Grants

16,469 grants found

24 grants worth up to $10.7M match your search

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Identification and Cataloging of Scientific Voucher Specimens

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of NPS' intention to fund the following project activities without full and open competition: Task Agreement P15AC00624 under master Cooperative Agreement P13AC00786 with the Point Reyes National Seashore Association, for the project titled, "Identification and Cataloging of Scientific Voucher Specimens".

rolling

natural resources

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

Identification and Characterization of Mutation-Induced Alternative Splicing Events in Cancer Using Multi-Omics Data

open

NCI - National Cancer Institute

Identification and Characterization of Mutation-Induced Alternative Splicing Events in Cancer Using Multi-Omics Data Project Summary The goal of this project is to discover mutation-induced alternative splicing events (MAS), understand their functional relevance, and identify neoantigens arising from these events to advance cancer immunotherapy. Large-scale sequencing efforts such as The Cancer Genome Atlas (TCGA) have primarily focused on identifying driver mutations in tumors, including single amino acid changes, insertions, deletions, and alterations that truncate or elongate wild-type protein sequences. However, traditional DNA mutation annotations often rely on canonical transcripts and may overlook alternative splicing events, and some mutations, such as synonymous changes, are considered silent despite their potential impact on splicing. Previously, we developed the MiSplice pipeline to detect mutation-induced splice sites and, when applied to TCGA data, identified thousands of somatic mutations that create cryptic splice sites. In this proposal, we aim to systematically investigate mutation-induced alternative splicing and its functional relevance in cancer, while also identifying the resulting neoantigens by leveraging data from the Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC-3), which includes comprehensive exome sequencing, RNA-Seq, and mass spectrometry data for 774 tumors across seven cancer types, as well as 126 prospective breast cancer samples from CPTAC-2. We hypothesize that mutation-induced alternative splicing plays a significant role in cancer etiology and that the associated neoantigens can serve as novel immunogenic peptide candidates for cancer immunotherapy. We propose to test these hypotheses through two specific aims. Aim 1: Identify mutation-induced alternative splicing events and assess their functional relevance in cancer using multi-omics data (Years 1 & 2). We will use MiSplice to detect mutation-induced alternative splicing events from CPTAC data and evaluate their impact by analyzing changes in protein and phosphorylation expression, as well as pathway activation. Aim 2: Identify neoantigens arising from mutation-induced alternative splicing events with mass spectrometry support (Years 1 & 2). We will construct a tailored protein database that integrates both reference proteins and mutant proteins generated from MAS events. Using state-in-art tools such as PepQuery, we will search for corresponding peptides in the mass spectrometry data, enabling identification of mutant proteins. Neoantigen peptides derived from these expressed mutant proteins will then be prioritized as candidates for cancer immunotherapy.

Up to $156K

2028-05-31

health research

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

Identification and characterization of novel antifungals against Cryptococcus spp

open

NIAID - National Institute of Allergy and Infectious Diseases

Cryptococcus neoformans and Cryptococcus gattii are major fungal pathogens that cause severe infections, including cryptococcal meningitis, particularly in immunocompromised individuals. The World Health Organization (WHO) has identified C. neoformans as one of the top four highest critical priority fungal pathogens due to its substantial disease burden, increasing drug resistance, and the lack of effective therapies. Even with available treatments, the mortality rate for cryptococcal meningitis often exceeds 50%, highlighting the urgent need for new therapeutic strategies. Dihydroorotate dehydrogenase (DHODH), a pivotal enzyme in the de novo pyrimidine biosynthesis pathway, is a promising antifungal target due to its essential role in fungal survival. The success of olorofim, a selective DHODH inhibitor effective against Aspergillus fumigatus, underscores the therapeutic potential of targeting DHODH. However, olorofim is ineffective against C. neoformans and C. gattii, likely due to structural and sequence differences in their DHODHs. Importantly, studies have shown that pyrimidine biosynthesis in C. neoformans is vital for survival, as serum and cellular pyrimidine levels are insufficient to bypass DHODH inhibition. This makes CneDHODH an attractive and actionable target for antifungal drug development. This proposal focuses on developing selective inhibitors of CneDHODH to address the critical therapeutic gap for cryptococcal infections. High-throughput screening (HTS) will be carried out to identify inhibitors from large compound libraries. Identified hits will be validated for potency, selectivity against human DHODH, and antifungal activity against C. neoformans and other clinically relevant pathogens. Iterative medicinal chemistry will optimize lead compounds to improve their pharmacokinetics, potency, and selectivity. Structural studies, including co-crystallization and molecular modeling, will provide detailed insights into inhibitor binding, enabling rational drug design. Finally, optimized compounds will be tested in animal models of C. neoformans infection to evaluate their in vivo efficacy, pharmacokinetics, and safety. The development of CneDHODH inhibitors will address a critical unmet need for effective antifungal therapies for cryptococcal infections while extending the applicability of DHODH as a drug target to fungal pathogens beyond A. fumigatus. This work has the potential to transform the treatment of invasive fungal infections caused by Cryptococcus spp., significantly improving outcomes for vulnerable patients. By leveraging innovative screening approaches, structural insights, and medicinal chemistry, this project aims to deliver novel antifungal agents that could save lives and reduce the global burden of cryptococcal infections.

Up to $3.1M

2030-05-31

health research

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

IDENTIFICATION AND CHARACTERIZATION OF T CELL EPITOPES FROM BACTERIAL PATHOGENS CAUSING PNEUMONIA

open

NIAID - National Institute of Allergy and Infectious Diseases

The contractor will identify and characterize T cell epitopes in bacteria capable of causing pneumonia through person-to-person transmission in the community (Community Acquired Pneumonia = CAP), as such infections cause significant morbidity and mortality worldwide, and T cell responses against these pathogens are understudied. Leveraging results from previous contracts, the contractor will bioinformatically identify peptide candidates that are then synthesized and screened for recognition by T cells to identify bona fide T cell epitopes. The contractor will identify epitopes in currently uninfected, likely exposed individuals and those who have a confirmed diagnosis and will be followed longitudinally. The contractor will characterize epitopes identified from these large-scale screens for their HLA restriction, their ability to bind different HLA molecules, and their recognition in different patient cohorts.

Up to $956K

2026-09-29

health research

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

Identification and elimination of antigen-specific expanded clones

open

NIAID - National Institute of Allergy and Infectious Diseases

Clonal expansion is a process where latently infected CD4+ T cells proliferate in response to their cognate antigen. It is thought that this process contributes significantly to the size of the HIV reservoir and therefore disrupting this mechanism could have a huge impact on the number of latently infected cells. We observed a significant decline in the number of expanded CD4+ T cell clones in an elite suppressor who received chemoradiation for lung cancer and have shown that we can recapitulate this in vitro by stimulating CD4+ T cells from this patient with a combination of cognate antigen to induce proliferation, and either chemotherapeutic or antiproliferative agents to selectively kill the dividing antigen-specific CD4+ T cells. If successful in other individuals, a two- step process of vaccination of individuals with cognate antigen and short-term treatment with chemotherapeutic or antiproliferative agents may be part of a strategy to reduce the size of the reservoir.

Up to $427K

2028-03-31

health research

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

Identification and Enumeration of Aquatic Macroinvertebrates to Support Long-Term Monitoring of Aquatic Macroinvertebrate Communities in National Park Service Units of the Mojave Desert Network

open

National Park Service

United State Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This funding opportunity is to provide public notice of NPS's intention to fund the following project activities without full and open competition. Cooperative Agreement P17AC01653 with Utah State University, a partner under the Great Basin Cooperative Ecosystem Studies Unit, for project titled "Identification and Enumeration of Aquatic Macroinvertebrates to Support Long-Term Monitoring of Aquatic Macroinvertebrate Communities in National Park Service Units of the Mojave Desert Network"

Up to $50K

rolling

natural resources

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

Identification and Evaluation of Five Natural Areas as Potential National Natural Landmarks in the Pacific West Region

open

National Park Service

United State Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This funding opportunity is to provide public notice of NPS's intention to fund the following project activities without full and open competition. Task Agreement # P14AC01727 under Cooperative Agreement H8W07110001 with the Portland State University, a partner under the Pacific Northwest Cooperative Ecosystem Studies Unit, for project titled "Identification and Evaluation of Five Natural Areas as Potential National Natural Landmarks in the Pacific West Region"

rolling

natural resources

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

Identification and Evaluation of Possible Approaches to Addressing Nitrosamine Impurities in Drugs (U01)

upcoming

Food and Drug Administration

The Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs (OND), is announcing this Funding Opportunity Announcement (FOA) for a Cooperative Agreement. The proposed work directly supports the U.S. FDA’s stated goal of protecting public health from unacceptable risks from nitrosamine impurities in human drugs. Although significant experimental and policy/regulatory initiatives have been undertaken in this area, there remains a need for further research into and development and refinement of translational and implementable practices that will protect the public against nitrosamine risks while ensuring continued safe access to critical therapeutic drugs. The aim is to improve the safety of human drugs with potential nitrosamine impurity liabilities. In addition to the work outlined above, the award recipient will assess how best to ensure that this research and practices development continues among industry members, non-profits, and/or academic institutions once the FDA funding for this cooperative agreement ends.

$350K

Rolling

consumer_protectionAgriculturefood_and_nutrition

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

Identification and Evaluation of Possible Approaches to Addressing Nitrosamine Impurities in Drugs (U01)

upcoming

Food and Drug Administration

Identification and Evaluation of Possible Approaches to Addressing Nitrosamine Impurities in Drugs (U01)

Rolling

general

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

Identification and Evaluation of WWII and Mexican Period Resources at Point Reyes National Seashore

open

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of the NPS' intention to fund the following project activities without full and open competition: Cooperative Agreement P19AC01148 with Sonoma State University, a partner under the Californian Cooperative Ecosystem Studies Unit (Cooperative and Joint Venture Agreement NPS-CALI-CESU-2018), for the project titled, "Identification and Evaluation of WWII and Mexican Period Resources at Point Reyes National Seashore."

Up to $130K

rolling

other

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

Identification and inhibition of the novel downstream effectors of mutant Ras for mutant Ras-driven cancer targeting

open

NCI - National Cancer Institute

Summary KRas is the most commonly mutated oncogene in human cancers. A deregulated KRas GTPase activity is the consequence of each of the mutations. Currently, there are limited FDA approved drugs to counter tumors having activating Ras mutations. An active anti-KRas remedy would be a major advancement for the treatment of many cancers. To that end, the AM510 is an improved version of the KRasG12C inhibitor that is the first to enter to clinical testing and exhibited beneficial efficacy in 4 non-small cell lung cancer (NSCLC) patients recently approved by FDA for advanced lung cancer treatment. However, unlike other KRas mutants such as KRasG12V accounting for the vast majority of KRas mutations, KRasG12C only occurs in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid cancers, thus greatly limiting the use of AM510 in targeting human cancers with other types of KRas mutations and/or KRas overexpression. To overcome this problem, it will be crucial to identify other strategies and targeted agents to combat KRas-driven cancers. Although KRas mutations are frequently found in human cancers, amplification of KRas, albeit less frequent, has also been reported in certain types of human cancers. In both cases, activation of downstream Raf/MEK/ERK (MAPK) and PI3K/Akt kinase cascades represent key mechanisms that drive malignant tumor phenotypes through Ras, establishing a molecular basis for targeting Ras-driven cancers by inhibiting downstream kinase cascades. However, combination of inhibitors simultaneously targeting MAPK and Akt cascades fail to exhibit clinical efficacy in KRas-driven cancers, suggesting that other effectors downstream of activated KRas contribute to treatment failure. By screening an amide compound library with >30,000 compound in the cell-based viability assay and in vivo tumor assays, we identify the compound #1a as a promising lead compound that selectively and potently targets mutant KRas driven cancer survival and in vivo tumor growth in xenografts, patients- derived xenografts (PDXs) and genetic models without affecting normal cell survival and causing mouse toxicity. Of note, the lead compound #1a binds to a novel downstream effector of mutant KRas, which is crucial for cancer cell survival in the context of mutant KRas activation, and disrupts its activity leading to cancer cell catastrophe. In this proposal, we proposed three specific Aims to explore the efficacy of the lead compound #1a and its derivatives and their underlying mechanisms in targeting mutant KRas driven cancers using diverse tumor models. Our proposal is highly original and innovative, as we have developed a lead compound for targeting mutant KRas cancer and utilized cutting technologies including medicinal chemistry, genetic mouse models, and PDX models to validate our provocative concept. We have assembled a unique research team with diverse expertise that is highly capable of conducting the study. Our study provides novel downstream effectors for mutant KRas signaling and develops an effective strategy/agent for targeting mutant KRas-driven cancer, thus revolutionizing our understanding of KRas signaling and therapies for targeting mutant KRas driven cancers.

Up to $693K

2031-05-31

health research

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

Identification and Investigation of CD4+ T cell Clonotypes Comprising a Polyclonal Repertoire Against Aeroallergen in a Murine Model of Allergic Asthma

open

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Allergic asthma presents as either T2-high (Th2/eosinophilic) or T2-low (Th17/neutrophilic) inflammation. While external factors like co-stimulation and cytokines shape Th cell fate, the role of T cell receptor (TCR) affinity in directing Th2 vs. Th17 differentiation remains unclear. Our lab developed a fungal protease (Alp1)-driven allergic lung inflammation model and essential reagents, including an IL-5/IL-17A reporter mouse. We observed that Alp1 sensitization primarily induces a Th2 response (~30% IL-5+ Th cells, eosinophilia) but also elicits a smaller Th17 response (~5% IL-17A+ Th cells, neutrophilia). This suggests TCR-intrinsic factors influence effector fate. We hypothesize that TCR affinity dictates Th2 vs. Th17 differentiation in response to fungal protease allergens. A major limitation in allergy research is the lack of tools to study allergen-specific Th cells. We aim to develop peptide-MHCII tetramers to examine TCR affinity and its impact on Th2/Th17 fate within oligoclonal populations. Additionally, we will generate a TCR transgenic mouse and engineered protease allergens to directly test TCR affinity’s role in Th cell differentiation. Our lab has identified an immunodominant Alp1 epitope (aa 194-202) and developed a functional peptide- MHCII tetramer. We also created a transgenic mouse expressing tagged-MHCII in dendritic cells, enabling in vivo epitope discovery. With these tools, we will achieve the following aims: Aim 1: Define the relationship between TCR affinity and Th2/Th17 fate in a polyclonal response. Aim 2: Directly test the causal role of TCR affinity in Th2/Th17 differentiation. This study will advance allergy and immunology research by overcoming technical barriers in epitope discovery and immunodominance. Our transgenic models, cytokine reporters, and tetramer technology will provide a framework for understanding allergen-driven Th cell responses, with implications for new diagnostic and therapeutic strategies in allergic diseases.

Up to $421K

2028-03-31

health research

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

Identification of Ancient Antiviral Defenses Using Viral Ubiquitination Modulators

open

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Arthropod-borne viruses or “arboviruses” are insect-transmitted viral pathogens that pose a significant threat to human and animal health worldwide. However, we still lack effective therapeutics to combat most arbovirus infections. A deeper understanding of the conserved innate immune mechanisms that restrict arbovirus replication in insect and mammalian hosts may reveal strategies for preventing or treating arboviral disease. Thus, we sought to develop an innovative, yet simplistic, approach to identify conserved antiviral host factors affecting arbovirus replication that, at the same time, inherently provides insight into virally-encoded strategies that evade these host defenses. Here, we propose to use a novel arbovirus "rescue" assay wherein candidate immune evasion proteins (IEPs) encoded by unrelated mammalian viruses can be transiently expressed in insect cells and assayed for their ability to sensitize insect cells to arbovirus infection. The rationale behind this approach is that mammalian virus-encoded IEPs that enhance arbovirus replication in insect cells likely do so because they happen to inhibit key antiviral factors/pathways that are conserved between insect and mammalian hosts. One can then use these IEPs as “tools” to identify and characterize the conserved immunity factors these IEPs target. Thus, this screening methodology provides a mechanism to both identify novel IEPs encoded by mammalian pathogens and the functionally-relevant components of the eukaryotic innate immune response these IEPs inhibit. To discover IEPs that promote arbovirus replication in insect cells, we will screen an expression library encoding 93 “viral ubiquitination modulators (VUMs)” derived from 33 different mammalian viruses. VUMs are virally-encoded proteins that inhibit, usurp, and/or re-direct the host ubiquitination system to promote viral replication. Given that ubiquitination is a key post-translational modification that alters the stability and/or function of cellular proteins, VUMs often hijack the ubiquitination system to inhibit or degrade host proteins that are critical for antiviral defense. We hypothesize that some VUMs may target cellular antiviral factors that are conserved between insect and mammalian hosts and that are critical for restricting arboviruses. Indeed, our initial screens identified VUMs from disparate mammalian viruses that enhance arbovirus replication in insect cells. These results, along with our prior successes in using this system to identify novel IEPs and conserved antiviral responses (Rex et al., 2024, Nat. Microbiol.; Embry et al., 2024, PLoS Pathog.), suggest that we can use VUMs as tools to both inhibit, and discover, conserved antiviral immunity factors. Our study will: 1) Identify VUMs encoded by mammalian viruses that promote arbovirus replication in insect cells; 2) Identify conserved insect and mammalian factors interacting with VUM “hits” from our arbovirus rescue assays; and 3) Identify the conserved host factors interacting with VUMs that normally block arbovirus replication. Our long-term goal is to use this system to define the critical eukaryotic innate immune mechanisms that restrict arbovirus replication.

Up to $249K

2028-03-31

health research

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

Identification of approved drugs for BDNF insufficiency

open

NINDS - National Institute of Neurological Disorders and Stroke

Summary Brain-derived neurotrophic factor (BDNF) exerts its biological actions mainly through TrkB receptors. BDNF-TrkB signaling plays a crucial role in regulating the development and function of neural circuits. BDNF impacts nearly all stages of neural circuit development by promoting neuronal differentiation, axonal and dendritic growth, synapse formation and maturation, and refinement of neuronal connection. In mature neural circuits, BDNF enhances the efficacy of glutamatergic synapses but weaken the efficacy of GABAergic synapses by changing either activity-induced presynaptic transmitter release or postsynaptic responses. BDNF can also alter the capacity of synapses to express activity-induced long-term potentiation or long-term depression. More recently, substantial evidence has established a crucial role for BDNF in the control of energy balance. Mutations in either the Bdnf gene or the Ntrk2 gene that encodes TrkB cause severe obesity in mice and humans. Given these important roles of BDNF in the nervous system, it is not surprising that hyperphagia, severe obesity, intellectual disability, autism, and impaired nociception are observed in approximately 50% of people with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) syndrome, due to contiguous gene deletion extended into the BDNF gene, leading to BDNF haploinsufficiency. Thus, a drug that can increase BDNF expression has potentials for treating a subset of WAGR patients with BDNF insufficiency. We have generated a new mouse strain, BdnfNLuc, in which the DNA sequence encoding the highly active nano luciferase (NLuc) was inserted into the Bdnf locus immediately before the stop codon. By using cortical and hippocampal neurons from BdnfNLuc/+ embryos, we developed a highly sensitive and highly reproducible phenotypic assay for detection of BDNF expression in 384-well plates. We had successfully scaled up the assay and performed a pilot screen of the 1280-compound library of pharmacologically active compounds (LOPAC). These results indicate that our assay is ready for high throughput screening. We propose to screen a collection of approved drugs (~4100 compounds) to identify a drug that can increase BDNF expression in both mouse and human neurons in vitro as well as in mice in vivo. We will then determine if administration of the drug can correct several phenotypes observed in Bdnf+/- mice. Findings from these studies could be quickly translated to therapeutic applications for patients with BDNF insufficiency, including the subset of WAGR patients with BDNF deletion. Finally, to find novel chemical structures that may be better suited or more active in increasing BDNF expression, we will screen 20,000 CNS-focused compounds. We aim to find 1-2 lead compounds that can increase BDNF expression in cultured mouse and human neurons and in the mouse brain for future drug development.

Up to $424K

2031-02-28

health research

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

Identification of attenuating mutations in the envelope protein for the rational design of a candidate West Nile live-attenuated vaccine.

open

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary. The Orthoflavivirus genus in the family Flaviviridae contains several pathogenic arthropod- borne viruses, including West Nile virus (WNV) a mosquito-borne orthoflavivirus in the Japanese encephalitis (JE) sero-/genetic complex. The United States has reported >27,000 cases of WN neuroinvasive disease and >2,900 deaths since the introduction of WNV in 1999, making WN vaccine development a public health priority. Live-attenuated vaccines (LAVs) have successfully controlled mosquito-borne orthoflaviviruses, yellow fever and JE virus. Thus, development of a WN LAV is realistic. The development of an attenuation strategy built on multigenic mutations will support the rational design of a candidate WN LAV. To date, attenuating mutations have been identified in 3 virally encoded nonstructural (NS) proteins, but few attenuating mutations have been identified in the structural proteins, including the envelope (E) protein. Because the E protein not only mediates the binding and membrane fusion with the cell but is the primary target of neutralizing antibodies, a correlate of protection for WNV, mutations in the E protein of a candidate WN LAV must not compromise immunogenicity. This project aims to identify attenuating mutations in the E protein to be incorporated into the rational design of a candidate WN LAV alongside those in the NS proteins. The E protein is a class II fusion protein that forms a fusogenic trimer to mediate the membrane fusion process, which is the fundamental viral entry mechanism and is crucial for WNV neurotropism in vertebrate hosts and transmission by mosquitoes. The formation of the E protein trimer requires the rearrangement of its 3 domains (EDI, EDII, and EDIII). The 4 motifs between the EDI and EDII exert a hinge effect for the EDI-EDII interdomain movement to initiate the formation of the E protein trimer, hence the name EDI-EDII hinge region. Site-directed mutagenesis of the EDI-EDII hinge region in WNV strain NY99 rescued from an infectious clone (WNV-NY99ic) demonstrated that the E-A54 and E-Y201 residues each control the formation of the E protein trimer. WNV-NY99ic retained 13 alternative amino acid (aa) substitutions of the respective residues. The E-A54I and E-Y201P mutations each fully attenuated the neuroinvasive phenotype of WNV-NY99ic in outbred Swiss mice, while retaining induction of serum neutralizing antibodies. Built on the attenuated phenotype and immunogenicity of the E-A54I and E-Y201P mutants, the central hypothesis is that impairment of the membrane fusion process by mutations of either the E-A54 residue or the E-Y201 residue will attenuate murine neurotropism and mosquito transmission of WNV- NY99ic without compromising antibody-mediated neutralization. This project will select the lead mutation of the respective residues based on 1) attenuation of the mouse neuroinvasive phenotype and neurovirulence, 2) impairment of transmission by Culex species mosquitoes that are WN vectors, and 3) immunogenicity that elicits serum neutralizing antibody responses conferring passive protection to identify the E protein mutation(s) suited for the rational design of a candidate WN LAV.

Up to $421K

2031-05-31

health research

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

Identification of axon length-dependent gene expression programs

open

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors. However, our understanding of this specific vulnerability is limited. We hypothesize that axon length represents a molecularly definable source of vulnerability common to many NDDs, and indeed we found that Drosophila neurons with long axons are intrinsically more vulnerable to degeneration than same-type neurons with short axons. In preliminary studies we have defined molecular markers whose expression covaries with axon length and have developed a robust platform for single cell transcriptomics, in vivo analysis of axon length-dependent effects on synaptic connectivity, and behavioral diagnostics of length-dependent axon degeneration. We will leverage the significant advantages of this system to systematically identify genes whose levels covary with axon length and assay functions for these genes in length-dependent axon degeneration. Altogether, our studies will provide fundamental insight into mechanisms of axon length-dependency in degeneration, addressing a fundamental gap in our understanding of NDDs.

Up to $428K

2028-04-30

health research

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

Identification of bacterial isolates and communities that influence male life history traits and mating success among genetically diverse Ae. aegypti mosquitoes

open

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Mosquito population control is a primary means to prevent mosquito-borne disease worldwide, and many novel approaches to population control involve traditional or modified versions of Sterile Insect Technique (SIT). One thing these methods all have in common is the need to rear healthy adult male mosquitoes en masse. These males are then released to mate with wild females, which they sterilize and prevent from producing offspring, thus causing a decline in mosquito population size. Males used for SIT must be able to compete for mates in a field setting for the method to be successful. Moreover, modifications to rearing that improve mass production of males, increase their competitive ability, or increase the duration of their field efficacy, will improve the success and reduce the cost of these programs. The microbes found in larval development water and within the mosquito body have been shown to impact multiple traits that are relevant to SIT and mass rearing, including pupation time and body size. Here, we propose to comprehensively determine the impact of the microbiota on adult male life history traits relevant to the success of SIT. We will experimentally colonize mosquitoes with multiple candidate bacterial communities and determine the impact of different communities on male longevity, flight capacity, mating success, sperm quantity, and ability to induce refractoriness to re-mating in female mosquitoes. Additionally, we will assess the impacts of these colonies on male traits in semi-field conditions We will also assess the impact of the microbiota on male life history traits across a genetically differentiated group of mosquito strains. Finally, we will assess the role of B vitamins as a mechanistic determinant of male mosquito-microbe interactions. This work will reveal, for the first time, the comprehensive impact of the microbiota on traits relevant to the success of SIT. Additionally, it has the potential to reveal specific bacterial treatments that could be used to improve male quality in mass rearing operations and the extent to which effects of the microbiota may differ depending on mosquito genetic background. Each component of the proposal is critical to understanding mosquito-microbe interactions in male mosquitoes and will provide key foundational knowledge as well as potentially actionable findings to improve the success of SIT.

Up to $526K

2031-03-31

health research

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

Identification of candidate genomic regulatory elements involved in oral clefts

open

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary/Abstract Disturbances in the molecular pathways that control lip and palate development during embryogenesis can lead to oral clefts, but knowledge of the regulatory interactions involved in modulating the expression of genes in these pathways remains limited. Because enhancers are critical to the spatiotemporal regulation of gene expression during embryogenesis, those that are active in craniofacial tissues during lip and palate development are likely to control the expression of genes relevant to oral clefts. The overall goal of the proposed research is to identify interactions between enhancers, transcription factors that bind the enhancers, and target genes of the enhancers in lip and palate development and oral clefts. Aim 1 is to identify the subset of enhancers that drive gene expression overall in human embryonic palatal mesenchyme cells. The transcription factors with binding site motifs that are enriched in the enhancers will be identified, and binding of the transcription factors within the enhancers in human embryonic palatal mesenchyme cells will be confirmed using assays of chromatin immunoprecipitation followed by sequencing. Aim 2 is to identify enhancers that regulate transcription specifically within human embryonic palatal mesenchyme cells, because such enhancers are more likely to be involved in craniofacial-specific processes during development. Enhancers that can distinguish between human embryonic palatal mesenchyme cells and other types of tissues and cells will be considered palate-specific enhancers. The palate specificity of a subset of the enhancers will be confirmed using in vitro assays.

Up to $385K

2027-08-13

health research

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

Identification of Causative Variants in Autoimmune Risk Loci

open

NIH

Genome-wide Association Studies (GWAS) have emerged as a transformative approach in deciphering the complex genetic underpinnings of autoimmune diseases. Autoimmunity arises from intricate interactions between genetic susceptibility and environmental triggers. A remarkable aspect of GWAS findings is the identification of genetic variants that are associated with multiple autoimmune diseases. These shared variants suggest overlapping pathways and mechanisms underlying these diseases. For example, the HLA gene region is consistently implicated in multiple diseases such as type 1 diabetes, rheumatoid arthritis, lupus, and celiac disease. Using the Million Veterans Project (MVP) data, we created a cohort of Veterans with at least two reports of any one of 71 different autoimmune phenotypes (n= 83156) and a cohort of controls (n=335647) that did not have any autoimmune phenotypes and performed a GWAS to identify common autoimmune risk loci. Twenty-six regions of the genome were identified with variants surpassing genome wide significance (5x10-8). The largest region identified spanned the HLA region on chr 6 from 29.5 to 32.7 Mb. In the non-HLA loci, linkage disequilibrium (LD) pruning identified 44 independent associations. Thirty-one of these associations have been identified in previous autoimmune GWAS, showing the robustness of our results. Interestingly, the 13 remaining associations have not been previously identified in the GWAS catalog for an autoimmune disorder. These results suggest that these 13 associations are novel associations and provide new insight into the genetic mechanisms of autoimmune risk. GWASs only identify associations between variants and disease, they do not identify which of the associated variants cause increased risk of disease or identify which gene(s) are involved in increased risk. To fully understand the genetic mechanisms involved, we must identify the variants that impact cellular biology in an allele specific manner and which genes are impacted. The goal of this project will focus on these two specific issues. Most associations detected in autoimmunity, and in our results, are in non-protein coding regions of the genome, which suggests that disruption of gene regulation is the major mechanism increasing risk of disease. To identify all potential “causative” variants, we have used LD expansion to identify 2108 variants with an r2>0.4 with each of the non-HLA independent associations. We propose using a Massively Parallel Reporter Assay (MPRA) to screen these variants in multiple cell types relevant to autoimmunity with and without stimulation. From these experiments we will be able to determine not only which of the variants have the capacity to alter gene expression, but also the type of cells showing allele specific expression and the relevant environmental conditions that alter gene expression in an allele specific manner. While these variants would be strong candidates to be causative, the MPRA does not identify which genes the variants target. To address this issue, we propose applying a combination of bioinformatic tools and Perturb-seq techniques using either dCAS9-KRAB (suppressor) or dCAS9-PVR (activator), variant targeted gRNA’s and RNAseq to identify the genes that are regulated by our top candidate autoimmune risk variants. Four variants were identified that alter the amino acid sequence of proteins. Functional assays will be performed to determine the effect of the risk allele on protein function. Combined, these data sets will provide a deeper understanding of the genetic mechanisms that promote increased risk of autoimmunity and could lead to the design of potential therapeutics. In addition, by examining the genetic associations common to multiple autoimmune diseases, we will be able to identify Veterans that have the greatest risk of developing autoimmune disorders and potentially identify which disease will develop. This will allow earlier clinical identification of disease as well as earlier intervention which can result in better outcomes.

2029-12-31

health research

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

Identification of cell type-specific insulin responsive quantitative trait loci in human skeletal muscle

open

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Type 2 diabetes (T2D) is a complex polygenic disease that results from a multifactorial interaction of environ- ment and lifestyle factors. The estimated heritability of T2D ranges from 30 – 70%, and over 1,000 independ- ent genetic loci have been associated with T2D. However, most loci map to non-coding regions of the genome, leading to challenges elucidating their functional significance. Non-coding genetic variation has the most proxi- mal effect on the molecules bound to DNA (epigenome), which in turn influences the expression of target genes (transcriptome) in a cell-type and context specific manner. A powerful approach to mechanistically link these layers is through identification of quantitative trait loci (QTL) for epigenomic modalities such as chromatin accessibility QTL (caQTL) and gene expression quantitative trait loci (eQTL), followed by testing whether dis- ease associated loci underlie the molecular QTL. In the current study, we will identify cell type-specific and dy- namic molecular response QTLs (rQTLs) in humans in vivo that are relevant to skeletal muscle insulin re- sistance, a core pathophysiologic defect in T2D and related comorbidities. Skeletal muscle accounts for ap- proximately 80% of all glucose uptake in the postprandial state in humans. We and others have shown that skeletal muscle insulin resistance predates glucose intolerance in normoglycemic individuals at high risk of de- veloping T2D, and is evident decades before β-cell failure and overt hyperglycemia develops. In preliminary studies sing single nuclei gene expression (snRNA-Seq) and Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-Seq), we have identified novel response eQTL (r-eQTL) and caQTL (r-caQTL) that are acutely sensitive to insulin during an hyperinsulinemic-euglycemic clamp. These loci include distinct insulin- responsive rQTLs in parenchymal and non-parenchymal cells, including in type 1 and type 2 muscle fiber cells and fibro-adipogenic progenitor cells (FAPs), which are important regulators of muscle homeostasis and regen- eration. In the current application, we build on our pilot data and test the hypothesis that targeted interventional approaches in humans, combined with modern genomic techniques, will uncover novel mechanisms linking common genetic variation to relevant pathophysiological pathways in T2D. In Specific Aim 1, we will Identify cell-type specific insulin responsive molecular QTLs in human skeletal muscle using by collecting muscle biop- sies before and after a hyperinsulinemic-euglycemic insulin clamp (80 mU/m2 ⋅ min). In Specific Aim 2, we will determine acute skeletal muscle insulin resistance molecular QTLs in humans: by using an acute lipotoxicity model of insulin resistance. These studies leverage our unique combined expertise and existing productive col- laboration to integrate whole-body physiological approaches in humans with cutting edge molecular and ge- nomics techniques to reveal dynamic response QTLs that connect disease-relevant metabolic pathways to ge- netic variation.

Up to $708K

2031-03-31

health research

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

Identification of cellular functions involved in Hepatitis B Virus infection via a novel RNA sensing and editing dependent reporter system

open

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Hepatitis B virus (HBV) chronically infects 254 million people worldwide and accounts for 1.1 million deaths per year due to cirrhosis and liver cancer. Finding a cure for this disease is urgently needed, which requires a more thorough understanding of the key molecular events driving establishment and persistence of HBV infections. Thus far, identification of HBV-hepatocyte interactions is mostly achieved through conventional focused screens or one-gene-at-a-time approaches. Due to the overlapping feature of the HBV genome, unbiased genetic screens by reporter HBV viruses allowing phenotypic selection have not been possible. To overcome this challenge, our lab recently developed an RNA sensing and editing based HBV reporter without modifying the viral genome, but instead introduces reporter genes containing stop codon (UAG) that becomes contingently translatable upon precise RNA editing (UIG, translate as UGG) guided by the complementary HBV RNA sequences. Our preliminary data demonstrated that it functions in an HBV RNA-sensing and ADAR RNA-editing dependent manner, and an HBV puromycin reporter allows for HBV infection-dependent survival of cells following puromycin treatment. Therefore, this novel cell culture-based HBV infection reporter system permits unbiased genome- wide screens using sgRNA, cDNA and chemical libraries, etc. The purpose of this R21 grant application entitled “Identification of cellular functions involved in Hepatitis B Virus infection via a novel RNA sensing and editing dependent reporter system” is to further validate the newly developed system and to identify still elusive host factors required for early steps in HBV infection and for amplification of the viral genome. We anticipate that our novel HBV infection reporter assay will allow us to perform the most comprehensive loss-of-function and gain-of-function screens in tissue culture cells to date, and most likely reveal new knowledge on virus-host interactions critical for the HBV life cycle, which will in a short-term enhance our understanding of HBV replication and advance current HBV model systems, and in a long-term, provide potential novel targets for antiviral therapies to combat chronic HBV infections.

Up to $196K

2028-01-31

health research

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

Identification of chromatin regulators required for enhancer hijacking in cancer genomes

open

NCI - National Cancer Institute

PROJECT SUMMARY Genomic instability is a hallmark of cancer, and many human cancers display structural variants such as translocations, inversions, deletions, and duplications. These structural variants can promote cancer development through various mechanisms, including "enhancer hijacking," where non-cognate enhancers aberrantly activate oncogenes. This phenomenon has recently been identified in a broad range of cancers, suggesting that enhancer hijacking is an underappreciated mechanism of oncogene dysregulation across many cancer types. Enhancer hijacking is characterized by the regulation of genes by ectopic enhancers, suggesting that the genes that are subject to enhancer hijacking are capable of being regulated promiscuously by enhancers they have never otherwise seen before in evolution. However, whether there are mechanisms that facilitate such promiscuous gene regulation events is unclear. As enhancer hijacking is a cancer specific phenomenon, understanding the mechanisms that drive enhancer hijacking may help identify potential future therapeutic targets that would be effective in diverse cancers. Therefore, there is an urgent need to better understand the processes that contribute to enhancer hijacking in cancer genomes. In preliminary data supporting this proposal, CRISPR/Cas9 genome wide knock-out screens using engineered enhancer hijacking reporters identified two paralogs, STAG1 and STAG2, as have opposing effects in regulating enhancer hijacking. STAG1 and STAG2 are mutually exclusive components of the cohesin complex, and in the CRISPR/Cas9 screens, STAG1 is critical for promoting enhancer hijacking, while STAG2 represses it. Given that STAG2 is frequently inactivated in cancers, our overarching hypothesis is that the balance of STAG1 and STAG2 containing cohesin complexes regulates ectopic gene expression in enhancer hijacking. This proposal aims to investigate the mechanisms of STAG1 and STAG2 regulation of enhancer hijacking and to identify general and lineage-specific regulators of enhancer hijacking. Specific Aim 1 will determine how STAG1 and STAG2 influence the stability of 3D chromatin interactions between hijacked enhancers and oncogenes. Specific Aim 2 will explore the impact of STAG1 and STAG2 on enhancer hijacking of different genes across diverse lineages in cell lines and patient-derived organoids. Specific Aim 3 will develop scalable genome-wide methods to identify additional regulators of enhancer hijacking, employing Perturb-seq-based approaches. The successful completion of these aims will enhance our understanding of enhancer hijacking in cancer genomes, offering insights into potential therapeutic strategies for cancers driven by these events.

Up to $795K

2031-04-30

health research

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

Identification of Drug-related and Formulation-Related Factors that Result in Alcohol Dose Dumping of Modified Release Oral Drug Products (U01) Clinical Trial Not Allowed

upcoming

Food and Drug Administration

Identification of Drug-related and Formulation-Related Factors that Result in Alcohol Dose Dumping of Modified Release Oral Drug Products (U01) Clinical Trial Not Allowed

Rolling

general

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

Identification of Drug-related and Formulation-Related Factors that Result in Alcohol Dose Dumping of Modified Release Oral Drug Products (U01) Clinical Trial Not Allowed

upcoming

Food and Drug Administration

Modified release (MR) oral drug products are considered to have a high risk for alcohol dose dumping (ADD) because they contain large quantities of drug(s), designed to release over a prolonged period of time. Accidental exposure of these products to alcohol can result in the relatively rapid release of large quantities of drug with severe side effects, including death. To mitigate this risk, the FDA recommends conducting an in vitro alcohol dose dumping assessment in 0%, 5%, 20%, and 40% alcoholic dissolution media for all prospective generic versions of MR oral drug products. To date, ADD assessments have not been harmonized globally. For instance, the U.S. FDA recommends testing up to 40% alcoholic media while the European Medicines Agency recommends testing up to 20% alcoholic media. This type of difference can present a challenge for formulators designing products for multiple markets, as historical data has shown release from MR oral products do not always follow a linear response (either increasing or decreasing) to increasing alcohol concentrations. In addition, interpretation of an ADD assessment may be limited by the inability of the test to predict in vivo behavior.  The purpose of this research is to develop tools that 1) facilitate the development of MR generic drug products that have a low potential for ADD, 2) support regulatory decision making during the assessment of such products, and 3) provide evidence that enables FDA to develop more specific recommendations for efficiently demonstrating a low or comparative potential of alcohol dose dumping for MR oral drug products containing high risk drugs.

$250K

Rolling

consumer_protectionAgriculturefood_and_nutrition+1

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