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East Tennessee Foundation

East Tennessee Foundation ($400M in assets) supports nonprofits in TN through grants focused on education, environment, community development, arts. Awards range from $2,000 to $100,000.

East Tennessee Foundation

East Tennessee Foundation ($400M in assets) supports nonprofits in TN through grants focused on education, community development, arts, environment. Awards range from $1,000 to $75,000.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Over 750,000 Americans experience acute respiratory failure in the United States each year. The mainstay of treatment for these patients is artificial respiratory support via conventional mechanical ventilation. Increasingly, the most severely ill of these patients are also treated with veno-venous extracorporeal membrane oxygenation (ECMO), an advanced form of life support which adds oxygen to the blood via an external circuit. Traditionally, ECMO was provided only to highly selected patients and only at high-volume hospitals. However, in recent years this pattern changed dramatically, with rapid increases in both the number of hospitals providing ECMO and the number of patients receiving ECMO. Despite the rapid adoption of ECMO, extremely little is known about the impact of these changes on patient outcomes and the health system as a whole. In this project we will directly address this knowledge gap by examining the comparative effectiveness and system-level effects of ECMO adoption. We will use a combination of all-payer utilization data and private payer claims data to obtain a comprehensive view of ECMO adoption, focusing on veno-venous ECMO for patients with severe acute respiratory failure. First, we will characterize ECMO adoption and identify the hospital and system-level factors driving the rapid uptake of ECMO in the United States. Second, we use state-of-the-art econometric modelling to determine the comparative effectiveness of ECMO relative to traditional mechanical ventilation alone, with additional analyses focused on identifying heterogeneity of treatment effects across patients and hospital types. Third, we will determine the potential unintended consequences of ECMO adoption, examining how intensive care unit case-mix and throughput change after hospitals launch ECMO programs. Together these studies will provide clinicians, hospital administrators and policy makers with much needed real-world data to guide future ECMO adoption and ensure that this costly and invasive technology is used for maximal benefit.

Edmonton Community Foundation

ECF provides grants to charitable organizations in the Edmonton area for community development, education, arts, environment, and social services.

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

Sickle cell disease (SCD) affects approximately 100,000 Americans, making it the most common inherited blood disorder in the United States. Over 1.2 million people are living with HIV in the U.S. Both chronic illnesses are endemic in overlapping geographic areas and reported in thousands of U.S. patients. A systematic review found conflicting conclusions on the effect of HIV on SCD and revealed numerous knowledge gaps, including the clinical profile of SCD patients living with HIV (PLWHIV), and the impact of HIV infection and HIV treatment on SCD outcomes. The clinical management of the comorbidity is currently uncertain in the U.S. because of lack of evidence. The previous studies were unable to include SCD severity due to the phenotype variability within SCD genotypes that may have different associations with severity of SCD and HIV status. Although the study results will be applicable to the medical care of Americans with HIV and SCD, the study will be conducted in Cameroon because the higher HIV prevalence allows the enrollment of more HIV+ patients with SCD. In addition, four of the five SCD genotypes are found in Central Africa allowing the study of this important covariate. Findings from Cameroon are generalizable in the U.S. because the diagnosis, the pathophysiology, and the ART regimens are similar. Based upon the genotypic, clinical, and biological particularities of SCD the project will address the gap in knowledge on the effects of HIV infection on SCD in two Specific Aims: Aim 1: We shall establish a clinical registry that includes all SCD patients to measure HIV prevalence, demographic and clinical characteristics in Cameroon. This will be a cross-sectional and descriptive study involving all SCD patients registered and followed-up in in the country. The investigators will screen all the 866 patients for HIV to confirm their status and to potentially identify new HIV positive patients. This research phase will describe the baseline clinical profile of SCD, determine the frequency of HIV infection in SCD patients and compare socio-demographic and clinical factors between HIV+ and HIV- SCD patients. Aim 2: Using a sample from the same patient population, we shall conduct a cross-sectional study on a matched random sampling of 48 HIV-positive SCD patients, and 96 HIV-negative SCD patients. Additionally, we shall randomly select 48 consenting HIV positive non-SCD patients among the HIV patients currently followed-up at the YUTH HIV care center as a second control group for the study. We shall measure prospectively the levels of biological markers of thrombosis, hemolysis, inflammation and organ failure and compare them according to HIV status. We shall assess if the SCD genotype will be an effect modifier of the relation between HIV status and SCD biological markers. The medical registry and data collected during this exploratory study will serve as the preliminary data for a future R01 application. The study will provide important data to improve specific ways US care through future interventional studies on immune system modulation, targeted infection prophylaxis, iron management, tailored ART regimens and gene therapy optimization in American SCD patients living with HIV.

NIA - National Institute on Aging

PROJECT SUMMARY Family plays a central role in shaping the experiences of aging. Any health shock not only affects the patient but also reverberates throughout the family unit, taking a physical, emotional, and financial toll on family members. The effect on families is likely to be particularly pronounced for health shocks that lead to a pronounced decline in independence, as, for example, happens with the progression of Alzheimer’s Disease and Related Dementias (ADRD). The ways families manage sharp changes in health can have profound effects on both the patient’s well-being and that of their caregivers. Despite the intricate relationship between family dynamics and health outcomes at older ages, public policies and much of the existing research in the U.S. have predominantly focused on individual patients rather than the broader family context. The dearth of evidence relates not to the lack of interest, but to the absence of datasets that could allow studying the effects of health shocks on families. In this project, we propose to start closing this gap in knowledge by leveraging the new extensive U.S. Census Bureau infrastructure for linking administrative data. We will construct and analyze a novel individual-level database that links the health trajectories of older adults to the physical, mental, and economic well-being of their family members across multiple generations, covering twenty-five years from 1999 to 2024. Using this new database, we will comprehensively examine the interdependencies between the mental, physical, and economic well-being of older adults and their families in the United States. First, we will describe the variation in family circumstances of older adults at the time of different health shocks. We will consider variation across demographic groups, local geographies, and socio- economic circumstances. Second, we will use state of the art econometric techniques for causal inference to quantify how much deaths and major but non-fatal health shocks affect the health and economic well-being of family members, including spouses and adult children.

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

PROJECT SUMMARY Over 1 million women living with HIV (WLWH) give birth annually. With widespread use of combination antiretroviral therapy (cART), vertical transmission has been significantly reduced, resulting in ~16 million HIV- exposed uninfected (HEU) children as of 2023. Despite being HIV negative, these children face increased risks of poor growth, infection-related mortality, and respiratory disease. These outcomes are believed to result from maternal HIV-induced inflammation and/or cART toxicity, as many antiretrovirals cross the placenta and may disrupt fetal immune development. However, distinguishing the effects of HIV versus ART is difficult in clinical studies due to challenges of studying non-HIV infected women receiving ART. Limited access to fetal tissues further hampers mechanistic insight, creating a need for translational animal models. To address this critical knowledge gap, we propose to use a rhesus macaque model of simian immunodeficiency virus (SIV) infection to investigate how maternal HIV and long-acting ART (LA-ART) affect fetal immune development. We hypothesize that despite the absence of vertical transmission, maternal SIV and LA-ART exposure dysregulates immune ontogeny in the offspring via altered hematopoiesis. A novel LA-ART regimen of FDA-approved drugs Lenacapavir (LEN) and Cabotegravir (CAB), shown to provide effective viral suppression in preliminary macaque studies, will be given bimonthly by injection to female macaques that will then undergo time-mated breeding following viral suppression. Three experimental groups will be studied: [1] SIV-infected, LA- ART treated; [2] uninfected, LA-ART treated; and [3] uninfected, untreated controls. Offspring will be delivered naturally and monitored through six months of age. Specific Aim 1 will assess how maternal SIV/LA-ART versus LA-ART alone affects infant immune maturation and function in the periphery and in tissues using flow cytometry, single-cell RNA/ATAC-sequencing, and in vitro stimulation. We will evaluate vaccine responsiveness using Varivax™ and examine B/T cell responses and receptor repertoires. Specific Aim 2 will study the impact of maternal SIV/LA-ART versus LA-ART alone on hematopoiesis in the offspring. We hypothesize that SIV/LA-ART exposure impairs differentiation and maturation of hematopoietic stem and progenitor cells (HSPCs). Bone marrow will be analyzed via flow cytometry, differentiation assays, and single-cell RNA/ATAC-sequencing. Functional HSPC capacity will be tested via transplantation into immunodeficient mice. This study uses a clinically highly relevant primate model for HIV cure research and neonatal immunity, and advanced immunological tools to uncover how maternal HIV and LA-ART exposure alter infant immune development. Findings will guide future strategies to improve immune outcomes in HEU children.

El Paso Community Foundation

El Paso Community Foundation ($400M in assets) supports nonprofits in TX through grants focused on education, health, community development, arts. Awards range from $2,500 to $150,000.

U.S. National Science Foundation

TheElectrochemical Systemsprogram is part of the Chemical Process Systems cluster, which also includes: 1) theCatalysisprogram; 2) theInterfacial Engineeringprogram; and 3) theProcess Systems, Reaction Engineering, and Molecular Thermodynamicsprogram. The goal of theElectrochemical Systemsprogram is to support fundamental engineering science research that will enable innovative processes involving electrochemistry or photochemistry for the sustainable production of electricity, fuels, chemicals, and other specialty and commodity products. Processes utilizing electrochemistry or photochemistry for sustainable energy and chemical production must be scalable, environmentally benign, reduce greenhouse gas production, and utilize renewable resources. Research projects that stress fundamental understanding of phenomena that directly impact key barriers to improved system or component-level performance (for example, energy efficiency, product yield, process intensification) are encouraged. Processes for energy storage should address fundamental research barriers for renewable electricity storage applications, for transport propulsion, or for other applications that could have impact towards climate change mitigation. For projects concerning energy storage materials, proposals should involve testable hypotheses that involve device or component performance characteristics that are tied to fundamental understanding of transport, kinetics, or thermodynamics. Advanced chemistries beyond lithium-ion are encouraged. Proposed research on processes utilizing electrochemistry or photochemistry should be inspired by the need for economic and impactful conversion processes. All proposal project descriptions should address how the proposed work, if successful, will improve process realization and economic feasibility and compare the proposed work against current state of the art. Highly integrated multidisciplinary projects are encouraged. When appropriate, collaborations with industrial technologists are encouraged through GOALI proposals. Collaborative projects with an integrated experimental and theoretical approach are also encouraged. Topics of interest include electrochemical energy storage and electrochemical production/conversion systems. Radically new battery systems can move the U.S. more rapidly toward a more sustainable transportation future and to greater renewable electricity production penetration. High-energy density and high-power density batteries suitable for transportation and renewable energy storage applications are of primary interest. Advanced systems involving metal anodes, solid-state electrolytes, nonaqueous systemsbeyond lithium, aqueous systems beyond lithium,and multivalent chemistries are encouraged. Research activities focused on commercially available systems such as lead-acid and nickel-metal hydride batteries or lithium-ion batteries for medical or consumer electronics applications will not be considered by this program. Novel electrochemical and photochemical systems and processes for the production of chemicals and high-value products are encouraged. Emphasis is placed on those systems that improve process intensification and process modularization with accompanying benefits in energy efficiency and environmental footprint. Additional fundamental science topics of interest to this program include the study of: <ul type="disc"> <li>advanced fuel cell systems or fuel cell components for transportation propulsion or grid energy storage applications;</li> <li>flow batteries for stationary energy storage applications including alternative redox chemistries (e.g., organic, inorganic, organometallic, macromolecular) and operating strategies (e.g., redox-mediation, suspensions); and</li> <li>photocatalytic or photoelectrochemical processes and devices for the splitting of water into hydrogen gas or for the reduction of carbon dioxide to liquid or gaseous fuels. Projects that largely focus on developing fundamental understanding of the catalytic reaction mechanisms and structure-function relationships may be more appropriate as submissions to the CBET Catalysis program (CBET 1401).</li> </ul> Projects submitted to the Electrochemical Systems program are expected to develop fundamental, molecular-level understanding of the key chemical reaction and transport phenomena barriers to improved system-level performance. Innovative proposals outside of these specific interest areas may be considered. However, prior to submission, it is recommended that the Principal Investigator contact the program director to avoid the possibility of the proposal being returned without review. Referrals to other programs within NSF: <ul type="disc"> <li>Proposals that focus on electric-field driven separations such as dielectrophoresis should be directed to theInterfacial Engineeringprogram (CBET 1417).</li> <li>Proposals that focus on thermal management of energy storage devices and systems should be submitted to theThermal Transport Processesprogram (CBET 1406).</li> <li>Proposals that focus on improving device and system performance of primarily organic, inorganic, and hybrid photovoltaic (PV) technologies, including perovskites, may be more appropriate as submissions to the Electronics, Photonics, and Magnetic Devices program in Engineering's Division of Electrical, Communications, and Cyber Systems (ECCS 1517). PV materials proposals that focus on the material science may be considered in the Division of Materials Research of the Directorate for Mathematical and Physical Sciences.</li> <li>Proposals that focus on the generation of thermal energy by solar radiation should be directed to theThermal Transport Processesprogram (CBET 1406).</li> </ul> INFORMATION COMMON TO MOST CBET PROGRAMS Proposals should address the novelty and/or<a href="http://www.nsf.gov/about/transformative_research/faq.jsp">potentially transformative nature</a>of the proposed work compared to previous work in the field. Also, it is important to address why the proposed work is important in terms of engineering science, as well as to also project the potential impact on society and/or industry of success in the research. The novelty or potentially transformative nature of the research should be included, as a minimum, in the Project Summary of each proposal. The duration of unsolicited proposal awards in CBET is generally up to three years. Single-investigator award budgets typically include support for one graduate student (or equivalent) and up to one month of principal investigator time per year(awards for multiple investigator projects are typically larger). Proposal budgets that are much larger than typical should be discussed with the Program Director prior to submission. Proposers can view budget amounts and other information from recent awards made by this program via the &ldquo;What Has Been Funded (Recent Awards Made Through This Program, with Abstracts)&rdquo; link towards the bottom of this page. Faculty Early Career Development(CAREER)program proposals are strongly encouraged. Award duration is five years.The submission deadline for Engineering CAREER proposals is in July every year. Learn more in the<a href="https://www.nsf.gov/career">CAREER program description</a>. Proposals for Conferences, Workshops, and Supplements: PIs are strongly encouraged to discuss their requests with the Program Director before submission of the proposal. Grants forRapid Response Research(RAPID)andEArly-concept Grants for Exploratory Research(EAGER)are also considered when appropriate. Please note that proposals of these types must be discussed with the program director before submission.Grant Opportunities for Academic Liaison with Industry (GOALI)proposals that integrate fundamental research with translational results and are consistent with the application areas of interest to each program are also encouraged. Please note that RAPID, EAGER, and GOALI proposals can be submitted anytime during the year. Details about RAPID, EAGER, and GOALI are available in theProposal &amp; Award Policies &amp; Procedures Guide(PAPPG), Part 1, Chapter II, Section E: Types of Proposals. COMPLIANCE: Proposals which are not compliant with the<a href="https://www.nsf.gov/publications/pub_summ.jsp?ods_key=pappg" target="_blank">Proposal &amp; Award Policies &amp; Procedures Guide (PAPPG)</a>will be returned without review.

U.S. National Science Foundation

The Electrochemical Systems program is part of the Chemical Process Systems cluster, which also includes: 1) the Catalysis program; 2) the Interfacial Engineering program; and 3) the Process Systems, Reaction Engineering, and Molecular Thermodynamics program. The goal of the Electrochemical Systems program is to support fundamental engineering science research that will enable innovative processes involving electrochemistry or photochemistry for the sustainable production of electricity, fuels, chemicals, and other specialty and commodity products. Processes utilizing electrochemistry or photochemistry for sustainable energy and chemical production must be scalable, environmentally benign, reduce greenhouse gas production, and utilize renewable resources. Research projects that stress fundamental understanding of phenomena that directly impact key barriers to improved system or component-level performance (for example, energy efficiency, product yield, process intensification) are encouraged. Processes for energy storage should address fundamental research barriers for renewable electricity storage applications, for transport propulsion, or for other applications that could have impact towards climate change mitigation. For projects concerning energy storage materials, proposals should involve testable hypotheses that involve device or component performance characteristics that are tied to fundamental understanding of transport, kinetics, or thermodynamics. Advanced chemistries beyond lithium-ion are encouraged. Proposed research on processes utilizing electrochemistry or photochemistry should be inspired by the need for economic and impactful conversion processes. All proposal project descriptions should address how the proposed work, if successful, will improve process realization and economic feasibility and compare the proposed work against current state of the art. Highly integrated multidisciplinary projects are encouraged. When appropriate, collaborations with industrial technologists are encouraged through GOALI proposals. Collaborative projects with an integrated experimental and theoretical approach are also encouraged. Topics of interest include electrochemical energy storage and electrochemical production/conversion systems. Radically new battery systems can move the U.S. more rapidly toward a more sustainable transportation future and to greater renewable electricity production penetration. High-energy density and high-power density batteries suitable for transportation and renewable energy storage applications are of primary interest. Advanced systems involving metal anodes, solid-state electrolytes, nonaqueous systems beyond lithium, aqueous systems beyond lithium, and multivalent chemistries are encouraged. Research activities focused on commercially available systems such as lead-acid and nickel-metal hydride batteries or lithium-ion batteries for medical or consumer electronics applications will not be considered by this program. Novel electrochemical and photochemical systems and processes for the production of chemicals and high-value products are encouraged. Emphasis is placed on those systems that improve process intensification and process modularization with accompanying benefits in energy efficiency and environmental footprint. Additional fundamental science topics of interest to this program include the study of: advanced fuel cell systems or fuel cell components for transportation propulsion or grid energy storage applications; flow batteries for stationary energy storage applications including alternative redox chemistries (e.g., organic, inorganic, organometallic, macromolecular) and operating strategies (e.g., redox-mediation, suspensions); and photocatalytic or photoelectrochemical processes and devices for the splitting of water into hydrogen gas or for the reduction of carbon dioxide to liquid or gaseous fuels. Projects that largely focus on developing fundamental understanding of the catalytic reaction mechanisms and structure-function relationships may be more appropriate as submissions to the CBET Catalysis program (CBET 1401). Projects submitted to the Electrochemical Systems program are expected to develop fundamental, molecular-level understanding of the key chemical reaction and transport phenomena barriers to improved system-level performance. Innovative proposals outside of these specific interest areas may be considered. However, prior to submission, it is recommended that the Principal Investigator contact the program director to avoid the possibility of the proposal being returned without review. Referrals to other programs within NSF: Proposals that focus on electric-field driven separations such as dielectrophoresis should be directed to the Interfacial Engineering program (CBET 1417). Proposals that focus on thermal management of energy storage devices and systems should be submitted to the Thermal Transport Processes program (CBET 1406). Proposals that focus on improving device and system performance of primarily organic, inorganic, and hybrid photovoltaic (PV) technologies, including perovskites, may be more appropriate as submissions to the Electronics, Photonics, and Magnetic Devices program in Engineering's Division of Electrical, Communications, and Cyber Systems (ECCS 1517). PV materials proposals that focus on the material science may be considered in the Division of Materials Research of the Directorate for Mathematical and Physical Sciences. Proposals that focus on the generation of thermal energy by solar radiation should be directed to the Thermal Transport Processes program (CBET 1406). INFORMATION COMMON TO MOST CBET PROGRAMS Proposals should address the novelty and/or potentially transformative nature of the proposed work compared to previous work in the field. Also, it is important to address why the proposed work is important in terms of engineering science, as well as to also project the potential impact on society and/or industry of success in the research. The novelty or potentially transformative nature of the research should be included, as a minimum, in the Project Summary of each proposal. The duration of unsolicited proposal awards in CBET is generally up to three years. Single-investigator award budgets typically include support for one graduate student (or equivalent) and up to one month of principal investigator time per year (awards for multiple investigator projects are typically larger). Proposal budgets that are much larger than typical should be discussed with the Program Director prior to submission. Proposers can view budget amounts and other information from recent awards made by this program via the What Has Been Funded (Recent Awards Made Through This Program, with Abstracts) link towards the bottom of this page. Faculty Early Career Development (CAREER) program proposals are strongly encouraged. Award duration is five years. The submission deadline for Engineering CAREER proposals is in July every year. Learn more in the CAREER program description. Proposals for Conferences, Workshops, and Supplements: PIs are strongly encouraged to discuss their requests with the Program Director before submission of the proposal. Grants for Rapid Response Research (RAPID) and EArly-concept Grants for Exploratory Research (EAGER) are also considered when appropriate. Please note that proposals of these types must be discussed with the program director before submission. Grant Opportunities for Academic Liaison with Industry (GOALI) proposals that integrate fundamental research with translational results and are consistent with the application areas of interest to each program are also encouraged. Please note that RAPID, EAGER, and GOALI proposals can be submitted anytime during the year. Details about RAPID, EAGER, and GOALI are available in theProposal &amp; Award Policies &amp; Procedures Guide (PAPPG), Part 1, Chapter II, Section E: Types of Proposals. COMPLIANCE: Proposals which are not compliant with the Proposal &amp; Award Policies &amp; Procedures Guide (PAPPG) will be returned without review.

Broad Foundation

Major funder of education reform, science research, and arts with $4B+ endowment.

NCI - National Cancer Institute

SUMMARY Neuroblastoma (NB) originates from immature nerve cells of the sympathetic nervous system and is the most common extra-cranial pediatric solid tumor. NB is remarkable in its diversity, displaying distinct genetic alterations, varied clinical manifestations, and heterogeneous responses to therapy. High-risk neuroblastoma can be rapidly progressive (e.g., in children whose tumors harbor MYCN amplification), while other patients present an indolent clinical course with months or even years of mild symptomatology prior to diagnosis. In such cases, ATRX in-frame fusions (IFFs) are among the most frequent and are significantly associated with indolent disease and chemotherapy resistance. The ATRX protein is a SWI/SNF-like chromatin remodeling factor that contains multiple domains essential for heterochromatin binding and the deposition of the histone variant H3.3 via its interaction with the histone chaperone DAXX. Therefore, its structural integrity is critical for maintaining chromatin organization and genome stability. Notably, ATRX IFF protein products lack these key chromatin- and protein-interaction domains, and the precise contribution of altered DAXX function and H3.3 deposition to the indolent NB phenotype remains unclear. We hypothesize that ATRX IFFs contribute to NB pathogenesis by disrupting the ATRX–DAXX– H3.3 regulatory axis, leading to accumulation of DAXX in the cytoplasm, altered H3.3 genomic distribution, and the aberrant activation of transposable elements (TEs) and other repetitive sequences. To address these questions, we will conduct a series of studies utilizing state-of-the- art genetic, epigenomic, and proteomic tools coupled to patient-derived NB cell lines, genetically engineered NB cellular models, and patient samples. In Aim 1, we will dissect the cytoplasmic role of DAXX and its potential as a biomarker in ATRX-altered NB, and in Aim 2 we will investigate the impact of ATRX IFFs on DAXX and H3.3 genomic distribution and the potential role of TE activation. With these proposed studies, we aim to reveal novel opportunities for therapeutic targeting and biomarker discovery in ATRX-altered NB with important implications for other ATRX- mutant cancers.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Viral pandemics remain a major threat to human health due to their capacity to transmit and cause disease globally. There is an urgent need to define the mechanisms by which viruses interface with our immune system and how our cells initiate antiviral responses. The OAS-RNase L innate immune pathway is an essential component of the antiviral response that restricts viral replication by sensing double-stranded RNA (dsRNA) and initiating RNA degradation. Oligoadenylate synthetase (OAS) proteins sense dsRNA and produce oligoadenylate molecules that activate RNase L to initiate robust RNA decay. Each catalytic OAS (OAS1, 2, and 3) is canonically thought to bind dsRNA and activate RNase L, although emerging evidence suggests each OAS protein may have non-redundant antiviral functions. Recent studies have revealed that OAS3 acts as the primary activator of RNase L and mediates this activation via condensation on dsRNA. In contrast, OAS1 and OAS2 do not often condense on dsRNA but rather bind and aggregate viral single-stranded RNA (ssRNA), potentially eliciting antiviral activity independent of RNase L. Additionally, OASL, a non-catalytic OAS, localizes to ribonucleoprotein granules, suggesting a potential role in RNA metabolism or translational control. Thus, there is an urgent need to define how each OAS elicits antiviral activity. This F31 fellowship proposal seeks to uncover the molecular mechanisms and RNA substrates recognized by each OAS protein in activating innate immune responses. The overarching hypothesis is that OAS3 recognizes dsRNA through multivalent interactions with dsRNA, while OAS1, OAS2, and OASL recognize ssRNA substrates and elicit antiviral activity independent of RNase L through unique protein-protein interactions. This hypothesis will be tested through three complimentary aims: 1) solve conformation of full-length OAS3 bound to dsRNA via structural studies and identify subcellular location of sensing via TEM, 2) identify the ssRNA sequence motifs recognized by OAS1, OAS2, and OASL during viral infection by using CLIPseq, and 3) define the OAS interactomes during infection using TurboID-based proximity labeling and mass spectrometry. These studies will characterize the molecular mechanisms of condensation, distinct RNA substrates recognized by OAS proteins, and the interactome of each OAS. The proposed experiments will be performed at the UF Scripps Research Institute which houses state-of-the-art facilities and a collaborative research environment. Access to advanced instruments and guidance from an experienced multidisciplinary teams of mentors will ensure the successful execution of the proposed training plan. The strong mentorship and collaborative setting will provide the ideal foundation for developing the technical and professional skills needed for a career as an independent researcher.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Cognitive impairment persists even with highly effective antiretroviral therapy (ART) in people with HIV (PWH). Persistent neuroinflammation is one of many factors that contributes to ongoing cognitive impairment in virally suppressed (vs)PWH. However, there is a critical gap in understanding the underlying cause of neuroinflammation and, as a result, no available therapies to target it. Long-acting broadly neutralizing antibodies (bNAbs) are considered the next generation of therapy for PWH. Currently, there are 50+ trials that involve bNAbs. Despite this substantial effort, there are no funded NIH studies focusing on if bNAb therapy in combination with ART may reduce neuroinflammation and improve cognitive function. As the mechanism of action for bNAbs is the rapid neutralization of virus and clearance of infected cells via engagement of the immune system, a downstream effect of this therapy may be lower levels of inflammation, as is observed with other Ab therapies. We have evidence that HIV-specific antibodies (Ab) play a protective role in the CNS, and others have shown that bNAb therapy enhances host Ab immunity to HIV and simian immunodeficiency virus (SIV). Therefore, our central hypothesis is that bNAb therapy will reduce neuroinflammation in the CNS, by directly eliminating infected cells capable of trafficking to brain resulting in a smaller CNS reservoir, neutralizing virus within the CSF, and indirectly by reducing peripheral inflammation, resulting in improved cognition. To test our hypothesis, we will use the SIVmac251 rhesus macaque model of HIV and an SIV-specific bNAb (ITS103). The SIV-infected ART-suppressed NHP model will allow us to assess the effects of bNAbs on CNS inflammation, reservoir, and cognition. Additionally, this model will allow us to determine if bNAbs have a direct effect on the CNS or indirect effect through altering peripheral inflammation. AIM 1: Determine if bNAb therapy during ART initiation reduces neuroinflammation. To model ART-naïve PWH receiving bNAb therapy simultaneously with ART, we will treat SIV-infected macaques with ITS103 at the time of ART initiation. We will assess the effect of acute ITS103 therapy on 1) brain macrophage transcription, 2) CNS reservoir size, and 3) cognitive performance after 1 year of suppression compared to ART alone. AIM 2: Determine if bNAb therapy during chronic ART reduces neuroinflammation. To model vsPWH receiving bNAb therapy combined with ongoing ART, we will treat SIV-infected macaques with ITS103 after 36 weeks of ART suppression and assess the effect of chronic bNAb therapy on the same outcomes as in Aim 1. AIM 3: Determine if bNAbs have a direct or indirect effect on neuroinflammation. To determine if ITS103 plays a direct role in the CNS we will assess 1) ITS103 concentrations in the CSF, 2) viral decay rates in CSF, 3) central vs. peripheral inflammation and 4) plasma and CSF Ab neutralization capacity with and without bNAb therapy. Our in vivo study utilizing a native SIV and SIV-specific bNAb is highly innovative as it will be the first to study on the effects of bNAb therapy on neuroinflammation and evaluate if this is a viable treatment for PWH.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Hirschsprung disease associated enterocolitis (HAEC) is the leading cause of death in children who lack enteric neurons in distal bowel, a birth defect called Hirschsprung disease. The etiology of HAEC is not well understood, but hypothesized disease mechanisms include altered gut microbes (“dysbiosis”), abnormal mucosal immune system and epithelial barrier defects. To date, there are no immune-targeted therapies to treat or prevent HAEC, but new treatments are needed. This proposal builds on the candidate’s preliminary data suggesting interleukin 22 (IL22) critically modulates HAEC risk and HAEC severity. The central hypothesis is that enteric nervous system (ENS) signaling induces IL22 release and facilitates IL22 epithelial responses to enhance mucosal immunity and strengthen epithelial barrier functions that prevent enterocolitis. The Piebald lethal (sl/sl) Hirschsprung disease mouse model of HAEC will be used, as survival of sl/sl mice is dramatically (> 3-fold) altered by diet (Tjaden et al, in BioRxiv and submitted) and IL22 mRNA is much higher in sl/sl fed a Protective diet that extends median survival (“late onset HAEC”). Aim 1 will define the cellular source(s) of IL22 from bowel regions of sl/sl model mice that develop early or late onset HAEC. In parallel, this aim tests the hypothesis that IL22 prevents HAEC, by using genetic and pharmacologic strategies to alter IL22 levels. Aim 2 will precisely define the role of IL22 on epithelial integrity, stem cell renewal and differentiation in organoids derived from sl/sl mice with early or late onset HAEC and from children with Hirschsprung disease with or without HAEC. Organoids facilitate studies of epithelial stem cell biology and IL22-epithelium interactions in the absence of microbes, neurons, or diffusible small molecules such as neurotransmitters. Collectively, these studies will determine cellular sources of IL22, the effect of ENS cells on IL22 secretion, the role of IL22 in enterocolitis, and the impact of Hirschsprung disease associated aganglionosis on epithelial cell biology. These studies build on the candidate’s training as a pediatric gastroenterologist, who has clinical exposure to the diagnosis and treatment of children with Hirschsprung disease and HAEC, as well as her basic science training in enteric nervous system biology. As the work proceeds, she will become an expert in mucosal immunology and epithelial biology with a focus on neuro-immune and neuro-epithelial interactions. The mentors, Dr. Robert Heuckeroth, and Dr. Kathryn Hamilton are experts in ENS biology and epithelial biology respectively. Both mentors have a strong commitment to mentorship and NIH funding track records. Experiments will be conducted at the Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, a collegial, collaborative and state-of-the art institution. The professional development and training plan will position the candidate as a successful pediatrician-scientist, who is focused on the prevention and treatment of Hirschsprung associated enterocolitis. These studies should determine if IL22-based therapies would likely be successful in HAEC, and if a human clinical trial is appropriate.

Velocity Dance Center

We propose a weekend of free community performances that are created by and for Black communities hosted in May 2025 at Kubota Garden in South Seattle. ?Elysium - Leviticus or Love and to walk amongst HUMANS: Book II?, is a site-responsive performance that leads audiences through a journey of death and revival to find themselves in a world where Black bodies are the blessed and dying to oneself is a rite of passage. Conceived and shaped by dani tirrell, choreographers Nia-Amina Minor, Quynn Johnson, Cyrah Ward, keyes wiley, and Majinn and performed by a cast of 20 local artists, this project is a celebration of the cultural practices of many overlapping identities held by the creators: the rituals of Black religious communities, Black LGBTQ+ nightlife practices like House and Club dance, and the power of gathering outdoors and sharing art together. The work will serve as a chance for Black communities to create and witness an arts event in an outdoor garden in their own neighborhood.

Gay City Health Project

The Emerge Arts Showcase offers emerging performance-based artists production and artistic mentorship and support alongside business and sustainability training. This framework will create a festival that is informed by, and seeks to address, artists' access to health and sustainability (as measured by social determinants of health) alongside artistic development and production. The anticipated project completion is August 31, 2022.

NIDA - National Institute on Drug Abuse

PROJECT ABSTRACT Emergency departments (EDs) face significant challenges managing mental health crises, often lacking specialized resources and leading to inappropriate placements and insufficient follow-up care. Emergency Psychiatric Assessment, Treatment, and Healing (EmPATH) units are designed to specially address these issues. However, a significant proportion of individuals experiencing mental health crises also have co-occurring substance use disorders, particularly opioid use disorder (OUD). Buprenorphine has been shown to reduce all-cause mortality. Furthermore, emergency department-initiated buprenorphine (EDIB) has demonstrated a doubling of 30-day treatment retention compared to referral alone. This significant success makes integrating EDIB into the EmPATH unit model a logical and potentially transformative step toward improved patient outcomes. However, adequately addressing workforce training needs is crucial for the successful implementation and sustained improvement of patient care. This project will develop and implement a training curriculum for EmPATH personnel focused on the acute management of OUD, emphasizing initiation of medication for opioid use disorder (MOUD) with buprenorphine. A phased approach will involve stakeholder input, protocol refinement, and rigorous evaluation. Phase 1 (R-61) will focus on curriculum development, incorporating input from an external advisory board, piloting the intervention in one EmPATH unit, and gathering qualitative feedback to refine the protocol. Phase 2 (R-33) will utilize a stepped-wedge design to: 1) assess the number of individuals identified with OUD while in EmPATH units (Primary Outcome) and the number of individuals administered buprenorphine and/or given a prescription for buprenorphine (Secondary Outcome); and 2) assess EmPATH staff satisfaction, burnout, confidence, knowledge, and stigma when working with patients with opioid use disorder prior to implementation and at 3, 6, 9, and 12 months post-implementation/training. This study aims to create a replicable and scalable model for integrating state-of-the-art OUD management into psychiatric emergency settings, improving patient outcomes and workforce preparedness. The collaboration with the South Carolina Hospital Association, Department of Mental Health, and DAODAS strengthens the project's impact and sustainability.

NIAID - National Institute of Allergy and Infectious Diseases

Despite currently available therapeutic approaches, multiple sclerosis (MS) remains an incurable disease. Studies in MS patients and corresponding animal models show that encephalitogenic T effector cells (TEFF) promote key autoimmune responses during MS pathogenesis. Within the central nervous system (CNS) of MS patients, these autoimmune T cells infiltrate the brain and then circulate back into the peripheral immune system, where they are maintained and reactivated, making such T cells a feasible diagnostic and therapeutic target. The mechanisms responsible for the maintenance of the encephalitogenic TEFF repertoire remain unclear. Stem- like T cells (TSTEM) that continue to differentiate into TEFF were proposed to contribute to the onset and exacerbation of human MS and its animal models. However, gaps in knowledge about the molecular characteristics of these encephalitogenic T cells and technical limitations severely hamper such advances. To overcome these limitations, we have developed a novel, state-of-the-art analytical tool, Seqtometry (sequencing- to-measurement), for analyzing single-cell sequencing data. As presented in this proposal, we performed an in- depth transcriptomic analysis of encephalitogenic T cells from the CNS and peripheral blood of MS patients and successfully identified MS-linked TSTEM, which were conspicuously absent in healthy or MS-free controls. We confirmed our findings using T cells specific for myelin oligodendrocyte glycoprotein (MOG), a relevant neuronal antigen, in an animal model of MS. Our most recent studies identified CD4+ T cells programmed for differentiation into TEFF with specific transcriptomic signature profiles corresponding to the MS-linked TSTEM, highlighting the conservation of encephalitogenic TSTEM. Based on these significant findings, we hypothesize that key transcriptomic characteristics that are conserved in T cells from MS patients and relevant animal models can foretell the early disease process and offer insights into the molecular mechanisms that govern the encephalitogenic differentiation of autoimmune T cells. Our further studies revealed in encephalitogenic TSTEM specific molecular mechanisms dependent on the homeodomain-only protein (Hopx) that governs effector differentiation of these cells. We additionally hypothesize that intrinsic mechanisms of Hopx in TSTEM orchestrate key pro-encephalitogenic functions. We will test our hypotheses in three aims: In Aim 1, we will determine the trajectories of encephalitogenic differentiation, In Aim 2, we will reveal the molecular mechanisms orchestrating fate and functions of TSTEM and clarify functions of Hopx, In Aim 3, we will determine the molecular characteristics of MS-linked TSTEM. Overall, the expected results of this research would provide us with key insights into molecular mechanisms underlying differentiation of encephalitogenic T cells, also helping to usher us into developing new MS diagnostic tools.

NIEHS - National Institute of Environmental Health Sciences

The ovary is a particularly important reproductive organ because it is essential for the production of oocytes and sex steroid hormones. Unfortunately, exposure to environmental endocrine disrupting chemicals (EDCs) can damage the ovary. EDC-induced ovarian damage leads to female reproductive dysfunction, which cannot be prevented or treated by eliminating EDC exposures. It is extremely important to understand the mechanisms by which EDCs damage the ovary so that we can develop strategies to prevent and/or treat EDC-induced reproductive toxicity. Towards this end, the overall goals of the proposed RIVER program are to: 1) unravel the intricate mechanisms underlying EDC-induced ovarian damage and female reproductive dysfunction, 2) decode the multigenerational effects of EDCs on ovarian function and female reproductive capacity, and 3) bridge the gap to human health by elucidating how EDC exposure is associated with ovarian function and reproductive aging in a prospective cohort of midlife women. To address these urgent clinical and public health needs, we will use single cell RNAseq to identify novel pathways of EDC-induced toxicity at the single cell level in the ovary as well as other female reproductive organs, spatial transcriptomics to map EDC-induced changes in gene activity while preserving spatial context, advanced 3-D ovarian follicle culture techniques to uncover the direct effects of EDCs on the ovary in a controlled environment, pioneering in vitro and in vivo experiments that include environmentally relevant individual EDCs and mixtures of EDCs, state-of-the-art LC-MS techniques to detect the concentrations of EDCs that reach the female reproductive organs and determine the ability of the ovary to detoxify or bioactive EDCs, high resolution LC-MS/MS techniques to conduct quantitative global and targeted proteomics, whole genome methylome analysis or reduced-representation bisulfite sequencing (RRBS) to identify the effects of EDCs on cell-type specific DNA methylation patterns in the ovary, spatial epigenome- transcriptome co-profiling to localize EDC-induced changes in specific cell types in the ovary and determine the interaction between EDC-induced methylation and gene expression changes, CRISPR-Cas 9 technology to correct EDC-induced DNA methylation errors in cells, LC-MS techniques at the forefront of the field to measure selected EDCs and biomarkers of reproductive function and aging in a prospective cohort of midlife women, and leading edge statistical models to assess associations between EDC mixtures and selected biomarkers/outcomes. The applicant is uniquely qualified to successfully lead the RIVER program. The applicant served as PI on 24 NIH-funded awards and her research produced over 325 peer-reviewed publications. The applicant has demonstrated a broad vision, conducted ground-breaking research, and made seminal contributions to the understanding of the impacts of EDCs on the ovary and female reproduction. The flexible and sustained RIVER support will help the applicant to continue pioneering and impactful research, mentoring, and leadership in environmental health sciences.

NIA - National Institute on Aging

ABSTRACT Numerous studies have demonstrated the "male-female health-survival paradox," where females exhibit a higher burden of age-associated disorders yet live longer than males. This paradox arises from a greater burden of chronic diseases in females, particularly those with a strong inflammatory or autoimmune component. A key factor contributing to inflammation-associated pathologies is endothelial cell (EC) dysfunction. This proposal aims to elucidate the molecular basis of sex-dependent differences in EC functions that may shape the outcomes of angiogenesis-driven diseases and aging in general. Our recent findings revealed that female ECs exhibit higher inflammation and reactive oxygen species (ROS) accumulation, with reduced angiogenic potential. These findings suggest biological sexual dimorphism in EC function, although the molecular mechanisms underlying these differences remain unclear. Toll-like receptors (TLRs), key innate proinflammatory mediators, recognize molecular patterns, including both pathogens and endogenous ligands generated by tissue damage and excessive oxidation. Analysis of multiple RNA sequencing datasets revealed that TLR2 and TLR4 pathways, specifically in ECs, are among the most significantly dysregulated in inflammation-associated pathologies and senescence. Moreover, gene expression profiling demonstrates that TLR2/4-related pathways are upregulated in female ECs compared to male ECs in vivo and in vitro. This upregulation seems to be driven by both increased TLR expression and higher levels of endogenous TLR ligands in females, collectively amplifying inflammatory responses. In vivo vascularization models showed a more substantial inflammatory component coupled with impaired angiogenesis and vascular remodeling in females. In EC-specific dual TLR2/4 knockout mice, eliminating these receptors abolished the pronounced differences between females and males in vascular models. This indicates that TLR2/4 pathways dominate sex-related differences in EC functions. While sex- specific differences in vascular diseases can arise from genetic, hormonal, or environmental factors, most research to date has focused on sex hormones. This project aims to shift the focus toward exploring the genetic components, particularly the role of endothelial TLR2 and TLR4 pathways in mediating these differences. Herein, we propose a new hypothesis: TLR2 and TLR4 on the endothelium are critical regulators of vascular responses, and augmented TLR2/4 activation contributes to increased vascular inflammation in females. We propose that endothelial TLR2/4-signaling is required for timely injury responses and tissue regeneration by regulating cytokine production and recruitment of inflammatory cells in females. We will utilize innovative transgenic mouse models, a pharmacological approach using phospholipid-based Reactive Carbonyl Scavengers (RCS) limiting the generation of TLR2 and TLR4, and state-of-the-art proteomics. Our studies will provide insights into the role of innate immune mechanisms in ECs and enhance our understanding of the genetic mechanisms responsible for sex differences in vascular pathologies, leading to more efficient therapeutics for both men and women.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Given the vast assortment of human monoclonal antibodies with potent neutralizing activity, one can envision long-term delivery of a combination of antibodies to achieve sterilizing immunity against most circulating HIV strains. Adeno-associated virus (AAV) vectors are well suited for such sustained antibody delivery. Our group has demonstrated high circulating levels of broadly neutralizing antibodies (bNAbs) following a single intramuscular AAV injection in rhesus macaques, as well as long-term virologic suppression for more than nine years after AAV-mediated delivery of 10-1074 and 3BNC117. These studies have not only demonstrated that long-term expression of AAV-delivered bNAbs can lead to a functional cure but can also eliminate the viral reservoir. In three macaques, intact proviral DNA levels were at or below the limit of detection five years following AAV delivery. Despite these successes, host immune responses against the delivered antibodies have frequently limited long-term transgene expression. To address the crippling effects of anti-drug antibody (ADA) responses, this proposal seeks to induce antigen-specific oral tolerance using engineered probiotics. We aim to determine whether pretreatment with these probiotics can prevent, and potentially reverse, immune responses to AAV-delivered bNAbs, thereby enabling sustained antibody expression in both uninfected and HIV-infected hosts. To test this concept, we will develop and validate designer probiotic strains that can be delivered orally, colonize the gut, and secrete functional bNAb immunoadhesins. Bifidobacterium longum will be engineered to secrete immunoadhesins derived from the bNAbs 3BNC117 and 10-1074, while Lactococcus lactis will be engineered to secrete the cytokine IL-10 to enhance tolerogenic signaling and support oral tolerance induction. Rhesus macaques will be pretreated with weekly oral probiotics prior to intramuscular AAV9 delivery. This approach will be evaluated longitudinally to assess ADA formation, regulatory T cell induction, microbial persistence, and the durability of AAV-mediated bNAb expression. This approach will be directly compared to oral delivery of purified bNAbs, as classically used in oral tolerance studies. In addition, we will assess whether sustained probiotic exposure can reprogram established humoral immunity and restore bNAb expression following AAV delivery. Finally, probiotic pretreatment will be evaluated in SHIV chronically infected rhesus macaques receiving antiretroviral therapy. This model is more clinically relevant and will allow us to determine whether oral tolerance can be established in the setting of chronic immune inflammation and dysregulation. If successful, this project will establish a microbiome-based, non-immunosuppressive strategy for overcoming the last critical barrier to AAV-mediated bNAb delivery. These studies could enable the development of long-term, ART-free HIV treatment and prevention and would provide a broadly applicable approach for improving the durability of AAV-delivered biologics across many diseases.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract The development of advanced biomaterials capable of electrical signal transmission is vital for regenerative medicine and bioelectronics, with injectable conductive nanogels showing significant promise. While naturally occurring, biocompatible extracellular conductive nanowires (ECNs) from anaerobic bacteria, such as the multi- heme cytochrome proteins, offer a compelling solution to the limitations of synthetic materials (e.g., solubility and biocompatibility), their widespread application is currently limited by challenges in their rational engineering and efficient production. Specifically, the recently discovered ECN protein family has not yet been integrated into recent novel AI protein design tools, and their complex in vivo assembly mechanisms remain poorly understood. This proposal will bridge these gaps by first identifying and engineering OmcE cytochrome nanowires that form large, ordered bundles. This involves comprehensive large-scale genomic and AlphaFold3-guided virtual screens to pinpoint novel OmcE homologs, followed by high-resolution cryo-EM characterization to elucidate their structural details and bulk conductivity measurements to confirm electrical properties. Subsequently, state- of-the-art AI tools will be employed to engineer novel OmcE variants exhibiting robust self-assembly into advanced conductive nanogels. Simultaneously, another major objective is to visualize the OmcE secretion system in situ to unravel its intricate assembly mechanism. We hypothesize that these nanowires assemble via a large outer membrane porin, analogous to the chaperone-usher pathway. Sub-tomogram averaging will be utilized to reconstruct the porin's structure at sub-nanometer resolution, providing critical molecular blueprints for the rational design of OmcE variants with enhanced self-assembly properties and enabling their efficient recombinant overexpression. Ultimately, this work will facilitate the precise engineering of "super" OmcE nanowires for conductive nanogels, offering transformative insights into their biosynthesis and establishing a foundation for a new generation of protein-based bioelectronic materials.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The kidney is responsible for maintaining an overall state of homeostasis, which it achieves by filtering a large volume of plasma through millions of epithelial units termed nephrons. It is estimated that 1 in 7 adults in the US suffer from chronic kidney disease (CKD), resulting from impairment of these functions. A seminal event in the development of every nephron is the formation of a connection with a collecting duct that establishes a patent pathway for the drainage of fluid into the collecting system and eventually out of the kidney. Human kidney organoids derived from pluripotent stem cells (hPSCs) are an innovative and powerful tool to study renal pathophysiology and to potentially inform new therapeutic avenues, but they suffer from several major limitations. One paramount deficiency is the lack of collecting ducts and failure of their nephrons to drain into a collecting system. To address this problem, we have recently developed a novel platform in which nephrogenic mesenchyme is combined with ureteric bud (UB) progenitor cells to produce an integrated system of collecting ducts within the organoids. Like in vivo development, the nephrons connect with the UB through a controlled fusion event with the distal GATA3+ segment that establishes a continuous passage for fluid flow. Currently, nephron connectivity in this system is limited by a relatively low efficiency of distal specification, and we hypothesize that finetuning the molecular processes underlying fusion will enable more complete integration of nephrons with collecting systems. In this proposal, we will apply this integrated organoid model to address major gaps in our mechanistic understanding of distal nephron patterning and fusion. In Aim 1, we will investigate how WNT and NOTCH signaling interactions coordinate and synergize to control nephron segmentation, and these mechanisms will be applied to enhance nephron-UB fusion in the organoid model. Aim 2 will delineate the cell- autonomous mechanisms underlying distal nephron fusion. Preliminary data show that expression of GATA3 is sufficient to induce fusion-competent distal tubules. Here we will build on this understanding by dissecting the genetic mechanisms downstream of GATA3 and how they regulate this unique cell biological property. Collectively, this work will generate novel and important insights into the mechanisms underlying nephron fusion, and simultaneously it will lead to further advancement in our state-of-the-art organoid model by informing methods to optimize nephron-UB connectivity. We anticipate that these approaches will yield seminal improvements in the structural organization of hPSC-derived kidney organoids, which will translate to progress in the functional capabilities of these tissues and their utility as models for investigation of renal pathophysiology and potentially for developing new therapies for CKD.