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NEI - National Eye Institute

SUMMARY Alpha herpesviruses are a subfamily of ubiquitous viruses that can cause a spectrum of clinically-significant diseases including blindness from acute retinal necrosis (ARN). Unfortunately, even with timely antiviral treatment, irreversible pathological changes occur within the retina and significantly increase the risk of vision- threatening complications to further compromise an already poor visual prognosis. Since the advent of acyclovir, there have been no major advances in the treatment of clinically-significant herpes infections despite the vision-degrading complications and very little is known in regards to the immune response to the virus within the retina. This proposal will provide a fundamental understanding of the innate immune response to HSV-1 within the retina, while developing critical skills in career development. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding and pursue novel therapies to preserve vision and reduce complications related to ARN as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that type I interferons (IFNs) are central to host defense to viral infection of the retina and that toll-like receptor-3 within retinal microglia activate this innate immune response. We propose evaluating the innate immune response to herpes virus infections of the retina by utilizing several immune knock-out mouse lines, human retinal cell cultures, and vitreous specimens from patients with ARN to assess the role of IFNs and their role in neuroinflammation. Three focused specific aims will be utilized to test our hypothesis: 1) Identify pathways and cell types responsible for HSV innate immunity within the retina; 2) Determine the role of downstream IFNs in host defense against viral infection of the retina; 3) Identify the predominate IFN subtype and cellular source in acute retinal necrosis from human samples. The career development objective is to develop the mentorship and expertise needed to become a productive and independent clinician-scientist. The Department of Ophthalmology and Visual Sciences and the University of Nebraska Medical Center have state-of-the-art laboratory facilities and world-class faculty with expertise in neuroimmunology, viral infections, and innate immune signaling to serve as the mentoring team. The institutional resources, mentorship team, and career development plan have been developed to specifically promote scientific independence in the study of neuroinflammation of the retina.

Inner-City Muslim Action Network

Supports community organizing, health services, arts, and transitional housing on Chicago's South Side. Model for faith-based community development.

Innovia Foundation

Innovia Foundation ($200M in assets) supports nonprofits in WA through grants focused on education, community development, health, arts. Awards range from $1,000 to $50,000.

NCATS - National Center for Advancing Translational Sciences

PROJECT SUMMARY The Penn-CHOP Clinical and Translational Science Award (CTSA) Hub proposes a transformative vision to catalyze a dynamic clinical and translational science (CTS) ecosystem that accelerates the delivery of innovative, life-altering therapies to individuals across the lifespan. Aligned with the NCATS mission to bring more treatments to all people more quickly, our Hub will leverage its nationally-recognized strengths in translational therapeutics, data science, community engagement, and workforce development to advance the science and practice of clinical translation. We propose four integrated aims: (1) Innovate novel approaches to advancing the development and dissemination of translational therapeutics; (2) Accelerate the application of state-of-the-art data science resources and dynamic data ecosystems to enable a Penn-CHOP academic learning health system (aLHS) framework and catalyze groundbreaking CTS; (3) Integrate our Hub with our communities and stakeholders to promote community-partnered and collaborative research within families and across the lifespan; (4) Educate, train, advance, and retain a skilled multidisciplinary workforce ready to meet the demand of an ever-evolving CTS and and CTR landscape. Our Hub will serve as a national model for integrated, community-engaged, and data-driven translational science. Through rigorous evaluation, continuous quality improvement, and dissemination of best practices, we aim to contribute meaningfully to the CTSA consortium's collective impact on public health.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY First-ever data from Zambia on people who inject drugs (PWID) demonstrates major gaps in the HIV epidemic response. A recent biobehavioral survey show sharp health disparities along the entire PWID HIV care continuum, with gaps in HIV testing, linkage to ART, and viral suppression, and limited knowledge of PrEP. Failing to detect early HIV infections and address unsuppressed viral load poses a risk of ongoing community transmission as well as increased risk for HIV comorbidities and mortality, threatening the overall HIV epidemic control response in Zambia. The Zambia Ministry of Health has adopted a harm reduction approach to address the health disparities experienced by PWID. Starting in November 2024, the Zambia Ministry of Health will provide Medications for Opioid Use Disorder (MOUD) at two health facilities which also provide HIV services. There is currently minimal evidence in sub-Saharan Africa on MOUD integration with HIV care. The arrival of MOUD in Zamvia presents an exceptional opportunity to collaborate with Ministry of Health and key partners to develop a person-centered integrated collaborative care model for PWID and pilot testing implementation, feasibility, and preliminary effectiveness within the Zambian health system. We propose the Integrated Services for PWID using Person-centered Interactions, Reach, and Engagement (INSPIRE) study to co-adapt and evaluate an HIV status-neutral system-level integrated approach using a Collaborative Care Management Model (CoCM) for HIV prevention, HIV care, mental health, and MOUD. This implementation science study includes the following Aims: Aim 1: Assess the multilevel determinants of early implementation of MOUD services using rapid qualitative analysis. Aim 2: Co-adapt an HIV status-neutral CoCM with key stakeholders. Aim 3: Implement and evaluate the co-adapted CoCM, guided by Practical, Robust Implementation and Sustainability Model (PRISM), and including the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) outcomes. The research team, led by Multiple Principal Investigators (MPI), has expertise in psychiatry, HIV clinical care, implementation science, behavioral and social sciences, HIV clinical care, epidemiology, and mixed methods, and has a deep knowledge of HIV response and service delivery models in Zambia for marginalized populations, and experience implementing opioid use treatment both in the US, and in Kenya. We will also leverage the University of Maryland Baltimore’s decade of experience implementing MOUD and HIV programs in Kenya. Addressing the unmet needs of PWID is urgently needed to achieve and maintain HIV epidemic control; our findings will inform the implementation of integrated care models for PWID. Lessons learned from INSPIRE will help develop best practices for system-level approaches to improve OUD treatment and HIV prevention and treatment programs in both sub-Saharan Africa and the US.

NIDA - National Institute on Drug Abuse

Substance use disorder (SUD) is a leading public health challenge, with long-term consequences for physical and mental health. In-person peer support groups are well-established as beneficial for recovery. However, as digital platforms increasingly serve as spaces for peer support, little is known about how engagement in online peer support recovery groups is associated with recovery outcomes. Emerging research has yielded conflicting results, with some studies suggesting benefits while others indicating relapse risks. This underscores the need to examine the content of discussions beyond engagement frequency. The present application seeks support for Xiangyu Tao, Ph.D., a postdoctoral associate at the Rutgers Addiction Research Center, gain the necessary training and set up a line of research to examine the role of online peer support recovery communities in SUD recovery. Specifically, she will integrate state-of-the-art artificial intelligence (AI) techniques, including Large Language Models (LLMs), with co-production to identify communication patterns and to examine their associations with recovery outcomes. LLMs offer a promising avenue for analyzing large-scale online discussions, yet they require human oversight to address challenges such as contextual misinterpretation and ethical concerns. Co-production, i.e., involving individuals with SUD recovery experience in all research stages, mitigates LLM limitations and ensures that results reflect lived experience. The mentored K99 phase will identify and characterize communication patterns in online recovery groups. Peer support and co-rumination patterns will be classified using LLMs and co-production (Aim 1); latent class analysis (LCA) will identify distinct communication profiles among users engaging in these online groups (Aim 2). During this phase, Dr. Tao will receive mentorship in co-production and AI methodologies, longitudinal data analysis and management, and responsible AI research. The independent R00 phase will build upon this foundation by examining how communication profiles are associated with recovery trajectories using longitudinal survey data from online recovery group participants (Aim 3). This project is highly innovative in its integration of LLMs and co- production to analyze large-scale digital recovery discussions, ensuring that AI-driven insights are both computationally rigorous and socially informed. Findings will enhance understanding of digital peer support for SUD recovery and will inform future mechanistic studies and SUD interventions. By identifying communication patterns associated with recovery trajectories, this project will guide digital health platforms, peer support programs, and clinicians in optimizing online recovery environments to better support individuals with SUD. This project aligns with the NIDA Strategic Plan Cross-Cutting Priority to "Leverage Data Science and Analytics to Understand Real-World Complexity" by utilizing advanced computational methods to analyze digital recovery support interactions. The project is highly significant in bridging advanced AI computational tools with the lived experiences of individuals to produce impactful research to promote substance use recovery.

NIDA - National Institute on Drug Abuse

PROJECT ABSTRACT We seek to refine, field test, and deploy an intelligent AI-based chatbot in small, peer-to-peer mobile support groups for smoking cessation. The chatbot will complement the human support group members by responding to posts when no human can. We expect the chatbot to improve engagement by ensuring no post goes unanswered. By developing and testing this chatbot, we hope to breathe new life into research on mobile health support groups which have been challenged by low engagement. We have already built a chatbot using a state-of-the-art open-access LLM (large language model) and set it up on a local, dedicated, secure server. The LLM does not store data on the cloud and all posts are encrypted before server storage. We have trained our chatbot on 77400 posts from our past mobile support groups to accurately comprehend the 25 most common post types. We have developed 25 response libraries for the chatbot that contain over 1k responses developed from knowledge bases, e.g., it provides support for quitting, assists with study-provided NRT, and advises on coping with cravings and stress. Our chatbot intervention is based on the Supportive Accountability Model of Mobile Health. We expect the peers in the group to provide legitimate information that is relevant, trustworthy, and expert, and to form social bonds by being caring, nonjudgmental, and timely, increasing accountability and adherence. By adding a chatbot, we hope to provide additional legitimate information and social bonding. Aim 1 is to refine the chatbot using human-centered design methods. Before putting the chatbot into groups, we want to ensure it can communicate 1:1. We will recruit 4 groups of 5 smokers (N=20), and ask each person to interact with the chatbot, using all 25 post types. They will think aloud in the presence of trained staff to identify and solve usage problems. The sessions will be taped, a survey conducted, and usability metrics assessed. Aim 2 to conduct a one-armed field trial to assess the chatbot’s feasibility and acceptability within human support groups. We will recruit smokers in 2 groups of 10 (N=20). Participants will be placed in a mobile group with the chatbot and asked to support each other in quitting for 2 weeks. We will download and analyze posts and conduct exit interviews. Aim 3 is to conduct a pilot RCT of chatbot efficacy. We will recruit 4 cohorts with 30 smokers per cohort, randomizing 15 smokers to intervention arm (support group with chatbot) and 15 to control arm (support group without chatbot). We will measure primary and secondary engagement outcomes and will have adequate power to compare intervention vs. control. We will also measure intervention-end bioconfirmed abstinence to power a larger RCT.

NCI - National Cancer Institute

PROJECT SUMMARY The overall goal of this project is the comprehensive structural and dynamic characterization of the highly flexible human K-Ras oncoprotein and its interactions with protein-binding partners and small-molecule ligands in both its normal and dysregulated states by the combined use of state-of-the-art experimental and computational methods. K-Ras is well-known to be exceptionally susceptible to carcinogenic mutations in certain key amino-acid positions, which through a cascade of protein signaling processes dysregulate cell proliferation. K-Ras is directly associated with about 25% of all human cancers. As a GTPase, K-Ras is a molecular switch with wild-type K-Ras being in its on-state when bound to GTP and turning to the off-state through catalytic hydrolysis of GTP to GDP. In oncogenic mutants, such as G12C, G12D, and G12V, K-Ras is perpetually locked into active signaling of the Ras-Raf-MEK-ERK pathway leading up to malignancy. This project builds on recent breakthroughs in the applicant’s lab overcoming two key obstacles that have severely impaired past efforts to understand K-Ras and its interactions with its protein partners and potential drug ligands: they made the functionally critical Switch I and Switch II regions of K-Ras fully visible and assigned by NMR and overcame the need to work with non-hydrolyzable GTP-analogs instead of native GTP as an integral K-Ras ligand. Leveraging these advances, it is proposed to comprehensively investigate the structural-dynamics ensembles of K-Ras in the presence and absence of its functionally critical protein binding partners and small-molecule ligands by NMR and computational modeling. This entails the full characterization of the modes of interactions of K-Ras wild-type vs. G12 mutants and GTP- vs. GDP-bound with the small-molecule drug candidate MRTX1133, protein GTPase activating protein (GAP), and the RBD and CRD domains of the downstream signaling protein-kinase B-Raf. The wealth of quantitative NMR data at atomic resolution will give novel information essential for our understanding of the driving forces underlying K-Ras and its function in health and disease. These data will provide powerful synergies with computational approaches, such as AlphaFold and extended molecular dynamics computer simulations for obtaining a realistic, experimentally validated in silico description of K-Ras behavior in the presence of its binding partners for wild-type and the mutants. Validated conformational ensembles will be subsequently mined for allosteric effects and used for virtual ligand screening including cryptic pockets uncovered during this process. Due to its highly dynamic nature, the fully quantitative atomic-level structural-dynamic model of K-Ras and its binding partners is likely to be directly beneficial enabling the discovery of key molecular determinants of K- Ras cancer biology and guiding the design of new therapeutic strategies to silence mutationally activated K-Ras.

NIGMS - National Institute of General Medical Sciences

Tulane University was started as the Medical College of Louisiana in 1834 and has a long track record of training physician scientist leaders in US Medicine including Dr. Michael DeBakey, Dr. Ruth L. Kirschstein, past Director of NIGMS and NIH, and Dr. Clyde Yancy, Chief of Cardiology at Northwestern University. Recognizing the need to train the next generation of physician scientists, the Dean established the Physician Scientist Program in 2002 that provides tuition support for 2 trainees per year from the Dean’s office. Over 90% of these trainees have stayed in academic research and some of the trainees have been awarded independent research grants already. Tulane has made a strong commitment to research with establishing the American Association of University (AAU) recruitment program that has led to the recruitment of several AAU scholars that have increased Tulane’s investigator initiated R01 funding by over 70% in the last five years. Moreover, President Fitts has established the Presidential Chairs of which two reside in the School of Medicine. This strategic investment has greatly increased the training opportunities for MD-PhD students. Recognizing the need to expand this program, Tulane has developed this MSTP application to take advantage of the exceptional training faculty in the School of Medicine, the School of Public Health, and the School of Science and Engineering. This program takes advantage of several pipeline programs already established at Tulane to target STEM based students in clinical and bench research and provide these undergraduates, the skillset to be competitive applicants to the MSTP program. Moreover, this program will complement the NHLBI funded R38 that focuses on the resident pipeline. The goal of TuLEAD is to train a cohort of MSTP students in innovative research in the areas of infectious disease, immunology, cardiovascular and renal physiology, and pharmacology. Aim 1: Tulane MSTP will develop a highly innovative national and local campaign to identify and encourage meritorious students to train as physician scientists and provide them with rigorous dual degree training in clinical medicine and in wet-lab or dry-lab (or both) research. Aim 2: We will train clinician-scientists with the necessary qualifications to conduct rigorous scientific research and engage in clinical and translational research across the spectrum of human disease. Training will be a through a combination of didactics, simulation, and state of the art rigorous research training. Aim 3: A key component of physician scientist development is not only learning and conducting rigorous research but to also serve as educators for the next generation. With the interaction of this program with Tulane’s undergraduate programs we well our summer research programs, MSTP trainees will also have the opportunity to serve as mentors. We have strong relationships with several undergraduate universities in New Orleans (such as Dillard University), and an established summer program for their undergraduates to work in Tulane laboratories, with current MD/PhD students mentoring one on one.

Turkish American Cultural Association of Washington

The International Children's Friendship Festival (ICFF-https://childrensfest.tacawa.org/) fosters cultural understanding and empowers Seattle youth. Inspired by International Children's Day, ICFF celebrates diverse young voices through a vibrant 2-day festival and year-round arts programs. Youth collaborate in art, public speaking, and civic advocacy, attracting thousands and gaining recognition from the City of Seattle. Celebrating its 15th anniversary in 2024, ICFF builds a more inclusive future through youth arts.

International Women’sDay - 2017

This event on March 11, 2017 from 9 am to 4 pm at The Brockey Center at South Seattle Community College will be held in celebration of International Women's Day. Through story-telling, facilitated conversations, collaborative art and dance, participants will know they are part of a caring and vibrant community of women. It is free and open to the public.

Somali Family Safety Task Force

On March 8, 2023 the Somali Family Task Force will be hosting the International Women's Day Celebration at New Holly Gathering Hall located at 7054 32nd Ave S from 4pm to 8pm. The event is a day to value women's achievements, raise awareness of their contributions to society, and a opportunity for immigrant women to come together for friendship, cross-cultural conversations, music, art, food and dance. The event is free and open to public.

NIEHS - National Institute of Environmental Health Sciences

Project Summary Up to 40% of the U.S. population is exposed to unhealthy air pollution, with particulate matter (PM) being a major contributor. PM exposure induces oxidative stress and inflammation and leads to severe lung diseases, which is mediated by the Aryl-hydrocarbon receptor (AhR) pathway and epithelial cytokines. Despite growing evidence, the underlying molecular mechanisms are not fully understood, limiting the development of targeted interventions. Emerging research suggests that PM exposure influences N6-methyladenosine (m6A) RNA modification, which regulates RNA stability and translation, through altering the expression of proteins adding, removing and binding to this modification ("Readers", "Writers", and "Erasers", abbreviated as "RWEs"). Intriguingly, RNA m6A "read- ers" can recruit epigenomic regulators such as DNA demethylase TET1 to alter DNA methylation and chromatin accessibility, highlighting crosstalk between RNA m6A and TET1-mediated epigenomic mechanisms. Whether RNA m6A interacts with TET1 and TET1-mediated epigenomic mechanisms in airway epithelial cells, how they interact and contribute to PM-induced lung inflammation remain as significant research gaps. In response to NIEHS RFA-ES-25-001 (EPCOT), this proposal aims to investigate the interactions between TET1-mediated epigenomic mechanisms and RNA m6A in PM-induced lung inflammation. Our preliminary data established a novel role of TET1 in protecting against PM-induced lung inflammation and remodeling, through promoting the expression of detoxifying enzymes downstream AhR signaling and restricting proinflammatory cytokines. Our data also suggest a novel, noncanonical role of TET1 in regulating chromatin accessibility and CTCF looping to regulate gene expression, in addition to DNA methylation and histone modification, in human bronchial epi- thelial cells. Importantly, we found that TET1 regulates the expression of RNA m6A RWEs in HBECs and mouse lungs, through both canonical and non-canonical roles, resulting in changes in global RNA m6A. Collectively, we hypothesize that TET1 mediates interactions between multiple epigenomic mechanisms and RNA m6A to re- strict PM-induced lung inflammation. To test this hypothesis, we will examine how TET1 regulates m6A RWEs in airway epithelial cells by analyzing 5mC/5hmC, histone modifications, chromatin accessibility, and CTCF-medi- ated looping in response to PM exposure in Aim 1. In Aim 2, we will identify genome-wide RNA m6A changes following PM exposure and TET1 loss and determine the impact of these changes on mRNA stability and protein translation of target genes, especially those contributing to lung inflammation. In Aim 3, we will identify genomic locations with both RNA m6A and TET1-regulated epigenomic features, investigate interactions between TET1 and m6A readers at these locations, and evaluate the impact of PM exposures on these interactions. Leveraging a highly collaborative research team with complementary expertise, unique PM samples and resources, and state-of-the-art technologies, the proposed research is expected to provide novel mechanistic insights into PM- induced pulmonary toxicity and disease, potentially leading to targeted interventional strategies.

NIDA - National Institute on Drug Abuse

Project Summary Investigating and Addressing Modifiable Factors in the HIV Care Continuum for People with HIV (PWH) affected by Substance Use and Mental Health Social determinants of health like poverty, and unstable housing, combine synergistically with comorbidities like substance use (SU) + mental health (MH) as a syndemic to disproportionately burden disadvantaged populations people living with HIV (PWH). Substance use and mental health comorbidities are associated HIV Continuum of Care Outcomes (HCC) like delayed entry into care, lower retention in care, reduced ART adherence, poor VL suppression, and higher mortality for PWH. For the US to end the HIV epidemic (EHE) by 2030, the underlying mechanisms of SRD- driven health disparities on viral suppression and HCC outcomes among all PWH experiencing substance use and mental health syndemic must be elucidated and addressed. The lack of suitable comprehensive longitudinal data to examine substance use, and mental health impact on dynamic changes in HCC outcomes limits our ability to end the HIV epidemic. Defining and describing the impact of substance use and mental health on HCC outcomes requires examining the complex interactions of sociocultural, economic, environmental, and geographic contexts influencing these interactions. To address the knowledge gaps on modifiable factors related to the intersection between SU+MH, we propose using real-world multiple linked datasets, including enhanced HIV/AIDS surveillance (e-HARS), Electronic Health Records (EHR), Department of Mental Health data, Department of Alcohol and Other Drugs of Abuse (DAODAS) data, corrections data administrative claims, and other relevant public data sources, to investigate the disparities in SU, MH recognition, treatments, and HCC outcomes using data science. We will use qualitative methods to examine interpersonal and intra-individual factors to identify modifiable factors for moderating the effects of the intersection of SU+MH on viral suppression and the HCC. The specific aims are to: 1. Examine and visualize the longitudinal patterns/trends, heterogeneity, and disparities arising from SU on viral suppression and other HCC outcomes among PWH in SC; 2. Determine the interactive effect of SU+MH on viral suppression and other HCC outcomes; and 3. Understand experiences and impact of SU+MH on viral suppression and other HCC outcomes among PWH population in SC using focus group discussions/in-depth interviews.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Neuroprosthetic interfaces provide paralyzed patients increased agency and independence. These intracortical implants interface with cortex at the cellular level, readout neural activity in real-time, and transform this activity into the actuation of computer cursors, robotic prostheses, and speech generators. Recent advances in the software underlying these devices have led to highly accurate brain-computer interfaces (BCIs) for improving health outcomes in patients with severe spinal cord injuries, neurodegenerative diseases, and stroke. However, there are still many fronts that require improvements. Namely, these devices have a learning curve on the order of days to weeks very similar to that of learning a new skill. In addition, even when accurate performance is reached, the natural drift of neural recordings necessitates system recalibrations, which requires the patient to briefly re-learn the new algorithmic parameters. Here, we propose that these learning periods can be reduced by augmenting the neural signaling pathways the brain uses to learn new BCI skills. A structure deep in the brain called the basal forebrain is known to play a strong role in learning new tasks, such as new motor movements. This region extends axons from cholinergic neurons up to cortical regions, where they are extremely active during the learning phase of new tasks, enhancing the local plasticity of cortical circuits. Recently, studies have shown that manipulating these axons can influence learning and task performance. For example, stimulating the vagus nerve can increase cholinergic activity and when timed properly can lead to faster learning rates and more accurate performance on a variety of sensorimotor tasks. In this work, we propose that the cholinergic neurons in the basal forebrain also play a major role in the learning and control of neuroprosthetic interfaces, particularly when these devices are implanted in motor cortex. To investigate this hypothesis, we will use a state-of-the-art combination of multiphoton imaging and transparent electrode arrays to record cholinergic axon activity near the implanted BCI as rodents learn to perform neuroprosthetic skills. In addition, we propose that vagus nerve stimulation can be used to excite cholinergic activity and reinforce neuroprosthetic learning, reducing the training time needed for animals to achieve expert-level control. Importantly, vagus nerve stimulation is an approved human treatment. Therefore, not only will our work reveal a fundamental circuit mechanism critical for BCI control, but our research opens the door to new applications of vagus nerve stimulation for enhancing neuroprosthetic performance in humans.

NIMH - National Institute of Mental Health

Project Summary HIV-1 associated neurocognitive disorders (HAND) affect 15 to 40% of people living with HIV (PWH), despite the use of anti-retroviral therapies (ART). Persistence of HAND in the presence of ART suggests that factors outside of viral replication contribute to neurocognitive impairment. The HIV-1 transactivator of transcription (Tat) is a neurotoxic viral protein that recapitulates cognitive impairment in the absence of viral replication and persists in virally suppressed PWH, likely generated from cellular reservoirs including microglia and astrocytes. Prior studies have separately shown that in the presence of Tat, the microglial transporter xCT is upregulated – increasing extracellular glutamate – and astrocytic EAAT2 is downregulated. Nonetheless, these mechanisms have been demonstrated with varying techniques and agnostic to how Tat expression within cellular reservoirs affects Tat-mediated toxicity and cognitive symptoms of HAND. Thus, we hypothesize that Tat expressed independently from microglia and astrocytes promotes aberrant glutamatergic neurotransmission causing NMDAR dependent excitotoxicity in the prefrontal cortex and cognitive impairment in HAND. In this proposal, we will use lentiviral transduction to model Tat expression from microglia and astrocytes, as the HIV-1 reservoirs of the CNS. We will then assess glutamate toxicity in this model in vitro and in vivo, by evaluating 1) EAAT2 or xCT expression and markers of gliosis [GFAP, Iba1], 2) extracellular glutamate levels in culture supernatants, 3) neuronal NMDA receptor expression and signaling via calcium levels. These outcomes will provide an understanding of how microglia and astrocytes respond to Tat and influence NMDAR- mediated neurotoxicity. To understand how these cell types drive toxicity and cognitive impairment in turn, lentivirus will be injected intracerebrally to prefrontal cortex of Sprague-Dawley rats. Two weeks after surgery, we will assess behavioral and molecular outcomes; or calcium levels in neurons and astrocytes. Animals will undergo testing in novel object recognition, spatial object recognition, and attentional set-shifting tasks, to assess learning and memory and cognitive flexibility. Brain tissue will then be assessed by immunoblot, RT- PCR, and calcium imaging to correlate cognitive impairments with molecular mechanisms; further paralleling the in vitro results to contextualize the contribution of Tat-mediated mechanisms to cognitive impairment. This study will elucidate the role of microglia and astrocytes as separate sources of Tat for their effects on glutamatergic neurotransmission and PFC-mediated cognitive functions. The proposal addresses a significant gap in the literature on microglia as the primary viral reservoir generating Tat, while accounting for the distinct impacts of each cellular reservoir on Tat-mediated glutamate toxicity and cognitive impairment. This will prompt future study into the microglial reservoir, and glutamatergic disease mechanisms that could be refined as therapeutic targets that are clinically relevant to neuropathology in PWH.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY / ABSTRACT A vaccine that elicits broadly neutralizing antibodies (bNAbs) against the Envelope (Env) protein of HIV-1 would be the best approach to end the AIDS epidemic; however, no efficacious vaccine has been developed to date. bNAbs targeting the conserved V3-glycan epitope of Env such as PGT121, 10-1074 and BG18 bind to the conserved GDIR motif of Env and to a key glycan at position N332 (N332 glycan). The absence of the N332 glycan in multiple HIV-1 strains limits the neutralization breadth of these bNAbs to ~60-70%. Based on observations by us and others, we hypothesized that V3-glycan antibodies that do not require the N332-glycan for binding can be elicited and matured into bNAbs by vaccination. We further hypothesized that N332-glycan independent V3-glycan antibodies will have greater neutralization breadth and that immunotherapies combining N332-glycan dependent and independent bNAbs will impose strong restrictions to viral escape, resulting in longer periods of suppressed viremia. To test these hypotheses, we developed WIN332, an Env-based immunogen that lacks the N332-glycan. Immunization with WIN332 in nonhuman primates (NHPs) induced a new class of N332-glycan independent V3-glycan antibodies. Most importantly, WIN332 elicited N332-glycan independent neutralizing antibodies to the V3-glycan epitope as early as three weeks after a single immunization. Our studies established a new classification of V3-glycan antibodies into Type-I (N332-glycan dependent) and Type-II (N332-glycan independent) and presented WIN332 as a promising vaccine candidate to streamline bNAb development (Relano et al, Nat.Immunol. in press). Further supporting our overarching hypothesis and this proposal, now two Type-II human bNAbs that target the V3-glycan epitope in a N332-glycan independent manner, EPTC112 and 007, have been reported, demonstrating that Type-II lineages can develop in humans and are a significant target for vaccine design. In this proposal, we will build on these studies and leverage WIN332 to investigate the new class of Type-II V3-glycan antibodies and its potential as a novel target for vaccine and immunotherapy design. In Aim 1, we will leverage WIN332 as a probe to isolate new Type-II bNAbs and bNAb precursors from infants and adults living with HIV-1 and from healthy donors respectively. We will characterize the newly isolated Type-II bNAbs and evaluate their capacity to increase neutralization coverage and restrict viral escape. In Aim 2, we will use our state-of-the-art methodology to produce new immunoglobulin knockin (Ig KI) mice that express unmutated precursors of human and NHP Type-II bNAbs and use these mice to investigate the maturation pathways of these bNAbs. Through advanced protein engineering approaches, structural studies and assessment in humanized mice, we will design novel vaccination strategies to mature N332-glycan independent lineages. We expect our innovative vision of the V3-glycan epitope will enable the identification and characterization of previously overlooked bNAb lineages of potential clinical value and will result in new immunization protocols to streamline bNAb development.

NCI - National Cancer Institute

Small cell lung cancer (SCLC) is a highly aggressive, recalcitrant neuroendocrine carcinoma associated with a dismal prognosis. Despite recent progress, the molecular mechanisms that promote the development of SCLC remain incompletely delineated and there is an urgent need for refined, more effective therapies. Our long-term goal is to elucidate the chromatin, epigenetic and transcriptional mechanisms that promote and are required for SCLC, and to translate these mechanistic findings to the clinic. We have recently identified recurrent inactivating mutations in genes that encode for subunits of the polybromo-associated BAF (PBAF), a SWI/SNF chromatin remodeling complex. Yet, the functional consequences, underlying mechanisms and therapeutic targets associated with PBAF inactivation are unknown. Our project is based on the following preliminary findings: 1) Genomic analyses of ~1200 SCLC patient samples reveal recurrent loss of function mutations in PBAF. 2) PBAF exerts tumor suppressor functions in cellular models. 3) PBAF-deficiency leads to a marked acceleration of SCLC development and a stark reduction in overall survival. 4) PBAF-deficient SCLC models exhibit increased chromatin accessibility and an upregulation of pro-growth, pro-metastatic gene expression programs. 5) PBAFdeficient SCLCs are reliant on residual SWI/SNF complexes for growth. Altogether, our results pinpoint a critical function for PBAF in SCLC. Our central hypothesis is that PBAF-deficiency promotes SCLC development by altering chromatin structure, transcription factor binding and gene expression programs, and that such alterations lead to the development of SCLCs with unique biological features and therapeutic vulnerabilities. To test these hypotheses, we will pursue the following three aims: 1) Establish the functional importance of PBAF during SCLC initiation, progression, and metastasis. 2) Elucidate the transcriptional and epigenetic mechanisms underlying PBAF-deficient SCLCs. 3) Evaluate SWI/SNF inhibition as a therapeutic strategy for PBAF mutant SCLCs. This project is significant because it focuses on understanding the function of a recurrently mutated chromatin remodeling complex in SCLC and will guide future translational efforts for the most aggressive form of lung cancer. It is conceptually and mechanistically innovative because it leverages the first PBAF-deficient mouse model of SCLC. Our investigations require the use of these innovative animal models to study the functions of PBAF during SCLC initiation, progression and metastasis, which is currently not possible with any other model. While there is no equivalent non-animal alternative that allows us to effectively perform the proposed investigations, the animal studies will be complemented, when suitable, with human centric models such as ex vivo human systems, patient derived xenograft models (PDXs) and human SCLC specimens. Finally, our study is technically innovative as it implements state-of-the-art epigenomic profiling techniques. Collectively, our research will improve the understanding of SCLC biology and reveal new therapeutic avenues for patients.

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

SUMMARY Human milk provides nutrients and important non-nutritive factors for infants that promote growth, development, and protection from infection1,2. Therefore, the World Health Organization (WHO) recommends exclusive breastfeeding for 6 months, then combining breastfeeding with solid foods for 18 months3. Lactation disorders reduce breastfeeding rates, and negatively impact both mothers and children. In mothers, lactation disorders influence mood and maternal well-being, while in children, they affect cognitive and socio-emotional development4, and can cause malnutrition, hypernatremia, hypoglycemia, and death5. Moreover, breastfeeding rates are lower in some ethnic minorities, which may partially reflect poor access to lactation consultants and early initiation of infant formula. Lactation disorders that specifically impair milk production and secretion affect about ~40% of breastfeeding mothers, the major phenotypes including: (i) agalactia: complete absence of milk secretion following birth; and (ii) hypogalactia: insufficient volume for optimal infant nutrition6,7. While post-partum stress, obesity, diabetes, and socioeconomic considerations have been associated with hypogalactia, we and others have demonstrated that hypogalactia has an inherited maternal genetic component6,8,9,10. However, the genetic mechanisms responsible for human lactation disorders are mostly unknown and have not yet been extensively investigated. We hypothesize that variations in genes involved in human milk production and secretion underlie disorders of milk production and secretion, and that these variants and genes can be discovered by interrogating genomic and extensive health and metadata from women with lactation disorders cases compared to unaffected female controls. We therefore propose to conduct a comprehensive study on whole exome sequencing (WES) data of lactation disorders patients. We are uniquely positioned to perform the first such study with the largest lactation disorders cohort to date (1,382 patients and over 60,000 female controls), combining four major biobanks: Vanderbilt University’s BioVU11,12, Mount Sinai Hospital’s BioMe Biobank13,14, All of Us and UK Biobank15,16. We propose a rigorous pipeline combining various state-of-the-art with cutting-edge approaches developed by us and others to: (1) obtain a high-quality WES lactation disorders cohort by variant- and sample-level quality control (QC)17,18, annotations19, and impact predictions20-22; (2) perform computational case-control analyses for high impact variants23,24; (3) prioritize variants and genes by biological relatedness approaches25-27 and use a novel quad-culture organotypic mammary gland model to characterize the molecular pathology of high impact variants; and (4) perform phenome-wide association studies (PheWAS)28 and polygenic risk score (PRS) analyses29. We expect that our findings of human lactation disorders genetics will be vital for understanding the physiology and pathophysiology of human milk systems, directly informing maternal, perinatal, neonatal health decisions, and ultimately guiding precision medicine approaches to improve women’s health.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Retrotransposons are interspersed genomic repeats that constitute almost half of the mammalian genome. Largely residing in the heterochromatin, retrotransposons are transiently induced during early development to regulate lineage differentiation, and kept silenced in adult terminally differentiated tissues. However, in human diseases such as cancer and aging, retrotransposons often exhibit aberrantly elevated activities, whose underlying molecular trigger and functional consequences are less understood. Murine skin represents an excellent model to study retrotransposon silencing mechanisms. As our largest organ, skin harbors highly abundant, well characterized, and genetically accessible adult stem cells. Hair follicle stem cells reside in an anatomically distinct niche known as the bulge, alternating between quiescence and activation in a synchronized fashion to fuel cyclic bouts of hair growth. Over repeated insults, hair follicle stem undergo functional exhaustion, the molecular driving events of which were often unclear. In the current proposal, I plan to examine chromatin regulators that couple adult stem cell activation with retrotransposon suppression during adult skin and hair follicle regenerations. Two central heterochromatin pathways are known to silence retrotransposons: tri-methylation on histone 3 lysine 9 (H3K9), catalyzed by histone lysine methyltransferases (KMTs), and DNA cytosine methylation, catalyzed by DNA methyltransferases (DNMTs). Moreover, lineage gene expression during stem cell differentiation depends on DNA demethylation, catalyzed by the DNA demethylase ten-eleven translocation (TET). While TETs are crucial for DNA methylome remodeling in early development, their regulations of retrotransposons in adult tissues remain underexplored. My preliminary analysis of genetic models in which the endogenous retroviruses (ERVs, a type of retrotransposons), are reactivated to drive skin stem cell exhaustion and hair loss, afforded me a unique tool to tackle these questions. Specifically, my prelim data indicated that a critical signal connecting TET to H3K9 KMT and DNMT function is the post-translational modification known as O-linked-β-N-acetylglucosamine (O-GlcNAc). I hypothesize that OGlcNAc catalyzed by the OGlcNAc transferase (OGT) is essential to suppress ERVs by interacting with H3K9 KMT and DNMT in the skin. I will examine OGT-deficient skin phenotypes and O-GlcNAc changes upon ERV reactivation, and dissect the mechanisms of OGlcNAc-orchestrated ERV suppressions. Study proposed here leverage my previous training in mouse genetics, development, epigenetics, and skin biology, and are designed to further train me with the state-of-art technologies such as CRISPR and classic methodologies in biochemistry and molecular biology. My training plan and my sponsor/co-sponsor support have been tailored to further foster my critical thinking, scientific communication, leadership and career development goals within MDACC and GSBS training environment. The proposed study, if successful, will provide important mechanistic insights into retrotransposon biology in adult skin, and mature me into an independent researcher.

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

PROJECT SUMMARY More than 39.9 million people are living with HIV worldwide, including 1.2 million women who become pregnant annually. Suppressive antiretroviral therapy (ART) to pregnant women with HIV (WHIV) has been highly successful in reducing the number of new pediatric infections. However, HIV/ART exposure in utero and infancy can lead to reduced early life growth predisposing children for lifelong metabolic disease risk, so understanding adverse effects of HIV/ART exposure on infants is critical to protect millions of children worldwide. Human milk (HM) is essential for early infant metabolic health, and breastfeeding is recommended globally for WHIV on ART. However, HM is a complex mixture that is highly dependent on the maternal environment and HM components may influence child health. HM is rich in extracellular vesicles (EVs), nano-sized packages that survive digestion to deliver their bioactive cargoes. EV miRNAs (small noncoding RNAs) and metabolites (small polar metabolites and lipids) are important bioactive molecules that hold promise as drivers of these effects. Our goal is to investigate the role of maternal HIV/ART exposure on the HM EV-metabolome and EV-miRNAs and their subsequent impacts on child growth and body composition. To address this, we propose to leverage the Africa-based Obesogenic oRigins of maternal and Child metabolic Health Involving Dolutegravir (ORCHID) study of pregnant WHIV receiving tenofovir + lamivudine + dolutegravir (TLD) and HIV-seronegative pregnant women and their children (analyzing a subset, N=500; 250/group). Using anthropometry at 1, 2, 3, 6, 12 and 24 months of age and gold standard air displacement plethysmography to assess body composition, we will construct trajectories of overall infant growth and adiposity. In HM samples collected at 1 and 3 months postpartum, we will evaluate EV-miRNA expression with next-generation sequencing and the HM EV-metabolome with ultrasensitive metabolomics and lipidomics to address the following aims: Aim 1. Assess the association of maternal HIV/ART exposure with the human milk EV-metabolome and EV-miRNA across lactation; Aim 2. Investigate the associations of the human milk EV-metabolome and EV-miRNA with child growth; and Exploratory Aim 3. Develop a predictive multi-omic fingerprint of milk EV cargoes that can be used to identify HIV-exposed uninfected children (CHEU) with elevated risk of reduced growth and adiposity. Using machine learning approaches that account for joint effects and interactions, we will characterize miRNA-metabolome profiles in combination with traditional risk factors that identify children with elevated metabolic risk due to HIV/ART exposure during breastfeeding. With more than 1 million WHIV becoming pregnant each year and increasing numbers of children being exposed to HIV/ART through breastfeeding, our work will provide critical knowledge on how HIV/ART exposure impacts breastmilk composition and maternal-child communication to affect child health, providing key insights on nutrition and future targets for intervention and prevention.

Iowa Arts Council

Supports arts education projects in Iowa schools and communities, funding artist residencies, professional development for educators, and programs that integrate arts learning across the K-12 curriculum.

Iowa Arts Council

The Iowa Arts Council provides operating support grants to Iowa arts organizations, funding programming, staff, and operations that deliver arts and cultural experiences across the state's communities.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The antisense gene asp maps in the HIV-1 genomic region overlapping env at the SU/TM boundary. Asp is found in pandemic strains of group M, but not in other primate lentiviruses including non-pandemic HIV-1 groups N, O, and P. We showed that asp is highly conserved despite constraining the evolution of env. We also reported that the asp gene is found at a higher frequency in people living with HIV-1 (PLWH) who progress to AIDS in <3 years (rapid progressors) compared to those who progress to AIDS in >12 years (long term non-progressors). The asp gene encodes the 189-aa hydrophobic protein, ASP. We reported that ASP shows high sequence iden- tity across HIV-1 isolates from all group-M subtypes. Work from our lab described the presence of ASP on the plasma membrane of infected cells, and on the envelope of infectious HIV-1 particles. Our unpublished studies demonstrate that the presence of ASP on the surface of HIV-1 particles facilitates viral entry. Several studies have shown the presence of cellular and humoral immune responses to ASP in PLWH, which proves its expression in vivo. A recent report reported that antibodies against ASP were specific for epitopes in the predicted ectodomain of ASP. Our preliminary studies confirmed the presence of antibodies against the ASP ectodomain in Elite Controllers (EC). Yet, none of the studies published so far endeavored to isolate ASP anti- bodies from PLWH and to test their functional activity as a way to investigate the role of ASP in HIV-1 infection. The overall aim of this application is to isolate monoclonal antibodies (mAbs) against the ectodomain of ASP from EC, Viremic Controllers, and PLWH both on and off ART. We will test their activity in in vitro and ex vivo assays. These studies will be performed in collaboration with Dr. Mohammad Sajadi (Institute of Human Virology, University of Maryland School of Medicine), who has established a cohort of >200 PLWH from whom he has already obtained paired serum and PBMC samples that are immediately available for the studies proposed here. Dr. Sajadi has developed a method for the identification, isolation, and cloning of mAbs that led to the discovery of best-in-class mAbs against HIV-1, SARS-CoV2, and CCHFV. Here, we propose the following specific aims: In Specific Aim 1, we will generate pools of overlapping peptides that span the ectodomain of ASP, and we will use these peptide pools to screen serum samples from PLWH in Dr. Sajadi’s cohort to identify those with strong- est binding to each of the five ASP peptide pools, and to determine their peptide sequence specificity. Next, we will use single-cell PCR and mass spectrometry to isolate and clone high affinity anti-ASP mAbs from the paired PBMC samples of the same donors. We will then validate the ASP specificity of these mAbs in ELISA and virion capture assays. In Specific Aim 2, we will test the activity of the ASP mAbs in mediating antibody dependent cellular toxicity (ADCC), reducing viral entry in single-round infection and viral replication in multiple rounds of infection, and detecting ASP on the cell surface, in the cytosol, and within nuclei.