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NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT: A key problem in the treatment of cancer is targeting master transcription factors (TFs) that drive oncogenesis. Many malignancies are characterized by TFs that regulate aberrant epigenetic and gene expression programs. A phenomenon that has been observed in the regulation of malignant TFs is the necessity to restrain oncogenic TF activity in order to preserve cancer cell wellbeing. We have identified DDX19A as a top genomic dependency in Ewing sarcoma (ES), an aggressive bone malignancy driven by the fusion oncoprotein and potent TF EWSR1:FLI1 (EWS/FLI). Intriguingly, we have observed that loss of DDX19A leads to marked global upregulation of transcription, chromatin opening, and increase in enhancer binding by H3K27Ac in ES cells, suggesting that this RNA helicase is a crucial negative regulator of transcription in ES tumors. We have gone on, through chemical screening efforts, to develop seed compounds that selectively target DDX19A. The objective of this proposal is to examine the mechanism of action of DDX19A in ES, and to use medicinal chemistry optimization to develop small molecule probes with which to target this protein. Our central hypothesis is that DDX19A constrains transcription and epigenetic programs directed by EWS/FLI, and that the loss of DDX19A leads to toxicity from transcriptional overload subsequent cell death. Thus, we believe that DDX19A is a promising new target for therapeutic development. We will test this hypothesis in two parallel specific aims: 1) Interrogate how DDX19A regulates gene expression programs controlled by EWS/FLI, and 2) Develop potent and selective allosteric inhibitors of DDX19A. First, we will use state-of-the-art functional genomic, epigenomic, and proteomic approaches to examine how DDX19A activity is critical specifically in EWS/FLI-driven tumors. Next, we will rigorously interrogate how DDX19A regulates nascent transcription specific to ES. Next, we will use chemical biology methods to validate specific DDX19A engagement and functional modulation in ES cells. Through a hit-to-lead strategy, we will obtain inhibitors with optimized pharmacokinetic properties, which will serve as lead compounds for therapeutic discovery. We will test optimized compounds for efficacy using in vitro ES cell lines as well as in vivo in ES PDX models. Importantly, animal subjects are indispensable for establishing pre-clinical rationale for development of new targeted therapeutics. Specifically, animal subjects are the only available means to study in vivo pharmacokinetics, test dosing schedules/routes, examine pharmacodynamics (in tumor-bearing animals), and measure toxicities that may impact human patients. These studies are innovative as they combine extensive molecular biologic investigation with sophisticated chemistry approaches to target ES, an aggressive, difficult-to-treat malignancy. Our proposal is significant because it will expand our understanding of how cancer cells control oncogenic transcription in order to promote cell survival. Successful completion of these aims will provide proof-of-concept that de-repressing TF activity and initiating transcriptional overload is a viable strategy for treating TF-driven malignancies.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Hypoplastic left heart syndrome (HLHS) is a congenital heart disease (CHD) characterized by a small left ventricular (LV) chamber, thick LV wall, and negligible LV function. HLHS has the highest morbidity and mortality rates among CHDs. There is an urgent need for novel therapies, ideally through correcting LV growth defects before birth. However, these efforts have been impeded by limited understanding of molecular underpinnings of HLHS. To study the underlying mechanisms of HLHS, we focused on MYRF, a transcription factor (TF) recently linked to HLHS but the disease mechanisms remain unknown. Moreover, it is still unclear which cardiac cell type(s) contributes to the MYRF-mediated HLHS. To address these major gaps in knowledge, we examined the expression pattern of MYRF in mammalian heart and found it was expressed in epicardial cells (EPCs), endothelial cells (ECs), and cardiomyocytes (CMs). More importantly, specifically ablating MYRF in EPCs and ECs, but not in CMs, recapitulates many critical disease features of HLHS. Based on our preliminary data, we hypothesize that epicardial and endothelial MYRF regulate the expression of genes essential for left ventricle morphogenesis. We propose to test this hypothesis with two specific aims. In Aim 1, we will determine the role of MYRF in EPCs and ECs. we will fully characterize the cardiac phenotypes of Myrf EPC- and EC-KO mice, including determining the roles of epicardial degeneration and the defective endocardium on LV morphogenesis, respectively. We will investigate potential EPC and EC impairments in proliferation, survival, migration, and the capacity of EPCs to differentiate into other cardiac cell types via epithelial-to-mesenchymal transition (EMT). scMultiome (scRNA-seq + scATAC-seq) in conjunction with spatial transcriptomics will be used to untangle the multi-cell-lineage contribution to the phenotypes of EPC-KO and EC-KO mice. Aim 2 will elucidate the respective roles and mechanisms of MYRF nuclear-translocating N-terminus and ER-resident C-terminus. We will utilize state-of-the-art techniques routinely employed by our group to study MYRF N-terminal TF function: MYRF ChIP- seq, histone modification profiling, and IP-MS will be performed and integrated with scMultiome data to elucidate MYRF-driven transcriptional networks across diverse cardiac cell types. Mouse models specifically abolishing the function of MYRF N-terminal domains or C-terminus will be analyzed to determine the contributions of MYRF N- and C-terminus to its transcriptional regulatory activities and the pathogenesis of HLHS. The completion of these studies will substantially advance our understanding of the essential role of MYRF in the etiology of HLHS, paving the way for novel therapeutics to combat the devastating disease. Additionally, the multi-omics datasets generated by our study will greatly facilitate the research on CHD.

NIDA - National Institute on Drug Abuse

Summary/Abstract People with HIV (PWH) remain vulnerable to central nervous system complications (e.g., neurocognitive impairment) despite antiretroviral therapy (ART) that suppresses viral replication. While many etiologies of these complications exist, mitochondrial dysfunction and inflammation are consistently implicated yet seldom studied simultaneously. PWH also use cannabis more frequently than the general population and recent evidence by our group and others indicates that cannabis may protect PWH from mitochondrial damage by improving metabolic homeostasis and reducing inflammation through triggering receptor expressed on myeloid cells (TREM) 2. Moreover, this mechanism may be more important as PWH age, with the average age of PWH currently being >55. This proposed multidisciplinary, translational project will combine a clinical observational study with cellular and in vivo preclinical models to determine the effects of cannabis use on TREM2-mnediated changes in mitochondrial function in the brain in PWH. The preclinical models will include a) personalized ex vivo/in vitro modeling of mitochondrial toxicity in brain macrophages and neurons, and b) a mouse model for HIV-induced neurotoxicity (Eco-HIV) and age-related neuropathogenesis (TREM2*R47H). Using this multilevel approach, we will test the hypothesis that cannabis effects on TREM2-mediated changes in brain mitochondrial homeostasis vary based on patterns of use: moderate use will be associated with beneficial effects, due to the TREM2 promoting and anti-inflammatory properties of cannabis, but chronic daily use will have detrimental effects. In a cohort of aged (>50 years old) PWH across a range of cannabis use from naïve to daily users, we will measure in plasma and cerebrospinal fluid (CSF) a panel of biomarkers that reflect the mitochondrial homeostasis, TREM2 function, and inflammation. These readouts will be correlated with neurocognitive assessments and PET imaging for TSPO, a marker of neuroinflammation associated with mitochondrial function (Aim 1). We will model brain macrophages using personalized ex vivo cultures of monocyte derived microglia collected from Aim 1 study participants and culture these cells with neurons to identify mechanisms of mitochondrial dysfunction (Aim 2). Using a cross-species approach, we will investigate how different precise doses of cannabinoids interact with HIV and TREM2 variants to affect mitochondrial homeostasis in wild-type and TREM2*R47H mice infected with EcoHIV (Aim 3). This highly innovative, multidisciplinary research proposal is very likely to generate impactful translational knowledge regarding mechanisms of pathogenesis and guide future therapeutic interventions. With our combined clinical and pre-clinical expertise in HIV infection, substance abuse, imaging, and mitochondrial homeostasis, we are uniquely suited to perform the proposed research.

NIA - National Institute on Aging

PROJECT SUMMARY The rapid aging of the global population presents a significant societal challenge, with an increasing number of older adults experiencing chronic diseases that compromise their health-span despite advances in medical technologies. This paradox results in substantial economic burdens due to lost productivity and healthcare expenditures. To address this, there is a critical need for strategies that enhance health-span, enabling older adults to maintain functional abilities, independence, and quality of life. The proposed Translational Gerontology and Geroscience (TG2) Training Program at the University of Alabama at Birmingham (UAB) aims to develop the next generation of interdisciplinary, aging-focused scientists. This program will support 5 predoctoral and 3 postdoctoral trainees; providing them with collaborative, interdisciplinary mentoring and comprehensive research training. The goal is to inspire and develop dedicated, motivated, and well-trained scientists capable of tackling society’s big challenges in the field of aging. TG2 will emphasize bidirectional training to create an interdisciplinary experience that addresses physical, mental, and social aspects of health necessary for healthy aging. The program will leverage an exceptionally rich institutional environment that offers a robust infrastructure in aging research, including NIA P30 awards for an Alzheimer’s Disease Research Center, Nathan Shock Center in the Basic Biology of Aging, and Resource Center for Minority Aging Research; as well as one of four McKnight Brain Institutes sites and a VA Geriatric Research, Education, and Clinical Center (GRECC). The program integrates 40+ faculty from five UAB Schools and Colleges (Medicine, Arts & Sciences, Nursing, Optometry, Health Professions) and includes established, independent investigators with strong mentoring history as well as rising stars in the aging field who will be part of our Mentoring on Mentoring Program. Together the trainee, mentor, and a Translational Mentoring Team will craft an individual development plan that includes coursework, laboratory and clinical research, professional development programs, workshops, presentations locally and at national meetings, and training in the responsible conduct of research. Overall, the program will build and develop a multidisciplinary cohort of scholars that will support, learn from, and challenge one another to think critically about how to address the complex challenges of aging and how to develop successful careers in gerontology and geroscience.

Triangle Community Foundation

Triangle Community Foundation ($600M in assets) supports nonprofits in NC through grants focused on education, community development, arts, environment. Awards range from $2,500 to $150,000.

National Institute of Food and Agriculture

The TCEG program (assistance listing 10.221) is designed to help build Tribal education capacity in the food and agricultural sciences for Native Alaskan/American Indian students. This NOFO will begin a new four-year continuation funding cycle. The six legislatively mandated priorities are: Curricula design and materials development. Faculty development and teacher preparation. Student experiential learning Equipment and instrumentation for teaching science, technology, engineering, arts and math. Student recruitment and retention. Instruction delivery systems and strategic partnerships.

Friends of the Troll's Knoll

The Friends of the Troll's Knoll is a community group dedicated to promoting and strengthening the safety and security of the community by maintaining and activating the green space right-of-way on the east side of the Fremont Troll, located at N 36th St and Winslow Pl N Seattle WA 98103 and turning it into a public park. The group will hire a designer to create a design plan for the space and hire an artist to create and install artwork. The anticipated end date for the project is August 31, 2020.

Friends of the Troll's Knoll

The Friends of the Troll's Knoll (FOTK) is a neighborhood group dedicated to engaging the community in beautifying and activating the urban forest around the Fremont Troll. This grant will fund: (1) site survey of the land, (2) arborist analysis, (3) detailed planting plan, (4) installation of a willow art feature, (5) addition of a Japanese style shade structure, known as a hokora, and to the existing moss turtle artwork (installed by us in 2020). The anticipated project close out is May 31, 2022

Friends of Troll's Knoll

The funding will cover benches, decommissioning of the damaged Mushroom Lantern sculptures (funded by DON in 2021), replacement art with stainless steel sculptures, and erosion control. Currently, we do not have seating for mobility impaired visitors and would like to purchase and install sturdy horizontal basalt column benches. Our site is open 24/7 and free and open to the public. The anticipated project completion date is December 31, 2026.

Tulsa Community Foundation

Tulsa Community Foundation ($4.5B in assets) supports nonprofits in OK through grants focused on education, arts, social services, community development. Awards range from $2,500 to $250,000.

NCI - National Cancer Institute

PROJECT ABSTRACT This proposal seeks to overcome critical limitations in personalized therapeutic strategies for triple-negative breast cancer (TNBC), an aggressive subtype marked by poor prognosis. We propose developing personalized cancer treatment, designed to stimulate antigen-presenting cells and induce robust, antigen-specific T cell responses against TNBC cells. We develop cost-effective Tumor-derived Cell-membrane Coated NanoVaccine (TCC-NV) armed with adjuvants, that bypass limitation of resource-intensive neoantigen prediction, prioritization, and validation process. Our proposed TCC-NV integrated with radiotherapy (RT) addresses the challenge of low mutation burden in TNBC that often limits personalized neoantigen-based treatments. This multifaceted approach leverages immune-competent mouse models that closely mimic human TNBC, focusing on the innate and adaptive immune system's role in anti-tumor responses. Specific Aims are: 1) Evaluate antitumor activity of TCC-NV in TNBC tumor models. 2) Investigate radiation impact on increasing neoepitope presentation and determine whether immune checkpoint inhibitors (ICI) therapy can synergize with TCC-NV to eradicate TNBC tumors. The TCC-NV platform's production simplicity facilitates clinical translation and increases the potential for future clinical success in personalized treatment of primary and metastatic TNBC. This mechanistic study is related to the mission of the NCI as it aims to contribute to closing the knowledge gap in understanding the role and function of neoantigen-based cancer vaccine therapy and to provide survival benefits for TNBC patients who urgently require more effective treatment strategies beyond traditional chemotherapy. Dr. Yazdimamaghani’ s career goals are to integrate research from nanomedicine, radiation biology, oncology, and immunology to launch a robust and successful research program by receiving a tenure track faculty position. By leading multidisciplinary research to push the boundaries of personalized cancer immunotherapy and mentoring the next generation of scientists in immunoengineering, he aims to build a successful career as an assistant professor. His vision is to establish a highly collaborative research team focused on unraveling the complex dynamics of immune cell-biomaterial-tissue interactions within the TME, driving the development of innovative immunotherapeutic strategies for effective disease treatment. The NCI Transition Career Development Award is a vital cornerstone for successfully launching his independent research laboratory. It provides essential support for developing expertise in grant writing, effective research management, communication skills, and fostering constructive collaborations. Closely collaborating with Dr. Charles Perou, a world-renowned expert in breast cancer genomics and molecular subtypes, and Dr. Benjamin Vincent, a specialist in cancer immunogenomics, ensures comprehensive expertise, support, and access to state-of-the-art resources for the proposed experiments. Both collaborators are affiliated with the UNC School of Medicine and the UNC Lineberger Comprehensive Cancer Center, fostering an ideal environment for advancing this research.

The U District Partnership

The U District Mural Program is an initiative to build vibrancy in Seattle's University District by adding new works of public art. Murals will be installed in the following locations: 1313 NE 42nd Street, 1319 NE 43rd Street, and 4261 Roosevelt Way NE. This project will be completed by August 31, 2021.

U.S. Mission to Colombia

PAS Bogota invites proposals for programs that strengthen societal and cultural ties, shared values, and bilateral cooperation between the United States and Colombia in support of U.S. Embassy Strategic Goals. All programs must include a U.S. cultural or educational element or connection with American expert/s, organization/s, or institution/s in a specific field that will promote increased understanding of U.S. policy and perspectives, and build partnerships between our citizens. Examples of PAS Small Grants Program programs include, but are not limited to: Academic and professional lectures, seminars and speaker programs; Artistic and cultural workshops, joint performances, and exhibitions; Awareness-raising programs on the challenges persons with disabilities face accessing the democratic process, including the lack of reasonable accommodations and information to exercise their political rights. Cultural heritage conservation and preservation programs; Policy advocacy programs that promote and advance the human rights of historically underserved and marginalized groups such as Afro-Colombians, Indigenous, lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI+), persons with disabilities, and persons otherwise adversely affected by persistent inequality. Workshops to strengthen networks of U.S. government (USG) programs alumni, CSO/NGO networks, entrepreneurial networks, and/or educational groups. Priority Program Areas: The Embassy s Cultural and Educational Grants Program supports U.S. Mission Bogota s strategic objective of enhancing opportunities for citizen participation in support of peace through cultural and educational program and advances the diversity, equity, inclusion, and accessibility (DEIA) and climate and environment priorities. Diversity, Equity, Inclusion, and Accessibility (DEIA) Disability Rights: o Projects that advance the rights of persons with disabilities, build capacity of organizations that advocate for enforcement and effective implementation of disability-inclusive legislation and policies, and promote democracy and political participation of persons with disabilities, among others. o Projects focused on improving access to educational opportunities for persons with disabilities. LGBTQI+: o Policy advocacy programs that advance the rights of lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI+) persons, including efforts to safeguard LGBTQI+ youth from harmful practices (e.g., so called conversion therapy ). o Programs that improve the quality of investigative journalism and transparency, increase awareness of the impact of stereotypical and biased reporting on LGBTIQI+ persons and women, and help counter disinformation. Climate and Environment Environmentally-focused activities addressing the climate crisis, combating wildlife trafficking, fostering resilience, conserving nature, water security, and reducing harmful pollutants, including, but not limited to, awareness raising campaigns, leadership, or capacity-building training workshops for youth and underserved communities, a recycled art installation or competition, among others. In addition to the outlined priority program areas, the Public Affairs Section may give consideration to project proposals focusing on the following topics: Science, Technology, Engineering, Arts, and Mathematics (STEAM) Economic empowerment of women, girls, Afro-Colombians, Indigenous communities, the Venezuelan diaspora, LGBTQI+ persons, and other underserved populations. Any other initiatives supporting Colombia s transition to a sustainable and inclusive peace. Project proposals managed by teams of U.S. government (USG) program alumni or designed to strengthen the USG alumni network in Colombia are highly desirable and will be given priority.

U.S. Mission to Tunisia

U.S. DEPARTMENT OF STATE U.S. EMBASSY TO LIBYA, PUBLIC AFFAIRS SECTION Notice of Funding Opportunity (NOFO) Funding Opportunity Title: U.S. Embassy to Libya PAS Annual Program Statement Funding Opportunity Number: PAS Tripoli FY2024 CFDA Number: 19.040 Public Diplomacy Programs Maximum for Each Award: $25,000 USD PROGRAM DESCRIPTION The U.S. Embassy Tripoli Public Affairs Section (PAS) is pleased to announce that funding is available through its Public Diplomacy Small Grants Program. This is an Annual Program Statement, outlining our funding priorities, the strategic themes we focus on, and the procedures for submitting requests for funding. Please carefully follow all instructions below. The objectives of the Public Diplomacy Grant Program are to build capacity and community, promote social good, and enhance mutual understanding between the people of Libya and the United States. The U.S. Embassy to Libya is seeking projects that: Capitalize on arts initiatives to increase unity, social cohesion, and reconciliation that deepen Libyan national identity and are consistent with U.S. values. Promote leadership, positive community engagement, volunteerism, entrepreneurship, and soft skills development among youth, women, and underserved communities. Increase Libyan youth capabilities to help them explore and develop technological solutions for social problems through Science, Technology, Engineering, Arts, and Math (STEAM) programs. Projects that address environmental challenges to mitigate the effects of climate change are highly encouraged. Note: Alumni of U.S. Government funded exchange programs are encouraged to apply. Initiatives that support diversity and inclusion of minority groups and link with U.S. universities or organizations are also welcome. Additional information on this link: https://ly.usembassy.gov/notice-of-funding-opportunity-nofo/

U.S. Mission to Morocco

The U.S. Mission in Morocco s Public Affairs Office (PAO) is pleased to announce that funding is available through the Public Diplomacy Grant Program for projects ranging in value from $5,000 to $25,000. Projects for lesser or greater values will be considered on a case-by-case basis. The objectives of the Public Diplomacy Grant Program are to promote positive relations between Morocco and the United States; reinforce shared values; and connect Morocco s emerging leaders to the American people through projects that: Strengthen understanding of U.S. values and institutions; highlight U.S. culture, including American Studies, English language teaching/learning, and study in the United States; and support diversity, acceptance of minority groups, and other areas of mutual interest. Help Moroccan youth explore and discover their potential through innovative science, technology, engineering, arts, and math (STEAM,) programs, as well as entrepreneurship programs. Encourage Moroccan youth to participate in civic life through social entrepreneurship, volunteerism, and community engagement. APPLICATION PROCESSApplication DeadlinesApplications will be reviewed three times during Fiscal Year 2020. The deadlines for application are:Round 1: November 30, 2019Round 2: March 31, 2020Round 3: June 30, 2020Proposal FormatTo apply, please complete these forms in English:The Project Narrative (DOC 47 KB)The Budget Proposal (XLSX 22 KB)SF424 (Application for Federal Assistance Must be signed) (PDF 265 KB)SF424A (Budget Information) (PDF 1 MB)SF424B (Assurances Must be signed) (PDF 70 KB)Submit all forms in electronic format to: Rabatgrants@state.gov

U.S. Mission to Australia

The U.S. Mission to Australia s Public Diplomacy Section (PDS) announces an open competition to implement projects that advance U.S. economic, commercial, and security interests in Australia. This Annual Program Statement (APS) outlines strategic goals, expected outcomes, target audiences, eligibility criteria, and application guidelines for cooperative agreements ranging from $25,000 to $100,000, with a project duration of up to 24 months. Project proposals must address at least one of the following goals: Promote flag football in Australia; Combat antisemitism through Holocaust education; Strengthen Pacific Islands partnership by highlighting shared cultural values among the peoples of the United States, Australia, and the Pacific Islands focusing on arts, cultural heritage preservation, education, and training.In addition to aligning with one of the strategic goals, applicants should clearly explain how they advance American leadership and excellence and how the projects deliver measurable results. All programs must include a clear connection to or inclusion of American expert(s), organization(s), or institution(s) or cultural elements in a specific field that will promote increased understanding of United States policy and perspectives.Please read the entire APS package before submitting an application. Applications must be submitted by September 20, 2026, for projects beginning as early as October 1, 2026. For more information, contact PASGrantsAustralia@state.gov. Applications that do not meet the eligibility criteria and do not contain all of the required information will not be considered.

U.S. Mission to Australia

<p>The U.S. Mission to Australia’s Public Diplomacy Section (PDS) announces an open competition to implement projects that advance U.S. economic, commercial, and security interests in Australia.&nbsp;This Annual Program Statement (APS) outlines strategic goals, expected outcomes, target audiences, eligibility criteria, and application guidelines for cooperative agreements ranging from $25,000 to $100,000, with a project duration of up to 24 months.&nbsp;Project proposals must address at least one of the following goals:</p><p>·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Promote flag football in Australia;</p><p>·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Combat antisemitism through Holocaust education;</p><p>·&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Strengthen Pacific Islands partnership by highlighting shared cultural values among the peoples of the United States, Australia, and the Pacific Islands focusing on arts, cultural heritage preservation, education, and training.</p><p>In addition to aligning with one of the strategic goals, applicants should clearly explain how they advance American leadership and excellence and how the projects deliver measurable results.&nbsp;All programs must include a clear connection to or inclusion of American expert(s), organization(s), or institution(s) or cultural elements in a specific field that will promote increased understanding of United States policy and perspectives.</p><p>Please read the entire APS package before submitting an application.&nbsp;Applications must be submitted by September 20, 2026, for projects beginning as early as October 1, 2026.&nbsp;For more information, contact PASGrantsAustralia@state.gov.&nbsp;<strong>&nbsp;Applications that do not meet the eligibility criteria and do not contain all of the required information will not be considered.</strong></p>

U.S. Virgin Islands Council on the Arts

Arts and cultural grants for organizations in U.S. Virgin Islands, supported by NEA federal funding.

Over Educated Minority Artists - OEMA

The Labateyah Harvest Feast scheduled for Saturday, November 18th at 9010-13th Avenue NW, from 3:00-8:00 pm will be a time of art, music, dance, poetry, and food. This gathering of people young and old, is an ancient tradition of the Northwest Indigenous tribes. History is told and artwork is traded in an effort to create relationships. Music and dance are performed to inspire and uplift.

OD - NIH Office of the Director

Project Summary/Abstract The newly established Andrew & Erna Viterbi Family Vision Research Center at UC San Diego currently does not have an ultracentrifuge. As research laboratories move into the building, there is a critical need for core instrumentation to support their work. We have selected the Beckman Coulter Optima XPN-100 IVD ultracentrifuge and three rotors (Type 70Ti, SW32Ti, SW41Ti). This instrumentation will support the work of nine Major users for applications such as density gradient preparation, high-titer virus production, lipoprotein isolation, vessel isolation and more. While similar ultracentrifuges exist on UC San Diego campus, they are typically located within locked lab spaces designated for specific departments or building occupants. In addition, transporting samples between buildings can disrupt density gradients, compromise sample integrity and delay downstream processing. It is therefore critical for researchers to have access to an ultracentrifuge within the building. The ultracentrifuge will be housed in the shared equipment room of Andrew & Erna Viterbi Family Vision Research Center. The new research center, opening in June 2025, will have state-of-the-art wet and dry laboratories for vision research and clinical trials for precision ophthalmology, as well as administrative and educational spaces. The ultracentrifuge is an integral piece of equipment for many research groups relocating to the building, and access to it will directly support efforts to understand and treat ophthalmologic diseases.

OD - NIH Office of the Director

ABSTRACT The University of Rochester has a long, internationally recognized history of research about the effects of airborne substances in the lungs and other organ systems. Indeed, Rochester is the birthplace of inhalation toxicology, as technology was developed here during the Manhattan Project to conduct studies on the effects of radionuclides. The infrastructure has grown over the decades into a dedicated Inhalation Exposure Facility (IEF) that supports basic and translational research about how airborne substances, by themselves or in combination with other stressors, contribute to cumulative health risk across the lifespan. Ambient air pollution is a mixture of particles, gases, and semi-volatile constituents that exhibits temporal and spatial variability in composition and concentration. It continues to be a significant threat to human health. Ambient pollutant fine and ultrafine (UFP, <100 nm in airborne diameter) particles are largely combustion- derived, e.g., from industrial and traffic sources, and have carbonaceous, inorganic salt, and metal/metal oxides compositional signatures. UFPs are of particular interest as drivers of adverse health effects due to their high number concentrations in air, large surface area-to-mass ratios, ability to deposit efficiently throughout the respiratory tract, and potential for transport to extrapulmonary tissues upon inhalation exposure. The study of UFP exposure-related health effects is an area of strength for the Rochester IEF. Its infrastructure has supported ground-breaking discoveries about the effects of UFP in the lung and extrapulmonary organ systems (cardiovascular, central nervous); transport of inhaled UFP to the brain via the olfactory system; perturbations in learning, memory, and impulsivity behaviors; and the mechanisms that lead to these adverse effects. The IEF tools for generating and characterizing UFP exposures are heavily utilized by multiple investigators who are funded by NIH and other agencies. To support these funded projects and to ensure that the research is conducted in a rigorous manner, replacement of and upgrades to the equipment that is used to generate, monitor, and characterize UFP-rich aerosols for inhalation exposures are urgently needed. Thus, this application seeks support to purchase a new integrated UFP aerosol generation and characterization system with modernized safety and monitoring features. This integrated system allows direct translation between species: knowledge about human exposures to UFP can be leveraged to conduct evidence-generating mechanistic studies in animal models or cell culture systems and, vice versa, health outcome data from basic science models can be translated to human-relevant exposures. Without this system that represents the state-of-the-art, the translatability of findings from UFP inhalation exposures is significantly weakened and, by extension, the impact of findings on evidence-based decision making.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY The goal of this F31 fellowship application is to support and promote my (Erin Burman’s) training as a pre- doctoral student in the Department of Environmental Health of the Harvard T.H. Chan School of Public Health and the Graduate School of Arts and Sciences at Harvard University. My long-term research interests focus on the association of air pollution on cardiovascular (CV) conditions and mortality. I have assembled a group of leading experts as my Sponsors and Co-Sponsors including Drs. Francine Laden, Andrea Bellavia, Eric Rimm, and Joel Schwartz. Air pollution is the second leading risk factor for death worldwide, with nearly half of these deaths due to cardiovascular disease (CVD). Airborne particulate matter (PM) is well-understood to be particularly harmful, with much research and regulation focusing on PM with diameter < 2.5 microns (PM2.5). However, PM2.5 is a complex mixture composed of various size fractions and a variety of chemicals, and it is unclear which of these constituents drive PM2.5’s toxicity. Identifying particularly harmful PM constituents has been challenging because constituents have complex correlation structures that are difficult to model with conventional statistical methods. Confounding bias has also made identifying causal effects challenging. In this study, we will investigate the effects of long-term exposure to ultrafine particles (UFPs) with diameter < 100 nm as well as fifteen chemical components of PM2.5 – including elemental carbon (EC), ammonium (NH4), nitrate (NO3), organic carbon (OC), sulfate (SO4), and elements Br, Ca, Cu, Fe, K, Ni, Pb, Si, V, and Zn -- on CV conditions and mortality. We leverage new spatial and spatiotemporal models of these pollutants, linking them to the Nurses’ Health Study II (NHS II), a nationwide longitudinal cohort. We will model UFPs and PM2.5 chemical components as a mixture, using methods such as weighted quantile sums (WQS), quantile g- computation, and other machine learning methodologies to account for correlations and identify especially harmful constituents of the mixture as well as its joint effects on incident hypertension (Aim 1) and incident CVD (encompassing coronary heart disease and stroke) as well as CV mortality and all-cause mortality (Aim 2). Finally, we will leverage a quasi-experimental design to investigate changes in the exposure mixture among the subset of nurses who moved residential addresses during follow-up, and those changes’ association with hypertension, CVD, and CV and all-cause mortality (Aim 3). As concentrations and sources of PM change in the U.S. and abroad, understanding which constituents of air pollution are most harmful will allow for informed response and targeted reductions of specific pollutants. In this research training plan, I will receive extensive training in multiple aspects of exploring the impacts of PM constituents on CV health and mortality. This will position me as a future leader in the field of air pollution epidemiology through high-quality mentorship and extensive professional development opportunities.

NIGMS - National Institute of General Medical Sciences

Project Abstract Despite over sixty years of research, many unanswered questions on Adeno-associated virus (AAV) biology exist. Following AAV delivery, a small fraction of AAV genomes persists as episomes, yet the mechanisms underlying this “Selective Persistence” remain poorly understood. Ours and others’ work has shown that AAV inverted terminal repeats (ITRs) play important roles in genome conversion, persistence, and safety. My recent work identified novel ITR design that attenuates toxicity and unique genetic “signatures” associated with long-term episomal persistence in mice, we have further shown proof-of-concept that grafting these persistence “signatures” onto synthetic substrates prolongs gene expression in mice. However, it remains to be determined whether the persistence “signatures” we observed in mice are also present in humans. To address this, we will answer three questions in this proposed work. First, what is the fate of AAV genomes across human tissues, and what molecular features the AAV episomes possess? Second, can genome fate be modulated by ITR engineering to enhance stable episome formation and reduce vector dose requirements? Third, to what extent can AAV-derived persistence mechanisms be grafted onto nonviral vectors to achieve durable expression? My lab integrates virology, genome engineering, genome–protein profiling and organ-on-chip systems with state- of-the-art techniques: long-read Sequencing, Spatial Biology, and Mass Spectrometry. Uniquely, through the human decedent H2H platform, we can directly examine AAV genome fate across human tissues—an unprecedented opportunity for the field. By combining these technologies, we may uncover how AAV episomes form, persist, and interact with host factors, expand our understanding of AAV biology, provide a foundation for safer and more efficient AAV therapies, and pioneer cross-platform strategies to enhance the durability of nonviral (including synthetic substrates) gene delivery.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The filoviruses Ebola virus (EBOV) and Marburg virus (MARV), cause severe disease in humans with high case fatality rates. Advanced metagenomic analyses led to the discovery of previously unknown filoviruses from a range of animal species. Newly discovered filoviruses include Lloviu virus (LLOV) and Dehong virus (DEHV). While recent work on LLOV suggests that it might not pose a threat to human health, it is not known if DEHV can cause disease in humans. The discovery of novel filoviruses provides an excellent research avenue for determining the molecular correlates that define pathogenicity or protection by comparing closely related pathogenic and potentially nonpathogenic viruses. In this application, we propose to perform comparative studies with pathogenic (EBOV, MARV), likely nonpathogenic (Reston virus, LLOV), and filoviruses of unknown pathogenicity (DEHV). We will analyze potential determinants of filovirus pathogenicity across viruses, including replication kinetics (Aim 1), the magnitude of the virus-induced inflammatory response in macrophages (Aim 2), and virulence in two humanized mouse models (Aim 3). By integrating findings from all three aims, we will be able to define key molecular signatures of filovirus infection that have the potential to inform the assessment of the pathogenic potential of known and newly emerging filoviruses. In Aim 1, we will compare the replication kinetics of the various viruses in distinct cell types, which will inform about the virus-intrinsic and cell-dependent factors determining replication efficiency. We will perform RNA FISH analysis to gain insight into the earliest events of viral transcription and genome replication at single-cell level. Since viral replication kinetics determine the timing and rate of viral RNA production and protein expression, they may play a major role in shaping antiviral host responses and virulence. In Aim 2, we will comprehensively profile the phosphoproteomic/proteomic and transcriptomic changes in filovirus-infected human macrophages to map the differences in the host response signatures induced by pathogenic and nonpathogenic viruses. These analyses will be accompanied by mechanistic studies aimed to dissect the molecular mechanisms of filovirus-induced immune activation using knockdown cells and targeted inhibitor approaches. In Aim 3, we will comparatively assess the ability of the various filoviruses to cause disease in two human immune system (HIS) mouse models. This includes state-of-the-art histopathological analysis of the tissues including spatial transcriptomics. Our multidisciplinary team combines expertise in filovirus biology, virus-induced activation of innate immune cells, omics analysis, humanized mouse models, and histopathology of filovirus-infected tissues. We are therefore well positioned to perform the proposed work.