up to $1.0M

2028-05-31

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Non-Autonomous Regulation of Cardiac Aging

NIA - National Institute on Aging

Project Summary/Abstract Among all classes of phospholipids, ether phospholipids (mainly plasmalogens) have recently emerged as a novel regulator of mitochondrial membrane dynamics and animal aging. Plasmalogen deficiency has been linked to impaired mitochondrial dynamics, respiratory disorders, cardiomyopathy, and Alzheimer’s disease. The levels of plasmalogens in the circulation and animal brain decrease with age. However, the exact mechanisms underlying age-related reduction in plasmalogen biosynthesis and plasmalogen-regulated tissue homeostasis are largely unknown. Our recent studies identify the kidney as the site of plasmalogen biosynthesis and the source of circulating plasmalogens. Inhibition of kidney plasmalogen biosynthesis increases the production of inflammatory cytokines and cardiomyopathy. In contrast, plasmalogen supplements rescue cardiac defects in plasmalogen biosynthesis mutants. These findings suggest a previously unappreciated role of plasmalogen in kidney-heart communication. In this renewal application, we aim to take multi-disciplinary approaches to interrogate the novel role of kidney-derived plasmalogen ether phospholipids in inter-tissue communication and cardiac aging. Four specific aims are proposed: Aim 1. Determine the mechanisms underlying age-associated decreases in kidney plasmalogen biosynthesis. Aim 2. Determine how plasmalogens are transported from the kidney to the heart. Aim 3. Determine how kidney-derived plasmalogens regulate cardiac contractile performance.

Up to $523K

2031-03-31

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Non-canonical EphB2-mediated signaling in AKI and its progression to CKD

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Transforming growth factor (TGF)-β promotes inflammatory and fibrotic responses via activation of the serine/threonine kinase receptor TβRII and consequent activation of SMAD3. In the kidney, TGF-β is activated in acute kidney injury (AKI) and is associated with proximal tubule epithelial cell (PTEC) responses that lead to the development of and progression to chronic kidney disease (CKD). To this end, PTECs produce inflammatory cytokines, extracellular matrix, and stimulate differentiation of fibroblasts into myofibroblasts, the major producers of extracellular matrix and drivers of fibrosis. Although a role for TGF-β in AKI and CKD has been established, anti-TGF-β therapy has not yet translated into successful treatment in CKD patients. A possible explanation is that TβRII can be activated in a ligand-independent manner which potentiates low dose TGF-β signaling. We showed that the cytoplasmic tail of TβRII contains several tyrosines which can be phosphorylated in a TGF-β independent manner, leading to SMAD3 activation and fibrotic responses in kidney cells. We found that the tyrosine kinase EPH receptor B2 (EphB2) forms a complex with and phosphorylates TβRII. EphB2 is expressed by PTECs and it contributes to organ injury by promoting inflammation and fibrosis. However, the contribution of EphB2 to AKI-to-CKD progression and the cells responsible for its deleterious effects have not been investigated. Using a model of AKI that progresses to CKD, we show that pYEphB2 and pYTβRII are evident in the acute and chronic phases of kidney injury. Ephrin B1-mediated activation of EphB2 leads to pYTβRII and enhances TGF- β-induced SMAD3 activation and epithelial-to-mesenchymal transition. Mice treated with a novel EphB2 inhibitor showed reduced tubular injury, inflammation, collagen production as well as pYEphB2 and pYTβRII following ischemia/reperfusion-induced AKI. Interestingly, we found that macrophage inhibitor factor (MIF), a cytokine that contributes to inflammation following kidney injury, is produced by PTECs when stimulated with Ephrin B1, but not TGF-β. Thus, there is a canonical EphrinB1/EphB2 as well as a non-canonical EphrinB1/EphB2/TGF-β axis in PTECs that can contribute to inflammation and fibrosis in AKI and its progression to CKD. We hypothesize that EphB2 expressed by PTECs contributes to inflammation and fibrosis following AKI and its progression to CKD by inducing the secretion of MIF and by potentiating TGF-β signaling via phosphorylation of TβRII. In this grant, we will: Determine the contribution of PTECs in EphB2-induced kidney inflammation and fibrosis (Aim 1). Determine the mechanisms whereby EphB2 contributes to inflammation and fibrosis (Aim 2). Determine whether the EphB2 small molecular weight inhibitor is beneficial in AKI and its progression to CKD (Aim 3). This study will identify a novel mechanism whereby EphB2 and TβRII interact; how EphB2/TβRII-mediated fibrotic signaling can be modulated in kidney disease; and devise new therapeutic interventions aimed to prevent EphB2 activation and function in kidney disease.

Up to $866K

2031-01-31

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Non-Canonical Functions of Polycomb Complexes in Health and Disease

NIGMS - National Institute of General Medical Sciences

Project Summary My laboratory investigates epigenetic mechanisms in health and disease. In 1R01GM141349-01A1, we proposed to investigate the mechanisms by which the E3-ligase RING1B, a core member of the Polycomb Repressive Complex 1 (PRC1), positively regulates the expression of oncogenic pathways in breast cancer. In 1R01GM146409-01, we proposed to study how the epigenome is remodeled, and genome instability is regulated, by the loss of H3K36me and Polycomb complexes (PRC1/2) in head and neck squamous cell carcinoma (HNSCC). By converting both R01s to a MIRA-R35 under the unifying umbrella of “Non-canonical functions of Polycomb complexes,” we intend to continue working on the aims we proposed in both grants and expand our research program. New research programs include to determine the role of the RING1B paralog RING1A in gene regulation in breast cancer (both in the settings of sensitive and resistance to current therapies) and the identification and characterization of the first set of non-histone substrates of RING1A and RING1B. To address these questions, we will use multiple model systems including new and established breast and HNSCC cellular models, knock-in (KI) and knock-out (KO) cell lines, patient-derived organoids (PDO), xenografts (PDX), and orthotopic xenograft models, biochemistry and mass spectrometry assays. These efforts aim to unravel novel epigenetic mechanisms deregulated in cancer to develop novel targeted therapeutic strategies, encompassing potential combinations with anti-epigenetic compounds. We also propose another original research program aiming to decode the role of novel de novo missense mutations on PRC1 genes that drive neurodevelopmental disorders. This is particularly significant because the prevalence of neurodevelopmental disabilities in children has risen sharply in recent years, while their underlying causes remain largely unknown and insufficiently studied. To address this, we generated the first set of mouse models, along with human and mouse embryonic stem cells, engineered to carry PRC1 variants newly identified by us in individuals with neurodevelopmental disorders. Our research into genetic disorders not only will provide clinical insights but also reveal fundamental mechanisms by which chromatin regulates brain development and neuronal networks underlying cognition. Overall, our program will uncover fundamental mechanisms of gene regulation that profoundly influence cell identity, differentiation, and oncogenesis, while paving the way for precision medicine and enhanced interventions for cancer and developmental disabilities.

Up to $318K

2031-02-28

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Non-canonical functions of the mitochondrial fission protein Drp1 in ovarian cancer

NCI - National Cancer Institute

PROJECT SUMMARY High grade serous ovarian cancer (HGSOC) is the most common histologic subtype of ovarian cancer and remains a deadly malignancy facing women. Late-stage diagnosis, development of chemoresistance and high rates of recurrence all contribute to the low five-year survival rate of advanced stage patients. Thus, identifying novel drivers of tumor progression and heterogeneity continue to be high research priorities. We find that enhanced mitochondrial fusion driven by a splice variant of the mitochondrial fission protein Drp1/DNM1L is a phenotype of HGSOC. Loss of exon 16 in the Exon16/17 variable domain, denoted as Drp1(-/17), leads to Drp1 redistribution from mitochondria to microtubules (MTs), and consequentially to dampened fission, a fused mitochondrial network and enhanced mitochondrial metabolism. Importantly, Drp1(-/17) expression drives proliferation, metastasis and chemoresistance, and this is of clinical significance as Drp1(-/17) high HGSOC tumors are associated with poor patient outcome. In the present proposal we will test the hypothesis that the extra-mitochondrial function of Drp1(-/17) contributes to HGSOC tumor progression and heterogeneity. Our preliminary data suggest that microtubules are not simply reservoirs for Drp1(-/17) to drive mitochondrial fusion, but that Drp1(-/17) has localized microtubule functions associated with its interaction and recruitment of the multi amino acyl tRNA synthase complex (MSC) to centrosomes. Based on observations that Drp1(-/17) high tumors display greater aneuploidy and copy number alterations leads us to predict that localized centrosome protein synthesis facilitated by the MSC interaction with Drp1(-/17) at centrosomes leads to centrosome amplification and chromosome segregation defects. Intriguingly, many of the amino acids that are required for tRNA charging by the MSC are derived from the TCA cycle. Coincidentally, we find that Drp1(-/17) cells display increased levels of TCA cycle metabolites and downstream amino acid. This leads us to predict that increased mitochondrial fusion due to Drp1(-/17) microtubule association drives TCA cycle flux, and that this works in concert with the MT-dependent function of Drp1(-/17) by supplying amino acids for the MSC. We further propose that de novo amino acid synthesis provides survival advantages to Drp1(-/17) under amino acid deprivation and that this contributes to tumor progression. Our work is conceptually innovative as it investigates the unique interplay between mitochondrial morphology, amino acid metabolism, and localized regulation of protein synthesis at the centrosome to chromosome instability, a common feature of HGSOC. The results from this work will have major impacts on our understanding of HGSOC tumor heterogeneity. Moreover, our research is the first demonstration that a splice variant of Drp1 has unique extra-mitochondrial functions in a pathophysiologic context.

Up to $639K

2031-05-31

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Non-canonical transcriptional activation of MITF in pigment cells.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary MITF, particularly the melanocyte-restricted m-MITF isoform, is a key transcription factor that regulates melanocyte differentiation, survival, and pigmentation. Its expression is dynamically regulated by the MC1R receptor through the PKA signaling pathway. For decades, it was thought that CREB1 was the PKA-controlled transcription factor that drove m-MITF transcription. However, I have discovered that a non-canonical mechanism activates m-MITF independent of CREB1 and its redundant paralogs. This mechanism requires the transcriptional co-activator CRTC, which must be recruited to m-MITF promoter DNA through an unknown factor. We propose here to define this non-canonical mechanism, discover its unknown regulators, and characterize the precise molecular interactions required for m-MITF transcriptional activation. Specifically, we will 1) generate a toolkit of mutant cell lines designed to perturb select events in PKA signaling and dissect the differences between non-canonical and canonical regulation, 2) perform functional genomic screens to unveil new regulators of m- MITF using cellular proliferation and transcriptional reporter readouts, and 3) investigate physical interactions between identified regulators and the m-MITF promoter to develop a molecular model for the non-canonical mechanism. As a feature of each of these aims, we will apply our findings to genetically modified, iPSC-derived primary melanocytes and organotypic skin reconstitutions to address this mechanism's role in physiological tissue pigmentation. This work will deepen our understanding of the molecular biology of pigmentation and give insight into PKA signaling in other specialized cell types. It will lay the foundation for molecular approaches to manipulate m-MITF in a melanocyte-specific manner for the chemoprevention and treatment of numerous sun- and pigmentation-related conditions, including skin cancer and aging.

Up to $108K

2028-04-30

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Non-canonical translation of pneumovirus mRNAs

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT ABSTRACT Pneumoviruses, including respiratory syncytial virus (RSV) and human metapneumovirus (HMPV), cause annual epidemics of respiratory infections that can cause serious disease in the young, elderly, and those with co-morbidities. The pneumoviruses are members of the Order Mononegavirales, the non-segmented negative strand RNA viruses. The RNA dependent RNA polymerase of these viruses produces capped and polyadenylated mRNAs resembling those of the host; however, pneumovirus mRNAs face unique challenges in engaging host protein synthesis machinery. Their unusually short 5´ untranslated regions (5´ UTRs) do not provide a sufficient platform for ribosome recruitment through the conventional eIF4E-mediated translation initiation pathway. In our preliminary studies, we have demonstrated that RSV protein synthesis occurs independently of the key translation initiation factor, eIF4E, contrasting with cellular mRNA translation. These findings show that RSV must utilize a non- canonical mechanism of translation initiation. The goal of this project is to identify the viral and cellular factors that enable this non-canonical translation mechanism. We will determine if the 5´ UTRs of pneumoviruses confer the ability to bypass canonical translation pathways and identify which proteins of the cellular translation machinery permit these mRNAs to be efficiently translated. To accomplish this, we will construct reporter viruses to dissect the role of viral 5´ UTRs in promoting this unique mode of translation, and generate auxin-inducible degron-tagged cell lines targeting key eukaryotic initiation factors. Our approach is designed to examine requirements for RSV protein synthesis and define the RSV RNA binding protein (RBP)-ome. We anticipate that this work will provide novel insights into the mechanisms governing pneumovirus mRNA translation and potentially identify targets for antiviral intervention.

Up to $245K

2028-04-30

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Non-coding RNAs and chronic limb threatening ischemia

NHLBI - National Heart Lung and Blood Institute

Peripheral artery disease (PAD), affecting over 200 million people globally, often advances to chronic limb- threatening ischemia (CLTI), characterized by chronic ischemic rest pain with high risk for amputation and heightened mortality. CLTI is the leading cause of amputations in adults, but there are no medical therapies available that generate a long-term clinical benefit. Recent clinical findings suggest that in CLTI, vascular growth factor overexpression acting on cells in ischemic skeletal muscle result in the formation of abnormally enlarged capillaries with decreased blood transit time and capillary detachment from skeletal muscle fibers. We hypothesize that future therapeutics in CLTI must address microvascular abnormalities to form stable, functional capillaries to improve perfusion to the ischemic limb. Non-coding RNAs (both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) are an emerging class of regulators of epigenetic modifiers, RNA, or protein-coding genes that has garnered attention for impacting diverse biological processes relevant to ischemic injury and for their therapeutic potential. However, the identity and roles of specific ncRNAs involved in CLTI are not well defined. Our published and preliminary studies reveal how ncRNAs can control stage-specific aspects of angiogenic growth, migration, sprouting, and permeability in CLTI. Furthermore, we have elucidated ncRNA functions in vivo and translated these findings into novel therapeutic approaches, including the demonstration that local delivery of ncRNAs potently regulate the angiogenic response in experimental limb ischemia in mice without toxicity. Looking forward, we hypothesize the existence of driver ncRNAs and their targets in early and advanced phases of disease and seek to uncover their expression, function, mechanism, and interactomes. Using a robust ncRNA platform established in the lab, we will bring together cross-disciplinary expertise to address focused questions that explore new molecular and cellular targets and abnormal endothelial cell (EC)-cell interactions that underlie defects in microvascular perfusion and function in CLTI. For this program, promising new leads have been discovered related to targets involved in: (1) EC permeability and angiogenesis; and (2) vascular smooth muscle cell-EC crosstalk as critical drivers in the microvascular response to CLTI. Single cell and spatial transcriptomics combined with other -omics-based technologies in specimens from patients with CLTI will illuminate driver cell types and targets underlying impaired microvascular perfusion. Novel bioengineered delivery platforms (e.g. colloidal hydrogels incorporating ncRNAs) will be utilized for sustained delivery of promising targets. The outstanding qualifications of our multi-disciplinary team in the ncRNA field, molecular imaging, vascular biology, nanomedicine, bioinformatics, and CLTI coupled with a strong training program uniquely position us to establish an unprecedented molecular view of ncRNAs in the development of CLTI that can inform new paradigms of ncRNA-based therapeutics for this and other ischemic disease states.

Up to $1.2M

2033-02-28

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Non-invasive close to real-time assessment of dynamic pupil responses to different light stimuli and the relationship between those pupil responses and circadian rhythm and sleep metrics

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY The lack of non-invasive, real-time assessments of circadian rhythm metrics hinders the translation of circadian rhythm knowledge into clinical practice. Circadian rhythms are internal physiological processes that cycle every ~24 hours. Light is the most potent stimulus for circadian rhythm entrainment to environmental time. Misalignment of the circadian system with environmental time increases the risk of both chronic diseases (e.g., cardiovascular disease, obesity) and acute mental and physical health impairments, underscoring the need for accessible clinical assessment tools. The mechanisms underlying individual variability in circadian (mis)alignment are unclear; one potential mechanism would involve variations in how light is processed in the eye. This project will test the hypothesis that differences in multiple metrics of pupillary response to light stimuli will correlate with differences in circadian metrics – and be a potential biomarker for individual differences. Wavelength, duration, and intensity of light differentially affect the response of retinal image-forming (e.g., rods, cones) cells and non-image-forming (NIF) intrinsically photosensitive retinal ganglion cells (ipRGCs) that contain melanopsin. The NIF pathway is crucial for circadian entrainment to environmental time and impacts the pupillary light reflex, melatonin concentrations, and other physiology. Variations in the post-illumination pupillary response (PIPR), an ipRGC- linked response, have been linked to neurological conditions, including circadian rhythm sleep-wake disorders (CRSWD), suggesting that pupillary response could be used as a potential non-invasive close-to-real-time diagnostic and monitoring tool. Relationships between pupil responses during and after light stimuli and circadian timing metrics should be established. Our specific aims are to quantify (i) different metrics of pupil response during and after light stimuli of various intensities, wavelengths, and durations (ii) and their relationships with dim-light melatonin onset (DLMO, the current gold standard measurement for circadian phase) (Aim 1) and in individuals with two intrinsic circadian sleep-wake phase disorders (CSWPD) with altered sleep timing (Aim 2). An outpatient week of monitoring of sleep timing will be immediately followed by the inpatient protocol for both participant groups (Aim 1, healthy controls, leveraging a funded R01 experiment; Aim 2: Individuals with CRSWD funded with the F32 funds). The inpatient protocol will consist of multiple pupillometry sessions and an evening saliva collection for DLMO. During pupillometry, participants will be exposed to wavelengths of light designed to target the ipRGC cells (blue light) or not (red light) with a matched number of photons of different intensities and durations. This F32 award will incorporate training in the measurement and analysis of physiological measures, circadian rhythms, and photobiology, phenotyping of people with CSWPD, advanced statistical training, grant and manuscript writing, scientific communication, and lab management. Establishing a strong foundation in these areas will facilitate Dr. McCullar’s transition to an independent scientist uniquely poised to establish outpatient testing that provides non-invasive close-to-real- time assessments of circadian metrics that can be used to evaluate and monitor individuals with circadian (or other NIF- linked) pathologies, as well as tools to help facilitate the integration of circadian system monitoring into clinical practice.

Up to $80K

2027-04-30

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Non-invasive Modulation of Microglia Gene Expression Using Peripherally Administered Antibody Conjugates

NIA - National Institute on Aging

The ability to selectively modulate microglia activity by increasing or decreasing the expression of one or more target genes is critical for defining and targeting the molecular pathways that govern normal physiology and diverse disease phenotypes. Unfortunately, adeno-associated viruses (AAVs) and other viral vectors – the workhorses of many in vivo studies aimed at modulating gene expression – are limited by immunogenicity and toxicity, as well as their relatively low activity in microglia compared to other CNS cell types. In contrast, antisense oligonucleotides (ASOs) are attractive agents for this purpose, especially given their clear advantages relative to AAVs – namely reversibility, lack of toxicity and immunogenicity, and insensitivity to gene size. However, progress has been limited by the need for invasive routes of ASO administration, limited cellular uptake, and lack of cell-type specificity. A technology capable of efficiently delivering ASOs across the intact blood-brain barrier (BBB) and specifically into microglia following intravenous (IV) administration – resulting in selective modulation of microglia gene expression without associated toxicity – would be a significant breakthrough with wide-reaching implications. Therefore, we have developed bispecific antibodies (bAbs) that target either transferrin receptor 1 (TfR-1) or CD98hc – the heavy chain of the large neutral amino acid transporter (LAT1) – and mediate shuttling of IgGs across the BBB and into the brain parenchyma. We also find that pairing a CD11b- specific IgG with both shuttles results in them crossing the BBB and localizing to microglia in the mouse brain after IV administration. Moreover, we have demonstrated selective in vivo gene silencing in microglia using peripherally administered CD11b bAb-ASOs. Therefore, the first objective of this proposal is a proof-of-concept study aimed at testing the therapeutic efficacy of our first-generation, microglia-targeted bAbs conjugated to ASOs that decrease expression of the transcription factor PU.1. This gene (Spi1) is a master regulator of myeloid cells, and reduced expression is linked to delayed age onset of Alzheimer’s disease (AD) and microglial- mediated pro-inflammatory responses in rodents and humans. We will test the impact of lowering PU.1 on microglia activation and associated pathology using mouse models of AD (APP/PS1 and 5xFAD). The second objective is to develop second-generation bAbs targeting additional cell-surface proteins enriched on microglia. Therefore, in Aim 1, we will evaluate the efficacy of first-generation bAb-ASOs for reducing PU.1 expression and pro-inflammatory microglia phenotypes, and modulating associated pathology in two AD (APP/PS1 and 5xFAD) mouse models. Next, in Aim 2, we will evaluate the extent and cell-type specificity of silencing a ubiquitously expressed gene (Malat1) for second-generation bAb-ASOs that target different cell-surface proteins (e.g., TMEM119, P2RY12, and CX3CR1) enriched on microglia. A key expected outcome is the identification and characterization of bAb-ASOs that selectively modulate gene expression in microglia after peripheral administration, which has a staggering number of fundamental and therapeutic applications.

Up to $655K

2030-11-30

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Non-Invasive Single-Cell Morphometry and Tracking in Living Bacterial Biofilms

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Biofilms are cohesive, multicellular microbial communities that adhere to biotic or abiotic surfaces. Biofilms play crucial roles in the human microbiome, but also cause over half of the 1.7 million hospital-acquired infections in the US. Phenotypic diversity and coordination of cellular behaviors within biofilms provide bacterial populations with emergent capabilities beyond those of individual cells. Most notably, biofilms are orders of magnitude more tolerant to long-term antibiotic drug treatments and host immune responses. It remains largely unknown how such remarkable capabilities emerge from the behaviors of individual cells and the interactions between them, mainly because currently available microscopy platforms cannot resolve and automatically track micrometer- sized bacterial cells within crowded biofilms. To address this challenge, the proposed research seeks to develop integrated microscopy and image processing technologies that enable long-term 3D fluorescence imaging of bacterial biofilm communities on and within living human epithelial tissues, and accurate single-cell 3D shape measurements and tracking of thousands of interacting bacterial cells over time. The resulting imaging platform will be applied to visualize, in 3D space and time, how bacterial populations colonize different niches on and within the human body, where they symbiotically support host tissue physiology or cause acute or chronic tissue pathology. Such information is critical to advance our understanding of microbial life and its impact on human physiology.

Up to $425K

2031-02-28

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Non-Invasive Vagus Nerve Stimulation in Subarachnoid Hemorrhage

NINDS - National Institute of Neurological Disorders and Stroke

Aneurysmal subarachnoid hemorrhage (SAH) carries high mortality in ~40% and poor outcomes in ~20% of all. About 30% of patients who initially survive the rupture develop early brain injury and delayed cerebral ischemia, both major causes of mortality, prolonged hospital stay, and disability. Microvascular dysfunction and vasospasm, inflammation, spreading depolarizations (SD), and seizures all contribute to poor outcomes. There is no established treatment after SAH except nimodipine and enhancing tissue perfusion via induced hypertension. Therefore, aneurysmal SAH management is an urgent unmet need. We here propose to develop non-invasive transcutaneous vagus nerve stimulation (nVNS) as a novel neuromodulatory intervention targeting SAH. Vagus nerve stimulation (VNS), a neuromodulation technique in clinical use for intractable epilepsy and depression, inhibits SDs and has anti-ischemic, anti-inflammatory, anti-hypertensive, and anti-epileptic properties. However, the need for highly invasive surgical implantation of electrodes around the vagus has so far limited its clinical applications. Recently, non-invasive VNS (nVNS) techniques with excellent safety and tolerability profiles have been developed and approved for clinical use. nVNS is a pleiotropic intervention on multiple targets relevant to SAH (Figure 1). We recently showed that nVNS improves outcomes in animals with ruptured aneurysms and SAH. Building upon these proof-of-concept data, our overarching aim in this translational proposal is to build a foundation for nVNS targeting SAH, better understand the mechanisms, and prepare this novel neuromodulatory therapy for clinical trials in SAH. Aim 1: We will test whether nVNS improves SAH outcomes in three complementary animal models of SAH: prechiasmatic blood injection, endovascular puncture, and skull-base elastase injection to induce aneurysms in the circle of Willis that rupture spontaneously. We will establish nVNS dose-response in both sexes, circadian stages, and aging animals on clinically relevant functional and tissue outcomes to define the therapeutic profile of nVNS in SAH. Aim 2: We will test whether nVNS improves biological substrates of SAH outcomes. We will examine optical resting-state functional connectivity, inflammation using myeloperoxidase MRI, blood-brain barrier integrity using dynamic contrast-enhanced MRI, cerebral blood flow autoregulation and cerebrovascular reserve using laser speckle flowmetry, and microcirculatory thrombi and neutrophil extracellular traps using histology. These will confirm target engagement and bolster our confidence in the therapeutic activity optimized in Aim 1. Aim 3: We will test whether nVNS efficacy in SAH is mediated via central or peripheral vagal pathways by ablating the vagus proximal or distal to the cervical nVNS site, lesioning the principal central vagal relay nucleus tractus solitarius, and pharmacologically manipulating the cholinergic anti-inflammatory pathway activated by nVNS. These experiments will identify the vagal projections and their downstream targets relevant to SAH.

Up to $511K

2031-01-31

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Non-Native Invasive Species (NNIS) Mastication – NRV Ranger District

AGRICULTURE, DEPARTMENT OF.FOREST SERVICE.USDA FOREST SERVICE

Non-Native Invasive Species (NNIS) Mastication – NRV Ranger District

2026-09-19

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Non-Personal Healthcare Services-Physicians & Other Professional Ambulatory Services for PRC Program

HEALTH AND HUMAN SERVICES, DEPARTMENT OF.INDIAN HEALTH SERVICE.ALBUQUERQUE AREA INDIAN HEALTH SVC

Non-Personal Healthcare Services-Physicians & Other Professional Ambulatory Services for PRC Program

2027-02-03

Health

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Non-siderophore function of peroxisomes in Histoplasma pathogenesis

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The fungal pathogen Histoplasma capsulatum infects and thrives within phagocytes of the immune system. Results from a genetic screen indicate that peroxisome organelles play a critical role in facilitating Histoplasma proliferation in macrophages. Preliminary work demonstrated that the known peroxisomal functions of fatty acid β-oxidation, the glyoxylate cycle, and catalase destruction of reactive oxygen are all dispensible for Histoplasma pathogenesis indicating that peroxisomes play a novel role. This proposal will uncover new peroxisome functions by definition of the peroxisome proteome and metabolome in pathogenic-phase fungal cells. Candidate peroxisomal functions will be validated by functional tests to determine their contributions to Histoplasma’s intramacrophage proliferation. This work will uncover new peroxisomal functions and reveal novel mechanisms for fungal exploitation of the macrophage.

Up to $354K

2028-01-31

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NON-TARGET MARKET LABOR CONSULTATION AND REPRESENTATION SERVICES - 10000186633

HINSHAW & CULBERTSON LLP

Management and Business Professionals and Administrative Services

2027-05-31

workforce

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Non-thematic actions targeting disruptive technologies for defence

European Commission - EDF

Non-thematic actions targeting disruptive technologies for defence. Call: Non-thematic actions targeting disruptive technologies for defence. Programme: EDF. Open call from the EU Funding & Tenders Portal.

$50K

2026-09-29

public_safety

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Non-thematic development actions by SMEs