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24 grants worth up to $7.3M match your search

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Harnessing Androgen-Driven Immune Modulation to Enhance Immunotherapy for Endocrine Cancers

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NCI - National Cancer Institute

PROJECT SUMMARY Immunotherapy has transformed cancer treatment, yet patients with endocrine tumors, including adrenal and ovarian cancers, rarely benefit due to poor immune infiltration and activation in steroid-rich environments. Androgens, traditionally viewed as cancer-promoting, may enhance anti-tumor immunity. High androgen receptor expression correlates with improved outcomes in adrenal, ovarian, and select breast cancers; however, the mechanisms underlying these effects remain poorly understood. Using a mouse model of adrenal cancer, my work revealed a sex bias in tumor incidence, with males exhibiting lower tumor burden, which was associated with androgen-driven immune activation. Androgen-secreting adrenal tumors in the clinic show better prognosis and greater immune infiltration, while androgen deprivation in our mouse model reduces intratumoral myeloid and lymphoid cells. Androgen supplementation increases circulating inflammatory monocytes, suggesting a tumor-protective role via immune activation. Similar androgen-driven immune responses occur in the ovary, paralleling clinical data linking androgens to reduced ovarian cancer risk. These findings support a translational potential for androgen-mediated immunity across endocrine malignancies. In the K99 phase, I will investigate how androgens enhance myeloid and lymphoid immune responses to improve ICB efficacy in ACC. Aim 1 will assess how androgens modulate myeloid cell function and recruit the adaptive immune response to promote anti-tumor immunity. I will use a syngeneic ACC mouse model with immune cell depletion and ICB, real-time ultrasound tumor tracking, and Xenium transcriptomics to dissect androgen-driven immune mechanisms. Findings will be validated in androgen-secreting ACC patient tumors. In the R00 phase, I will extend this work to ovarian cancer, a leading cause of gynecologic cancer mortality. Aim 2 will examine how androgen signaling enhances immune infiltration in the ovary and whether this can improve ICB efficacy in ovarian cancer. I will use AR-deficient myeloid mouse models, syngeneic ovarian tumor injections, and Xenium transcriptomics to define androgen-mediated immune effects. This will establish a potential rationale for androgen-based immunotherapeutics in ovarian cancer. My career development plan includes training in tumor immunology, Xenium transcriptomics, and ovarian cancer biology, supported by mentorship from leaders in the field. The research environment at Huntsman Cancer Institute offers state-of-the-art resources and collaborative opportunities to achieve these goals. The K99/R00 award will enable me to establish my independent research lab, where I aim to advance our understanding of how hormones impact the tumor immune environment and ultimately use this to improve therapeutic strategies.

Up to $127K
2028-04-30
health research

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

Harnessing Metabolic Machinery of Gut Bacteria for Metabolic Dysfunction-Associated Steatohepatitis

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a growing public health concern in industrialized nations, with an estimated cost of $1.66 trillion in the U.S. by 2039. Despite its prevalence, therapeutic strategies remain limited due to an incomplete understanding of its pathogenesis. Emerging evidence suggests that the gut microbiota plays a critical role in modulating metabolic and inflammatory processes in MASH through the production of microbiota-dependent metabolites (MDMs). Therefore, a promising approach is to augment therapeutic MDMs in the gut by reintroducing their producers. However, current microbiome-based interventions, such as fecal microbiota transplantation (FMT), have been largely ineffective in ameliorating MASH due to critical gaps in identifying potent MDM-producing bacterial strains and elucidating the mechanisms that enable their durable engraftment in the gut. My long-term goal is to develop rationally designed microbiome therapeutics for MASH and other metabolic diseases by leading a multidisciplinary research program. This proposal aims to establish a foundational strategy to combat liver inflammation in MASH by leveraging bacterial strains with high MDM-producing capacity, focusing on Clostridia isolated from the Hadza hunter-gatherers. The Hadza harbor a highly distinct gut microbiome enriched with bacterial strains that efficiently utilize dietary polysaccharides and synthesize health-promoting MDMs, presenting promising therapeutic potential. Aim 1 will identify Hadza-derived Clostridia that produce anti-inflammatory MDMs. Aim 2 will investigate the mechanisms enabling their stable MDM production in the gut, with a focus on their polysaccharide-utilizing machinery that facilitates engraftment. Aim 3 will determine their immune and therapeutic effects in diet-induced MASH models. The successful completion of this study will enhance our understanding of gut bacterial metabolism in MASH and establish a rational framework for developing targeted microbiome therapeutics beyond current FMT approaches. Additionally, this K99/R00 award will provide essential training in both scientific and career development, facilitating my transition to becoming an interdisciplinary independent researcher. My training will be supported by a distinguished mentoring team with expertise in microbiome science (Dr. Justin Sonnenburg, primary mentor), liver biology (Dr. Natalie Torok, co-mentor), metabolomics (Dr. Michael Fischbach, advisor), gut ecology (Dr. Kerwyn Casey Huang, advisor), and immune profiling (Dr. Holden Maecker, advisor). Stanford University, a renowned institution in biomedical research, provides extensive resources, state-of-the-art equipment, and unparalleled opportunities to support my training. In summary, this K99/R00 proposal will equip me with the necessary skills to launch an independent research program in microbiome therapeutics for MASH and other metabolic diseases. The research findings will provide key insights into the role of microbiota in MASH and establish the groundwork for translational strategies aimed at improving metabolic and liver health.

Up to $92K
2028-01-31
health research

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

Harnessing Technology to Develop a Just-in-Time Adaptive Intervention to Promote Physical Activity in Adolescents with Type 2 Diabetes

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT The incidence of youth-onset type 2 diabetes (T2D) is on the rise, with a 95% escalation rate since 2001, and a staggering 77% increase during the COVID-19 pandemic. Regular physical activity is a cornerstone of T2D treatment. Yet, physical activity engagement is alarmingly low among youth with T2D, and effective interventions are lacking. Dr. Gutierrez-Colina’s long-term career objective is to improve health outcomes for youth with T2D by developing state-of-the-art mobile health (mHealth) interventions that provide personalized support for T2D self-management. The goal of this K23 proposal is to develop a novel just-in-time adaptive intervention (JITAI) that integrates dissemination and implementation science with real-time assessments of physical activity barriers and facilitators to deliver tailored strategies for promoting physical activity in adolescents with T2D. In Aim 1, a sequential exploratory design will be used to identify time-varying factors (e.g., motivation, fatigue, self- regulation) that influence physical activity engagement in adolescents with T2D. Qualitative interviews with N=18 T2D stakeholders will be conducted to gather in-depth feedback about physical activity barriers and facilitators. Qualitative findings will be integrated into the development of a 2-week ecological momentary assessment protocol designed to examine daily temporal associations between real-world barriers/facilitators and physical activity in the daily lives of N=25 adolescents with T2D. In Aim 2, the intervention components of a physical activity JITAI (e.g., personalized text messages, tailoring variables) will be co-developed with an advisory board of adolescents and caregivers. Intervention development will draw from dissemination and implementation science frameworks, as well as the “Capability, Opportunity, and Motivation (COM-B) Model,” a well-established theory of health behavior change. The JITAI will target activity barriers/facilitators related to Capability, Opportunity, and Motivation and deliver tailored support at the right time, in the right dose, and only when needed. In Aim 3, a sequential factorial experimental design will be used to pilot a 28-day micro-randomized trial of the physical activity JITAI with N=30 adolescents. Study feasibility and acceptability will be evaluated through usability surveys and post-intervention end-user interviews. Findings will generate critical data to inform an R01 application focused on a full-scale micro-randomized trial to optimize the physical activity JITAI. The proposed K23 research and career development plan will be supported by an outstanding mentorship team and a rich research environment at Colorado State University and the University of Colorado/Children's Hospital Colorado. Completion of the K23 training goals in (1) qualitative/mixed methods, (2) JITAI intervention development with an emphasis on dissemination and implementation science, and (3) the design and evaluation of micro- randomized clinical trials will equip Dr. Gutierrez-Colina with essential expertise in digital interventions and the rigorous methods involved in their evaluation. This training will directly support her successful transition to an independent research career focused on advancing personalized digital interventions for youth with T2D.

Up to $184K
2031-03-31
health research

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

HEMATOPOIETIC STEM/PROGENITOR CELL BASED CAR THERAPY TARGETING HIV

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NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract HIV disease remains a considerable public health concern without a practicable cure. Drug-based therapy can control HIV but is costly, has severe side effects, and is not curative. Stem-cell based therapies have provided the only known cures for HIV infection, with only a handful of individuals functionally cured to date. However, replicating these successes has been challenging due to the high toxicities of treatment, need for transplant antigen matching, and require extensive myeloablation. However, these “cures” strongly suggest that immune system modification involving hematopoietic stem/progenitor cell (HSPC) transplantation can play a strong role allowing HIV clearance from the body. We aim to achieve a HIV-1 cure by enhancing and optimizing anti-HIV cellular immune responses through genetic modification of autologous Hematopoietic Stem/Progenitor Cells (HSPCs) with an anti-HIV Chimeric Antigen Receptor (CAR) molecule (CAR-HSPC). Unlike combined antiretroviral treatment (ART), which cannot eradicate HIV due to persistent reservoirs, our approach targets lifelong anti-HIV responses for HIV clearance. We will improve the engraftment of CAR-modified stem cells by using clinically relevant conditioning methods, maintain long-term progenitor phenotype in CAR stem cells for repopulation capability, and improve homing to the bone marrow. Additionally, we will characterize the differentiation and therapeutic effects of HSPC-derived CAR modified immune cells in various tissue reservoirs using humanized mouse models. We will develop an in vivo targeting regimen incorporating stem cell targeted nanocapsules encapsulating CAR lentivirus to generate CAR-modified stem cells in vivo and evaluate for feasibility and efficacy. Our proposed study will provide crucial insights for investigational new drug (IND) development of HSPC-based CAR immunotherapies, potentially leading to ART-free HIV suppression and a functional cure.

Up to $3.1M
2030-06-30
health research

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

High End Laser Scanning Confocal Microscope for the University of Chicago Integrated Light Microscopy Facility

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NIGMS - National Institute of General Medical Sciences

Project Summary / Abstract The University of Chicago Integrated Light Microscopy Facility (ILMF) requests funds to purchase a high-end laser scanning confocal microscope. The ILMF currently serves 420 users in 80 labs from across the University. Sixty-seven of those labs use laser scanning confocal microscopy, and 78% of those labs have NIH funding. Usage hours have increased as the ILMF’s microscope capacity has decreased. Two of our confocal microscopes, both Leica SP5 models, are over 14 years old. Leica has designated them end-of-life, meaning they are no longer manufacturing parts for these systems and replacements are not guaranteed. We have already experienced failure of the 488nm Argon and 592nm depletion lasers on one, and failure of the Mai Tai multiphoton excitation laser on the other, with no possibility of replacing any of these components. We expect to decommission at least one SP5 within the next year, making users hesitant to start new projects on those systems. This has stressed our two newer laser scanning confocal systems (purchased with institutional funds in 2016 and 2020), pushing them to use levels averaging 91% of AUT, defined as 3640 hours per year. The system proposed here is the Evident (formerly Olympus) Fluoview 4000 (FV4000), released in 2024. The system will increase the capacity and functionality of laser scanning confocal microscopes in the ILMF, allowing users to collect high-quality data more readily. Several features of the FV4000 will be new to the ILMF, and satisfy a number of outstanding investigator needs. Features include: state-of-the-art, patented, fast signal processing silicon photomultiplier (SiPM, Evident SilVIRTM) detectors, to significantly improve signal-to-noise levels, enhancing detection of Golgi cisternae and other organelle sub-structures; four high magnification, long working distance silicone immersion objectives for detailed, multi-color, 3-dimentional imaging of organoids, thick tissues and tumor samples; and three near-infrared wavelength lasers for excitation of fluorophores beyond the current imaging spectrum, allowing for investigation of a larger number of molecules of interest in a single sample. The FV4000 will also feature full environmental control, allowing users to take advantage of faster imaging speeds to image live samples. This will make it possible to image longer sessions at higher frame rates with less photodamage, resulting in more robust and reliable data from live samples than currently possible. Finally, the FV4000 base is modular in design, allowing for field upgrades with Evident or third-party resources (e.g. a single molecule localization module) as users’ experimental needs grow. In summary, adding an Evident FV4000 laser scanning confocal microscope to the ILMF will make it possible for users to gather information from samples that are currently challenging but valuable research models.

Up to $726K
2027-05-31
health research

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

High-dimensional, spectral flow cytometer

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OD - NIH Office of the Director

Summary. We request funds to purchase a new 6-laser (320nm, 355nm, 405nm, 488nm, 561nm, 637nm), SONY ID7000E spectral flow cytometer to alleviate excessive demand for existing multi-parameter flow cytometers and to add additional spectral capability to the Core. The requested instrument will support the research of 16 major users and 32 minor users holding 78 NIH grants, as well as additional projects supported by the Department of Defense, private industry, and foundations. Our users are agitating for an additional instrument because their students, postdocs and technical staff are having difficulties booking appointments on the current (over-subscribed) instruments. In addition, they realize that the new spectral instruments have important features (like compensation for autofluorescence, enhanced small particle detection, and detection of a wider array of fluorochromes and fluorescent proteins) that are not possible on our current flow cytometers. Thus, the requested instrument will help users perform their funded and future experiments that require high- dimensional antibody panels, including users who use the immunophenotyping service for clinical samples. To meet these needs, we are requesting funds to purchase a new state-of-the-art, 6-laser Sony ID7000E spectral flow cytometer. The requested instrument will be administered by the FCSC Core and will be incorporated into the Core's existing financial plan. The FCSC Core is part of the UAB Institutional Research Core Program (IRCP) and receives significant institutional support from the IRCP on a yearly basis. The FCSC Core also receives yearly support from the UAB Cancer Center, the UAB Center for AIDS Research (CFAR) and the UAB Immunology Institute. These entities will also contribute $50,000 towards the purchase of the requested instrument. Five highly experienced flow cytometry specialists in the FCSC Core, each trained to operate the ID7000E, will be available to train new users in instrument operation and to assist them with the development of multi-parameter antibody panels. Finally, the FCSC Core is located in the Shelby Biomedical Research Building, which houses the research laboratories of many of our major users and is within a short walking distance of our other users on campus. Thus, the requested ID7000E instrument will add urgently needed capability and allow us to provide state-of-the-art instruments and services to our users in a timely manner.

Up to $472K
2027-06-14
health research

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

High-throughput Liquid Chromatograph Triple Quadrupole Mass Spectrometer

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OD - NIH Office of the Director

Health sciences research in the modern age has been revolutionized by automation and the high sensitivity of mass analysis provided by state-of-the-art quantitative mass spectrometry (MS) instruments. The Lumigen Instrument Center (LIC) at Wayne State University has a mission to provide researchers at the university and in the regional area with reliable user-based high throughput targeted MS analysis to elevate their research productivity. As part of the strategic plan of the Mass Spectrometry Laboratory in the LIC, the Mass Spectrometry Advisory Committee identified two current challenges for users. First, the number of targeted mass spectrometry analyses has drastically increased to over 13,000 analyses per year, which has dramatically affected user research productivity. Second, development of new methods to address the unique needs of individual users is limited due to the absence of new and powerful technologies, including high throughput automation and more sensitive triple quadrupole mass spectrometers. To address these challenges, this application requests funds for a high throughput solid phase extraction liquid chromatograph Mass Spectrometer (HT-SPE-LC-MSMS) at Wayne State University. The instrument will significantly enhance research accomplishment in mass spectrometry (MS) on our campus. First, the HT-SPE- LC-MSMS will increase the LIC's targeted mass spectrometry analysis rate. Second, the instrument will provide the only mass spectrometer in a shared facility on campus with high throughput, online solid phase extraction, targeted analysis capability, which will enable NIH-funded researchers to expand and transform their research activities and lower laboratory sample preparation costs. The multiple capabilities of the instrument will include cyanotoxin and cyanopeptides, mycotoxins, VOC metabolites, PFAS, hormones, endocrine disruptors, drugs of abuse, and ADME, API stability, and purity analyses. The instrument will support the research programs of at least 20 users at Wayne State University and the regional area, which include chemists, biologists, environmental scientists, and medical researchers. The HT-SPE-LC-MSMS will be housed and maintained in the LIC, which has strong institution support from the University, the Division of Research and Innovation, and the College of Liberal Arts and Science. The LIC has an exemplary record of instrument stewardship, with dedicated staff, facilities, and management to support the long-term use of the instrument. Importantly, the user-focused structure of the LIC will promote development of a unique array of new methods for each user's individual research projects. The acquisition of a HT-SPE-LC-MSMS is aligned with the long-term strategic plan of the Mass Spectrometry Facility at the LIC, which seeks to provide state-of-the-art and reliable MS instruments to implement innovative user-initiated projects at Wayne State University and local area community.

Up to $750K
2027-06-14
health research

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

Historic Restoration Fund

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New Britain Museum of American Art

Historic Restoration Fund

Up to $200K
Rolling
arts

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

Historic Restoration Fund

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New Britain Museum of American Art

Historic Restoration Fund

Up to $113K
Rolling
arts

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

HIV-1 Reservoir and Host Cell Dynamics Over Twenty Years on ART: Reservoir Kinetics, Antigen-Specific T Cell Dynamics, and Model-Building

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Despite the success of antiretroviral therapy (ART) in suppressing viral replication, no cure for HIV has been found. This is because HIV persists in a reservoir comprised of intact, inducible HIV proviruses in CD4+ T cells and, to a lesser degree, myeloid cells. A deeper, more quantitative understanding of the forces that sustain the reservoir will allow us to engineer more effective HIV cure therapeutics. We know that the HIV reservoir decays in the first ~7 years after ART initiation, but reservoir dynamics in the second decade and beyond are not well characterized. Of the few individuals studied longitudinally out to 20 years, some experience continued reservoir decay while others show signs of reservoir expansion. In this work, we will conduct a large, multi-decade, multi- platform study of the dynamics of latently infected cells and host CD4+ T cells. We will use this data to estimate the relative contributions of the biological factors that sustain the reservoir at different points in time after ART initiation. We will test the hypothesis that the reservoir initially decays due to immune selection, after which the reservoir’s persistence is largely driven by the kinetics of the most highly-expanded, infected clones. In the first aim, we will characterize 20-year HIV reservoir trajectories using the intact proviral DNA assay in dozens of people living with HIV (PWH) on ART and identify biological factors that differ between those with continued decay and those with expansion in the second decade on ART. Biological factors examined include expansion rates of underlying HIV-infected CD4s and uninfected memory CD4s, CMV serostatus, and sex. In the second aim, we will quantify the contribution of antigen-specific clonal proliferation to overall memory (m)CD4+ T cell persistence in a subset of PWH on long-term ART. To do this, we will first use the ViraFEST assay to identify T- cell receptor (TCR)β sequences of mCD4+ T cells that proliferate in response to one of four viral antigens. Then we will obtain longitudinal resting mCD4+ TCRβ and paired TCRαβ repertoires from the same individuals and track each antigen-specific clone’s proliferative kinetics over 20 years on ART. We will model these thousands of antigen-specific clone trajectories to provide insight into how antigen exposure shapes long-term persistence of memory CD4+ T cells. In the third aim, we will refine, validate, and extend our stochastic model of HIV reservoir dynamics to incorporate 20 years of ART data. First, we will generate empiric data on clone kinetics of CD4s harboring intact and defective proviruses and uninfected mCD4s by performing near-full length sequencing and mCD4+ TCR repertoire sequencing on longitudinal samples. We will use this data to refine and validate our current model and extend its applicability to the first twenty years on ART, thus providing a comprehensive framework to estimate the relative contributions of various forces, such as immune selection and antigen-driven proliferation, in driving reservoir dynamics at different times after ART initiation. Our study will yield quantitative insight that will be immediately applicable to HIV cure efforts and will generate a freely available, advanced mathematical model of the reservoir that can provide predictions to optimize the design of future HIV cure trials.

Up to $812K
2031-06-30
health research

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

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