Grants

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to leverage NICHD clinical research Network infrastructure relevant to infants, children, women, pregnant and lactating women, and persons with disabilities to conduct innovative, multisite, investigator-initiated clinical trials and observational studies. This NOFO will utilize a bi-phasic (UG3/UH3), milestone-driven mechanism consisting of a start-up phase (UG3) and a full enrollment and clinical trial implementation phase (UH3). Applications submitted in response to this NOFO must address specific aims and milestones for both the UG3 and UH3 phases. A UG3 project (phase I) that meets its milestones will be administratively considered by NICHD and prioritized for transition to the UH3 award (phase II). This NOFO provides an opportunity to leverage NICHD clinical research Network infrastructure as a platform for investigator-initiated innovative hypotheses by any investigator in the extramural community. Applications must be submitted as investigator-initiated, multi-Project Director/Principal Investigator (PD/PI) grant applications in conjunction with the respective NICHD-supported Network Data Coordinating Center (DCC), or equivalent as determined by the NICHD.

Up to $6.3M

2027-11-15

Healthhealthcare

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Leveraging Nursing Research to Advance Healthy School Environments for All

upcoming

National Institutes of Health

Leveraging Nursing Research to Advance Healthy School Environments for All

researchHealthEnvironmental

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Leveraging phenazine cycling to understand maintenance metabolism in Pseudomonas aeruginosa

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Antibiotic tolerance hinders the treatment of chronic infections of diverse types, contributing to poor patient outcomes and burdening the healthcare system. Underpinning the failure of many conventional drugs to eradicate opportunistic pathogens in these contexts is that they target machinery needed to support rapid growth, yet cells in chronic infections typically exist as slow- or non-growing multicellular aggregates (biofilms). Cells in the biofilm interior experience anoxia yet maintain a low level of metabolic activity. How these cells conserve energy and how they spend energy economically is poorly understood, in part because we have lacked a good experimental system through which to quantify and study maintenance physiology. But thanks to recent technological advances, we now have one. Pseudomonas aeruginosa is an opportunistic pathogen found in chronic infections of the foot (diabetic ulcers), ear and lung (cystic fibrosis) and is a model biofilm-forming bacterium that is notoriously difficult to eradicate with standard antibiotics. A defining aspect of P. aeruginosa is its ability to make phenazines, redox-active pigments that promote biofilm development and energy conservation under anoxia, shifting it into a physiological state that is highly antibiotic tolerant. Phenazines are extracellular electron shuttles that transfer electrons from the cell interior (thereby promoting intracellular redox-balance and permitting ATP to be generated) to the exterior (where they pass electrons to an extracellular oxidant). When the extracellular oxidant is an electrode, the current measured at the electrode reflects the cellular metabolic rate. Using a novel 96-well electrode system, we have demonstrated that we can study phenazine maintenance metabolism under anoxic conditions in high-throughput. The mass-specific power output of this non-growth metabolism is amongst the lowest ever recorded for any organism. We now seek to leverage the unique properties of this phenazine-cycling platform to gain a mechanistic understanding of how maintenance physiology is achieved. What limits the metabolic rate generated by cycling different phenazines over a physiologically relevant concentration range? How do cells economize their anabolic expenditures in a way that harmonizes with their low-power output? Aim 1 will explore what sets the energetic threshold for cellular viability, and how the physicochemical properties of phenazines impact how they are processed by the cell. Aim 2 will test the hypothesis that cells engaged in maintenance metabolism rely on anabolic recycling to economically spend their low energy resources; we predict that many of the key anabolic strategies needed for phenazine maintenance metabolism overlap those needed to survive other growth- arrested, phenazine-independent states, whereas others are specific for phenazine maintenance metabolism. The proposed work will provide us with new insights into the physiology of maintenance, an underexplored yet pervasive biological state, pointing us in the direction of new targets for drug development to treat devastating chronic infections.

Up to $711K

2031-03-31

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Leveraging radiation to sensitize breast cancers to T-DXd

NCI - National Cancer Institute

PROJECT SUMMARY While HER2+ breast cancers (BCs) can be therapeutically targeted via HER2-targeted agents, response depends on HER2 status; tumors with residual HER2 expression (HER2-low) do not respond. HER2-low status have been described in triple negative (TNBC) and HR+ BCs, and includes primary tumors, metastases, and circulating tumor cells (CTCs). Recently, patient benefit has expanded to HER2-low tumors with the development of HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd), which suggest that the presence of a small reservoir of HER2+ cells is therapeutically actionable. This is of upmost importance, considering an estimated 50% of all diagnosed BCs are actually HER2-low. CTCs isolated and cultured from HER2-, metastatic HR+ and TNBC patients can divide to produce HER2+ cells with as few as 3 population doublings, without the acquisition of genomic alterations that activate HER2. Similar results were obtained from HER2+ CTCs, which can yield HER2- daughter cells with similar division kinetics. These results demonstrate HER2 expression is plastic and suggest that HER2- and HER2-low BCs may respond to T-DXd at least in part because of the maintenance of a heterogeneous HER2 state. Thus, designing treatment strategies to maximize therapeutic benefit to T-DXd in the HER2-/low patient population remains an unmet clinical need. We and others have found HER2 plasticity in cell culture models and CTCs derived from HER2- BC. We recently observed that ionizing radiation (IR) increases HER2 expression and HER2 heterogeneity in HER2- BC models. We also find that IR increases cell death when paired when T-DXd in models of HER2- BC. Taken together, we hypothesize that IR sensitizes models of HER2- and HER2-low BC to the HER2- targeted ADC T-DXd. To test this hypothesis, we will employ established cell culture and CTC models of heterogeneous HER2- and HER2-low BCs. We will first determine the extent to which IR sensitizes these models to T-DXd. Transcriptomics post-IR will provide insight into how IR remodels gene expression to support HER2 plasticity. Using these in vitro models, we will test whether IR sensitizes BCs to T-DXd. These studies will inform which patient populations may benefit from combined IR and T-DXd based on HER2 expression. We will then pivot and investigate whether IR sensitizes in vivo models of HER2-/low BC to T-DXd, by examining whether IR coupled with T-DXd reduces tumorigenesis and extends survival. Correlative studies will be performed to examine the duration of elevated intratumoral HER2 expression and heterogeneity to define the optimal time window for IR prior to T-DXd. We will then examine whether IR can resensitize T-DXd-resistant tumor models to T-DXd. These studies will provide insight into the timelines and context(s) that IR can be used to stimulate a therapeutic response to T-DXd, which could be leveraged for future investigator-initiated clinical trials.

Up to $402K

2028-03-31

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Leveraging Reconsolidation-Updating to Change the Feelings of Memories

NIMH - National Institute of Mental Health

Project Summary Retrieving memories of emotional events can result in (re)experiencing subjective feelings. Importantly, the feelings elicited by memories can influence current emotional states. For example, recalling positive events can both reduce current negative affect and diminish acute physiological stress responses. Similarly, recalling negative events can lead to current negative feelings and moods. The feelings of memories have also been linked to subjective clinical symptoms. The frequency of reported negative intrusive memories is related to both the severity of clinical symptoms in a treatment-seeking population and the likelihood of reporting clinical symptoms in a typical undergraduate population. Because of the impact of the feelings elicited by memories on current emotional health and well-being, understanding how the feelings of memories might change over time has to potential to suggest novel treatment innovations. The proposed research investigates techniques intended to alter the feelings associated with memories. Specifically, we take advantage of reactivation induced memory change (RIMC) to determine factors that may reduce or enhance the negative feelings elicited by memories. To explore how RIMC can modify the feelings of memories, the proposed studies examine three kinds of memories and two techniques to alter subjective feelings. There are three specific aims: Aim 1 examines whether RIMC interventions can be used to diminish the negative feelings elicited by memories for negative events. Aim 2 examines how RIMC mechanisms may enhance the negative feelings elicited by memories for negative events. Aim 3 examines if RIMC techniques can infuse negative feelings into previously neutral memories. In addition to examining the feelings elicited by memories, we will also examine the impact of these interventions on changes in physiological stress reactions and the pattern of blood oxygen level dependent (BOLD) signals when retrieving these memories. It is hypothesized interventions following the reactivation of a previous acquired memory will change the later expression of subjective feelings elicited by that memory more than interventions without reactivation. It is further hypothesized that the reactivation of a previously acquired negative memory without any intervention will result in strengthening the memory and enhancing negative feelings. We expect these changes will also be reflected in physiological stress reactions and BOLD response patterns during retrieval.

Up to $784K

2031-04-30

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Leveraging Social Media Influencers to Improve Anal Cancer Prevention

NCI - National Cancer Institute

Project Summary Although anal cancer is rare compared to other gastrointestinal cancers, its incidence and mortality have steadily increased over the past several decades. These trends disproportionately affect individuals with certain immunologic and behavioral risk factors, placing specific populations at markedly higher risk. Recent guidelines recommend targeted anal cancer screening based on individual risk, including annual digital anorectal exams (DARE), anal cytology with or without high-risk HPV testing, and follow-up with high- resolution anoscopy (HRA) for abnormal results. Despite effective prevention strategies, awareness remains low, stigma persists, and utilization of preventive services is uneven. This study will develop and evaluate a novel, peer-led social media intervention to promote anal cancer prevention in high-risk populations. Grounded in the Information-Motivation-Behavioral Skills (IMB) model, the Popular Opinion Leader (POL) model, and the SMILE Framework (“Social Media for Implementing Evidence”), the intervention will be co-designed with a community advisory board and delivered by trained influencers. The specific aims are: (1) Co-design and evaluate a peer-led social media influencer training program using adapted materials from a previously tested intervention and an evidence-based anal cancer prevention toolkit; and (2) Assess the feasibility and short- term impact of the resulting social media campaign. Using a mixed methods approach—including engagement metrics, social network analysis, qualitative interviews, and quasi-experimental methods—this study will generate essential data on the feasibility, acceptability, and potential impact of this scalable intervention. The long-term goal is to inform national communication strategies to reduce disparities in anal cancer.

Up to $408K

2028-05-31

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Leveraging targeted cell therapy to promote heart transplant tolerance through topical application of a nanoparticle infused polymeric membrane

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary/Abstract According to the organ procurement and transplantation network, every year more than 40,000 organs are transplanted in the United States; from those organs, over 4500 are related to heart transplantation. Two main limitations that exist with heart transplantation are #1: the waitlist continues to increase whereas the number of donor hearts has not changed. Unfortunately, over 60% of potential donor hearts are discarded. This leads to significant waitlist mortality and an unmet and growing need. #2: if fortunate to be transplanted, the recipient is subjected to lifelong immunosuppression leading to significant burden of infections, malignancies, and end-organ dysfunction while still experiencing a high risk of acute rejection (40% of recipients within the first year) and chronic rejection (over 50% of patients by year 5). This funding opportunity leverages a unique window of therapeutic opportunity by directly targeting the donor heart PRIOR to transplant when the heart is directly accessible. Using material science, nanotechnology and drug delivery, the investigators propose to engineer a novel delivery technology that can be applied ex vivo to the donor organ after procurement and prior to transplantation to improve organ transplantation. The proposed technology consists of a polymeric sheet that contains engineered nanoparticles (NPs). The NPs have a macrophage specific targeting peptide, a fluorescent marker for tracking, and a macrophage activation inhibitor in the core, to reduce pro-inflammatory signaling and recipient neutrophil and monocyte recruitment. Although heart transplantation will be investigated in this grant, this technology may be applicable to other organs to enable a broader use of previously discarded organs and to improve post-transplant outcomes. The goal of this R21 Trailblazer award is to develop an “off-the-shelf” therapy that can exist at every organ procurement organization (OPO) and that can be easily and reliably deployed to donor organs at the time of procurement. The invention will become part of the OPOs procurement pipeline. Importantly, we aim to create a workflow that will improve outcomes and allow increased utilization of “marginal” organs. This technology could be immediately translatable and can be modified to deliver therapies in a personalized medicine approach or can be applicable to other organs.

Up to $624K

2028-03-31

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Leveraging Technology to Promote Physical Activity in Patients with Prediabetes: Movement over Virtual Reality (MoVR)

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Physical inactivity is a significant public health concern contributing to numerous chronic diseases including diabetes. Inactivity contributes to 1 in 10 premature deaths and inadequate levels of physical activity are associated with $117 billion in annual health care costs. The Diabetes Prevention Program Outcomes Study showed that continued physical activity over the 12-years post-DPP was independently associated with a long- term decreased risk of incident diabetes. Unfortunately, adherence remains low to the Diabetes Prevention Programs (DPP’s) recommended national guidelines of 150 minutes of moderate to vigorous exercise per week. Certain communities, such as those in under-resourced settings have demonstrated low retention rates in the DPP and are also less likely to achieve DPP weight loss outcomes. Virtual reality (VR) technology is an increasingly popular approach to promote physical activity and improve weight loss. However, VR technology has had limited reach in under-resourced settings due to gaps in digital health literacy, and lack of access to new forms of technology. For this R03, we propose to partner with community health workers (CHWs) to develop a digital literacy toolkit with best practices for administering health promoting digital technology and using VR in the safety-net clinic settings (aim 1). We will train 10 CHWs and conduct a longitudinal single arm feasibility study (aim 2) with 20 DPP clinic participants to explore if using VR exercise programs can promote physical activity among patients with prediabetes. Data from this study will inform a larger, fully powered RCT evaluating the effectiveness of VR technology in promoting physical activity and weight loss among patients with prediabetes. This research is distinct yet complementary to the research being conducted as part of the applicant’s K23. The K23 focuses on enhancing the nutritional component of the DPP. For this R03, we expand the applicants research focus to digital health interventions to enhance physical activity and engagement. This funding will support the applicants trajectory toward independence by fostering new collaborations in digital health intervention design and physical activity assessment, further strengthening her expertise in the area technology-driven behavior change interventions to prevent chronic disease and obesity.

Up to $125K

2028-01-31

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Leveraging the GTP Biosynthetic Pathway for Anti-Tumor Therapies

NCI - National Cancer Institute

PROJECT ABSTRACT/SUMMARY (From the Parent Grant) Invasion is one of the most detrimental features of all cancers, including breast cancer, as it allows cells to escape the primary site and form metastases at distant organs. Despite progress in prevention and early lesions detection, the mortality associated with metastatic breast cancer is still extremely high. This is especially true for patients presenting with triple negative breast cancer (TNBC, characterized by lack of expression of ER, PR, and Her2), which is the most aggressive and deadliest subtype of breast cancer and the one that so far lack specific targets for therapeutic intervention. Understanding the mechanisms that facilitate the invasion of tumor cells will enable us to design more efficient therapeutic strategies to prevent or reduce metastasis. Our group has established a fundamental connection between GTP metabolism and tumor cell invasiveness; we have unveiled GTP and its metabolic enzymes (GME) as key players in tumor progression and metastatic potential. We have developed unique fluorescent reporters for intracellular GTP that have allowed us to determine that, in live cells, the intracellular GTP distribution is not uniform, and brought forward the hypothesis that local concentration of GTP can influence GTP-dependent processes. In particular, we have previously shown that genetic or pharmacological modulation of the GTP metabolic pathway deeply affected the activation status of small GTPases of the RHO-family and, with it, the tumor cells' invasive capability. Thus, in Aim 1 we will explore a novel mechanism of G-proteins activation based on GME subcellular localization. Our preliminary results showed that the rate-limiting enzyme for GTP de novo production, inositol monophosphate dehydrogenase 2 (IMPDH2) enriches at cell membrane sites that are critical for cell migration and invasion (namely focal adhesion, FA, and invadopodia). The role of IMPDH2 at these sites is virtually uncharacterized. Thus, in Aim 2 we will assess the catalytic and structural role of IMPDH2 in FA and invadopodia formation, as well as in focal adhesion kinase (FAK)-directed oncogenic motility. The understanding of GTP metabolic enzymes transcriptional regulation is far from complete. Identification of transcriptional master regulators of the GTP biosynthetic pathway that could be pharmacologically targeted would offer a more efficient way of suppressing this pathway. Our preliminary results suggest that Kruppel-like factor 9 (KLF9) and aryl hydrocarbon receptor (AHR) play antagonistic roles in the transcriptional regulation of GTP metabolic enzymes, with KLF9 suppressing, whereas AHR inducing GTP production. Thus, in Aim 3 we will elucidate this regulation and explore pharmacological treatments to regulate the activity of these transcription factors.

Up to $397K

2028-04-30

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Leveraging the Trusted Role of Churches to Disseminate Research, Resources, and Support to Communities Disproportionately Affected by Dementia

NIA - National Institute on Aging

ABSTRACT Alzheimer’s and Related Dementias (ADRD) illnesses affect the African American population at alarming rates, with African Americans twice as likely to have ADRD than White Americans. The rate of diagnosis and prevalence of ADRD among African Americans are disproportionately increasing compared with White Americans, and prevalence rates for ADRD in the African American community are expected to rise as the population of older adults increases. Because of the centuries-old disadvantaged social history of African Americans, several unique stressors and vulnerabilities exist for African American families affected by ADRD. Experiences by these families underscore the need to identify relevant and relatable support, resources, and research opportunities. Despite the elevated risk of ADRD among African Americans, they remain significantly underrepresented in research, accounting for less than 4% of participants in clinical trials on ADRD. This underrepresentation emphasizes the urgent need to improve the communities’ exposure to active research opportunities. Additionally, limited awareness and education about ADRD in these communities often contribute to delayed diagnoses and missed opportunities for early intervention. This conference grant seeks to build upon the work of the Alter program (a national dementia-friendly program for African American churches) and leverage the trusted role of places of worship in African American communities to disseminate resources, support, and research by hosting a Dementia Summit. This Summit also addresses the critical issue recognized by NIH, which is keeping participants informed about research findings. Building upon the success of the 1st Dementia Summit, we propose to host the Summit annually and pursue the following aims: 1. To generate a meaningful Summit agenda each year to address ADRD-related concerns in the African American community; 2. To present the NIA strategic directions for research and disseminate ADRD-related research findings to faith leaders and the African American community; and 3. To actively disseminate research opportunities to faith leaders and the African American community. This proposal aligns with the NIA 2020-2025 Strategic Direction for Research and ADRD Research Milestone (13.X) to expand the use of and disseminate information about community-engaged ADRD care and caregiving research to the public, healthcare professionals, and the scientific community. This application has the potential to support research enterprises by addressing the challenges associated with effectively communicating health information and research to historically disadvantaged populations. This “one of a kind” Summit series provides a unique and timely opportunity to accelerate the application of evidence into the real world by bringing together researchers, health professionals, and the African American community to address ADRD-related concerns, improve care support for families, and create and sustain change.

Up to $50K

2030-11-30

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Leverhulme Trust Research Project Grants

Leverhulme Trust

Funds innovative and original research across all disciplines. 100M+ GBP annual grantmaking for pure curiosity-driven research.

$63K – $1.3M

researchhumanitiesscience+1

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Lewis and Clark Outdoor Recreation Youth Leaders

National Park Service

These multi-day experiences are designed and led by experienced outdoor educators and blend leadership skill development, hands-on field science and stewardship work, vocational skill development, and outdoor fundamentals in the classroom of National Park backcountry. The overarching goal is to provide a gateway for underserved youth to lifelong engagement with nature, stewardship, and community and to provide opportunities for personal, academic and professional growth.

$5K – $50K

rolling

natural resources

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Lexington Arts & Cultural Council — Project Grant

artsculturecommunity arts

Lexington Arts & Cultural Council

Project and operating grants for arts organizations and individual artists from Lexington Arts & Cultural Council. Supports visual, performing, literary, and media arts.

$2K – $50K

2026-12-31

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LG Foundation Expanded Programs

LG Foundation

Supports education, disability services, and community development across LG markets globally.

$10K – $500K

Educationdisability servicescommunity development

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LG Foundation Social Programs

LG Foundation

Supports welfare, education, and cultural programs through LG group's social responsibility.

$10K – $100K

welfareEducationculture

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LGBTQ - Artist Reception

Lavender Rights Project

The Lavender Rights Project will organize an artist reception to foster awareness of local lesbian, gay, bisexual, transgender, and queer artists and to highlight the importance of LGBTQ voices and experiences. It will be held on November 2, 2019 from 5 pm - 7 pm at Hillman City Collaboratory located at 5623 Rainier Ave S. The event will feature approximately thirty local artists, live entertainment, and resource-sharing.

Up to $5K

workforce

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

LGR4 in HIV-associated atherosclerosis

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is the second leading cause of non-AIDS-related mortality among people living with human immunodeficiency virus (HIV) (PLWH). The number of PLWH is continuously growing due to the viral suppression and life-extending benefits of available antiretroviral therapy (ART). However, the PLWH, even on effective ART with undetectable viral loads as well as elite HIV controllers who are ART-naïve and aviremic, exhibit sustained systemic inflammation and accelerated atherogenesis. Accumulated evidence suggests an important role of persistent macrophage (Mɸ) activation in controlled HIV- induced ASCVD and significant transcriptional heterogeneity among Mɸs within atherosclerotic lesions. Moreover, recent research indicates the involvement of Mɸ-derived extracellular vesicles in regulating neighboring non-HIV-infected Mɸ lipid metabolism, phenotype, foam cell formation, and atherogenesis. However, the precise molecular mechanisms linking controlled HIV infection to Mɸ activation and accelerated atherosclerosis remain poorly understood. Our preliminary experiments utilizing an experimental EcoHIV/NDK model, which mimics the physiological conditions of aviremic patients on effective ART, demonstrate increased atherosclerosis following infection. Furthermore, treatment with conditioned media (CM) collected from HIV- infected Mɸs induces expression of leucine-rich repeat-containing GPCR (LGR) 4 at both transcription and translational levels in non-infected murine primary Mɸs. Notably, Lgr4 upregulation induced by HIV-infected Mɸ CM was significantly higher than that promoted by oxidized LDL, a well-known atherogenic agent. Consistently, LGR4 levels are elevated in human atherosclerotic aortic segments compared with non-atherosclerotic tissue, and in atherosclerotic lesional Mɸs of EcoHIV-infected mice. Additionally, CM-treated Mɸs exhibit increased lipid accumulation (foam cell formation), augmented inflammation, and impaired efferocytosis. Nevertheless, the role of Mɸ Lgr4 in regulating HIV-regulated efferocytic potential, inflammation, and atherosclerosis is unknown. Based on these findings, we hypothesize that controlled HIV infection accelerates atherosclerosis via Mɸ LGR4- mediated signaling. This hypothesis will be tested with the two independent specific aims investigating whether (1) LGR4 mediates HIV-regulated Mɸ foam cell formation and efferocytic capacity, and (2) controlled HIV infection contributes to atherosclerosis via Mɸ LGR4-mediated signaling. Myeloid-cell specific Lgr4-deficient mice, an LGR4-signaling inhibitory peptide, unbiased single-cell RNA sequencing, and atherosclerotic lesion analysis will be employed to test the hypothesis. The successful completion of the proposed studies will provide novel insights into the mechanisms governing accelerated atherosclerosis in aviremic PLWH and identify novel therapeutic targets. To ensure the success of the proposed studies, we have assembled a multidisciplinary team comprising a collaborator and consultants, and are well-positioned to have all the required key resources.

Up to $234K

2028-05-01

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LHCGR signaling and responses during ovarian aging

NIH

Significance to VA: According to the Centers for Disease Control and Prevention, female infertility is a major health problem and affects about 6-10% percent (~7.5 million) of women at the reproductive age in the United States. The infertility rates for women Veterans is greater than the general population and is also greater than age-matched active duty women. This translates to well over 100,000 female Veterans. The issue of infertility in Veterans is recognized by the recently introduced Veterans Infertility Treatment Act of 2023 (HR 544) requiring VA to furnish infertility care to veterans and their partners. Ovarian senescence begins about age 30 and over the next 10 to 15 years is manifest by infertility and decreased steroid output. Although ovarian aging is a natural physiological process, cessation of ovarian function at midlife increases susceptibility to the development of co- morbidities, such as osteoporosis, which decrease quality of life and increases healthcare burden. There is currently no intervention for infertility or preventing/delaying the cessation of ovarian function, thus, highlighting an unmet need for novel approaches to tackle this problem. Innovation and impact: Innovation lies in the use of aging ovary models: granulosa cells recovered from young and older reproductive aged women and mice. Innovation lies in the context of understanding the actions of hCG in the aging ovary. Innovation is also derived from our ability to obtain and analyze granulosa cells from patients that have good or poor responses to IVF stimulation, which would facilitate patient phenotyping and personalized treatment plans. Innovation lies in the application of state-of-the-art multi-omics approaches, RNA-seq, CUT&RUN, and ATAC-seq, on matched samples to identify differential binding patterns of selected transcription factors and to profile chromatin accessibility between young and advanced reproductive aged women in response to hCG. The approach will identify and test new candidate genes as potential targets to improve fertility. Specific aims: (1) Determine the transcriptional programs in granulosa cells of young and advanced reproductive age mice and women. We hypothesize that key transcriptional regulators (YAP1 and TAZ) are differentially regulated during aging. We also hypothesize that genomic occupation of YAP1 and TAZ is altered in granulosa of patients who are good responders and poor responders to ovarian stimulation for IVF. (2) Identify and determine the role of hCG-responsive, YAP- and TAZ-target genes in granulosa cells of young and advanced reproductive age mice and women. We will test the hypothesis that YAP1-specific and TAZ- specific target genes will have distinct roles in modulating granulosa cell function. Furthermore, we propose that hCG-mediated, TAZ-responsive genes will improve the health and differentiation of aging granulosa cells, whereas hCG-mediated, YAP1-responsive genes will promote proliferation. Methodology: This project makes use of in vivo aging mouse models using granulosa cells recovered from young and older reproductive age women and mice. We will employ multi-omics (CUT&RUN, ATAC-seq, and RNA-seq) on the same samples to determine and validate specific gene targets to improve the diagnosis and treatment of infertility in women. Path to translation/implementation: This study impacts the VA-ORD Translational Pipeline (TP) Stages T0-1, Disease Biology / pathology (Foundational Studies), T0-2, Target Identification, Evaluation & Efficacy (Proof-of-Concept Studies) and T0-3B, Validation of biomarkers in different populations. We anticipate discovering unique differences in the actions of hCG in granulosa cells as a function of age and patient IVF response. This research will identify and validate new targets, which will facilitate patient phenotyping based on patient age and response. Next steps are to employ in vivo preclinical models using small molecule inhibitors to demonstrate efficacy for improvement of ovarian function and fertility.

2031-05-31

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Li Ka Shing Foundation Expanded

Li Ka Shing Foundation

Funds medical research, education innovation, and disaster relief across Asia and globally.

$50K – $5M

medical researchEducationdisaster relief

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

Li Ka Shing Foundation Grants

Li Ka Shing Foundation

Major global foundation (3B+ USD) supporting education, healthcare, and community resilience.

$100K – $5M

Educationhealthcarecommunity resilience

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

Liberty Mutual Foundation Homelessness & Hunger Grants

Liberty Mutual Foundation

Addresses homelessness, hunger, and disaster relief through grants to nonprofits working on housing stability and food access.

$10K – $500K

homelessnesshungerdisaster relief

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LiDAR-based Resource Management for National Park Service Modification 1