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NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Genome editing is rapidly transforming biology and medicine by enabling the precise modification of DNA sequences in vivo. The technologies used for genome editing have also provided a means to modulate the expression of a target gene by facilitating the recruitment of transcriptional effector domains to a target site. One such tool capable of recreating the native mechanisms of gene activation consists of catalytically inactive Cas9 (dCas9) fused with the histone acetyltransferase p300, which, by acetylating histones near a target site, can activate gene expression through a nearly physiological approach. Nonetheless, current dCas9-p300 systems are inefficient, unpredictable, and incompatible with adeno-associated virus (AAV) delivery, which hinders future applications of this technology. Here, we propose to integrate state-of-the-art techniques including protein engineering, machine learning, and viral-vector design to create an innovative toolkit of epigenome editors that can be used to activate gene expression in vivo. Aim 1 will leverage phylogenetic diversity and directed evolution in mammalian cells to identify p300 variants with enhance gene activation capabilities. In Aim 2, we will develop machine-learning models that integrate target-site sequence features and nucleosome architecture to predict actionable target sites for efficient acetylation and gene activation. And, in Aim 3, we will engineer split-intein and ultracompact epigenome editors that can be packaged within single or dual AAV vectors to enable in vivo gene activation. To accomplish these objectives, we have assembled a multidisciplinary team with collective expertise in epigenome editing (Dr. Perez-Pinera), computational biology (Dr. Song) and AAV gene delivery (Dr. Gaj). Our collaborative efforts will: (1) yield a toolkit of programmable, tunable, and deliverable gene-activation tools, (2) facilitate the discovery of fundamental principles for epigenome editor design, and (3) enable the development of therapeutic applications for multiple disorders including developmental and metabolic disorders. We anticipate that the innovative and interdisciplinary nature of this proposal will yield technologies that will broadly impact biotechnology and medicine.

NIAID - National Institute of Allergy and Infectious Diseases

New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. This key obstacle to cure HIV consists of a reservoir of latently infected CD4+ T cells that persist despite long-term antiretroviral therapy (ART) and cause rebound of viremia if ART is interrupted. The R37 award AI157862 “Enhanced latency reversal and reservoir clearance in macaques” was funded in July 2021 with the overarching objective to obtain a deeper and broader understanding of the latency reversal induced by a SMAC mimetic (SMACm) and its potential to reduce persistent reservoirs using an innovative “kick and kill” approach. We have learned that treatment of SIV-infected, ART-suppressed macaques with the SMACm AZD5582, that activates the ncNF-kB signaling pathway, reactivates rebound competent latent reservoirs throughout the body. We also learned that the combination of AZD5582 and the BCL-2 inhibitor venetoclax reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ART interruption. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. We have three priority areas for the next phase of this R37 award that build on our body of work using venetoclax as well as broadly neutralizing antibodies (bNAbs), that have both antiviral and pro-immune effects. First, focus on reservoir establishment as an optimal time to intervene (rather than the maintenance phase). Second, focus on the antiviral immunity needed to complement venetoclax as a reservoir reducing intervention. And third, a deep dive into how the spatial landscape and immunovirologic features of infection are influenced by venetoclax. Our Central Hypothesis is that bNAb therapy will synergize with promotion of infected cell apoptosis through BCL-2 inhibition to limit reservoir formation. Using our expertise in conducting rigorous in vivo studies in nonhuman primates and immunovirologic multiomic analyses, we will test our hypothesis in three Specific Aims: 1) Define how venetoclax combined with bNAb therapy during early ART impacts decay of viremia, the intact reservoir, and the spatial landscape of infection; 2) Determine how venetoclax combined with bNAb therapy during early ART influences antiviral immune responses in a tissue-specific context; 3) Evaluate the virologic and immunologic impact of venetoclax and bNAb therapy given at start of ART versus at ART interruption. The experiments proposed will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed. Our experiments will evaluate safety and efficacy in a preclinical model. We hope that the results we generate will contribute to a cure for people living with HIV. RELEVANCE (See instructions): New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. The goal of our research program is to identify targeted immunotherapies that reduce HIV reservoir formation when given early in infection with antiretroviral treatment. Our experiments will evaluate safety and efficacy in a preclinical model to inform approaches to cure HIV.

NIAID - National Institute of Allergy and Infectious Diseases

Summary Actively replicating HIV infected cells are the source of progeny virions and the basis of persistent reservoirs. We will develop and test innovative strategies to eliminate actively replicating cells by enhancing NK-mediated Antibody Dependent Cellular Cytotoxicity (ADCC) responses against HIV. Recent evidence showing the ability of Broadly Neutralizing antibodies (BNAbs) to control viremia highlights the potential to complement the ADCC response with exogenous BNAbs able to target diverse HIV isolates. Bi-specific antibodies also enhance HIV-1 specific ADCC by high affinity bridging between effector NK cells (through CD16 targeting) and HIV infected cells (through envelope targeting). Tri-specific NK cell engager molecules (TriKEs) offer even more advantages for mediating ADCC against HIV-1 infected cells via the addition of an IL-15 cytokine moiety that stimulates NK cell activity while strengthening target cell engagement. Here, we will increase the half-life and anti-viral efficacy of HIV-specific TriKEs via Poly Antigen Cytokine Complex (PACC) enhancement and/or by directly loading similar IgGFc Killer Engagers ex vivo onto CD64 gene-modified NK cells that sustain Fc binding for days and are not subject to ADAM17-mediated negative regulation like CD16. Taken together, we hypothesize that CD4/HSA TriKE-PACC-IL-15 with an Fc component loaded onto CD64 expressing NK cells administered during early ART will be superior to soluble TriKEs in targeting HIV infected cells, reducing persistent HIV levels and viral rebound upon ART interruption in humanized mice. Two specific aims will test this hypothesis: Aim 1: Generation of CD4 Ecto-Domain 1 (CD4ECD1) TriKE and CD4/HSA TriKE/PACC for half-life and anti- viral efficacy assessment in the IL-15 transgenic NSG humanized mouse model of HIV. Two versions of an HIV-specific CD4 Ecto-Domain 1 (CD4ECD1) targeting TriKE with IL-15 cytokine moiety as well as a single domain antibody (sdAb/VHH) against CD16 will be created with and without a PACC complex containing the IL- 15 receptor alpha chain and human serum albumin (HSA) to enhance NK cell signaling and increase the molecule half-life, respectively. Activity will be tested in vitro and in vivo in an ART-suppressed HIV-infected IL- 15 transgenic NSG humanized mouse model. Aim 2: Demonstrate durable retention and anti-viral efficacy of a IgGFc Killer Engagers pre-loaded ex vivo onto CD64 expressing NK cells in vitro and in vivo. NK cells will be genetically modified using mRNA LNPs to express the high-affinity Fc receptor CD64 and then pre-loaded ex vivo with “IgGFc Killer Engagers” containing a HIV-specific CD4ECD1 domain along with IL-15 and an Fc component. Activity tested as in Aim 1. The culmination of both aims will allow us to compare and identify the best strategy between the CD4 TriKE, CD4/HSA TriKE-PACC, or CD64 NK preloaded with IgGFc Killer Engagers for anti-viral potency on HIV reservoir dynamics in the humanized mice. The best strategy identified will facilitate prioritizing a comprehensive single NK cell therapy strategy to advance into human Phase I studies.

NIGMS - National Institute of General Medical Sciences

This proposal requests funding to acquire a state-of-the-art Olympus IX85 Automated Inverted Microscope configured with Cicero Spinning Disc Confocal technology to support the biomedical research and educational missions at Sam Houston State University College of Osteopathic Medicine (SHSU-COM). This high-speed, high-resolution confocal imaging platform is essential for researchers investigating the molecular and cellular basis of neurodevelopment, cancer, reproductive biology, and toxicology using zebrafish models, human cell culture, and oocytes. The proposed instrument will directly support five active research programs: (1) dissecting the role of Selenophosphate Synthetase 1 (SEPHS1) in neural circuit formation and behavior through functional analysis of human alleles in zebrafish embryos; (2) developing EGFR-targeted nanoemulsions for treating metastatic colorectal cancer using xenografted zebrafish larvae; (3) characterizing the role of Integrin alpha 6 in zebrafish hindbrain neurovascular development; (4) evaluating endocrine-disrupting chemicals and their cytoskeletal and genotoxic effects in human granulosa cells and early embryos; and (5) enhancing biomedical education through hands-on microscopy training for medical and graduate students. The availability of this imaging system will significantly accelerate data acquisition, improve spatial and temporal resolution of live and fixed specimens, and enable multi-channel fluorescence imaging. This shared resource will support basic and translational biomedical research at SHSU-COM and strengthen educational training for students. Ultimately, this instrument will advance scientific discovery, support physician-scientist training, and enhance SHSU-COM’s capacity to contribute to the biomedical research enterprise.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Project Summary/Abstract The precise administration of the prescribed radiation dose is critical for the safe and effective delivery of radiotherapy in cancer treatment. Current clinical dosimetry standards, however, are limited by insufficient accuracy, a lack of real- time monitoring, and poor spatial resolution, particularly in complex treatment scenarios. This technological gap presents an unmet clinical need for a technology that enables high-resolution dose verification at the point of care. The goal of this research is to develop skin-conformal, tissue-equivalent wearable sensor platforms to enhance the precision of radiation therapy. We will design, fabricate and validate a transformative dosimetry platform using printed flexible RADiation-sensitive Organic Field-Effect Transistors (RAD-OFETs). The central innovation is the use of organic semiconductors with radiation absorption properties that mimic human tissue, thereby obviating the need for dose-correction factors. Their inherent mechanical compliance further permits fabrication on flexible substrates for direct, conformal application to the skin, enabling high-fidelity in vivo dose mapping. Such a platform will enhance the precision of radiation delivery, allowing clinicians to optimize treatment plans in real time and improve patient outcomes. Supported by strong preliminary results, including a U.S. patent directly relevant to this project, this proposal directly addresses key challenges hindering clinical translation through three specific aims: (1) To engineer RAD-OFET architectures with monotonic, sensitive dosimetric response, (2) To scale the single-pixel device into uniform, large-area flexible RAD-OFET arrays, and (3) To validate dosimetric performance of flexible RAD-OFET arrays in settings mimicking clinical parameters. The research team is composed of the principal investigator, graduate and undergraduate students from the Physics Department, alongside collaborators from the School of Medicine. This project will strengthen biomedical research at Wake Forest University by providing an immersive, multidisciplinary research environment for students, who will be integrally involved in all project aspects. The primary deliverable will be a tissue-equivalent, large-area flexible dosimeter prototype robustly benchmarked to agree within ±5% of current state-of-the-art methods, and that can monitor the radiation dose with high spatial resolution. Successful completion of this program will generate pre-clinical data for a subsequent project aimed at securing regulatory approval for clinical trials.

NIGMS - National Institute of General Medical Sciences

PROJECT ABSTRACT Metabolites are essential modulators, biomarkers, and signaling molecules in human health and disease, yet most metabolomic data remain unannotated due to limitations in computational workflows for liquid chromatography tandem mass spectrometry (LC-MS/MS). Nearly 90% of MS/MS features in untargeted metabolomics studies lack structural assignments, hindering mechanistic and translational discovery. Deep learning-based in silico fragmentation has improved annotation accuracy, but existing models depend on proprietary data, lack confidence measures, and are restricted to one-at-a-time structure prediction. This K99/R00 project will develop open, robust, and scalable workflows for metabolite structural elucidation. During the mentored K99 phase, the candidate will expand the ICEBERG geometric deep learning model to train entirely on curated open-source datasets (GNPS, MassSpecGym) through knowledge distillation from proprietary models and introduce atom-level confidence scoring analogous to pLDDT in protein folding. The open model will provide interpretable confidence maps and enable high-confidence substructure annotation without commercial data dependence. During the independent R00 phase, network-based reasoning will be incorporated to jointly analyze chemically related spectra through integer-linear optimization and graph-based propagation. This framework will create an open metabolite atlas by repository-wide substructure annotation of Pan-ReDU (with spectra and metadata curated from GNPS, Metabolomics Workbench, etc), empowering large-scale reanalysis and hypothesis generation. Proof-of-principle studies in cancer metabolism, inflammatory bowel disease and mitochondrial disease cohorts will demonstrate the biological relevance and translational potential of the approach. The candidate’s long-term goal is to establish an independent research program at the intersection of artificial intelligence and metabolomics, focusing on comprehensive elucidation of metabolites that drive biology, disease, and therapeutic discovery. The career development plan includes training in computational chemistry, untargeted metabolomics, and clinically relevant disease biology; mentorship from leading experts at MIT, Harvard, and the Broad Institute; and structured professional development in grant writing, teaching, and leadership. The institutional environment at MIT and its aZiliates provides exceptional computational, experimental, and translational resources, including access to high-performance computing, state-of-the-art LC-MS/MS facilities, and large clinical metabolomics datasets. Together, these resources and mentorship will ensure the successful transition to research independence and leadership in AI-driven metabolomics.

Beacon Arts

We are seeking funds to be able to pay local professional performers to entertain at the Beacon Arts Street Fairs. The festival starts on April 9th but the Small Sparks fund will pay for entertainment from May to September on the second Saturday of each month. The festival will be held on Roberto Maestas Festival Street and El Centro de la Raza grounds and Plaza. The anticipated project completion date is October 31, 2022.

NIA - National Institute on Aging

Alzheimer’s disease and related dementias (ADRD) are a growing public health burden and understanding modifiable ADRD causes is a national priority. Many classes of environmental chemicals, such as pesticides and per- and polyfluoroalkyl substances (PFASs) contain known neurotoxicants and are thus likely to contribute to ADRD risk, but we lack prospective data with appropriate temporality (exposures measured years before cognitive outcomes) in large and representative populations. Leveraging stored biospecimens from one of the largest, longitudinal, population-based United States cohorts, the Health and Retirement Study (HRS), we will generate a publicly available, prospective, environmental chemical resource, with exposure measures many years before the onset of ADRD or preclinical impairment. HRS participants are ages 50 and older and they have extensive existing biannual cognitive measures and ADRD fluid biomarker measures. Specifically, in Aim 1, we will perform new state-of-the-art non-targeted analysis in serum to measure chemical levels, including PFAS and pesticides, and test for association with cognitive function and decline, ADRD biomarker levels, and ADRD incidence. People are simultaneously exposed to pesticides, PFAS, and other chemicals in the neighborhoods where they live, work, play, and socialize. Social exposures, at the individual- and neighborhood-level contribute to stress and ADRD risk. Chemical and social exposure levels differ across US neighborhoods, with variation by geography and socioeconomic status. Therefore, in Aim 2, we will integrate mixtures of chemical and social exposures into the “exposome”, representing the totality of a person’s environment, when examining complex environmental contributors to ADRD. Additional evidence linking exposures and ADRD can be provided by intermediate molecular markers. These molecular intermediates may serve: 1) as biomarkers of exposure useful when direct exposure measures are not possible, 2) as mediators mechanistically linking exposure and ADRD, and 3) as connecting networks informing on overlapping pathways to deepen chemical and ADRD response understanding. In Aim 3, we will leverage existing measures of molecular intermediates, including DNA methylation, RNA expression, and immune cell profiles, with new measures of endogenous metabolomics and lipidomics, to assess molecular markers as exposure biomarkers or mediators to link exposures with incident cognitive status. Together, this project will identify individual chemicals, mixtures of chemicals, and their pathways that contribute to ADRD risk in a nationally representative sample, which will support ADRD prevention and intervention. Given widespread exposure levels to these environmental chemicals in the US, even modest associations with ADRD could represent a substantial number of preventable cases through individual- and population-level actions.

NIH

The overall goal of the proposed CDA-2 is for Dr. Fischer to obtain advanced training in various methods of psychiatric genomics (e.g., statistical genetics, epigenetics, transcriptomics) that he can use to supplement and strengthen his existing program of research, which examines environmental risk and protective factors for various psychiatric disorders and clinical problems, including suicidal thoughts and behaviors (STBs). This training will enable Dr. Fischer to systematically and comprehensively examine the biopsychosocial etiology of STBs, which will ultimately help to inform the treatment and prevention of STBs in U.S. Veterans. To accomplish this goal, Dr. Fischer will investigate how environmental (i.e., psychosocial) risk and protective factors interact with polygenic liability for STBs, along with how epigenetic processes are associated with STB phenotypes (i.e., suicidal ideation and suicide attempts). This project is innovative in that it will be one of the first to examine whether psychosocial risk and protective factors potentiate or mitigate polygenic risk for suicide in U.S. Veterans. It will also be, by far, the largest study to date on the epigenomics of STBs and the first to derive methylation risk scores for STBs. The proposed study will leverage cutting-edge statistical methods and state-of-the-art bioinformatics to provide novel insights into the complex etiology of STBs that will ultimately help inform efforts to reduce Veteran death by suicide. This CDA-2 grant will build on Dr. Fischer’s strong scientific background in Veteran mental health, psychiatric epidemiology, and environmental risk and protective factors, along with his ongoing experiences as a clinical psychologist, to provide him with crucial new knowledge and skills, which will support the generation of novel, multidisciplinary research. Through the proposed CDA-2, Dr. Fischer will develop the ability to: 1) generate polygenic risk scores; 2) conduct gene enrichment analyses and transcriptome-wide association studies (TWAS); 3) perform drug repurposing analyses; 4) conduct epigenome-wide association studies (EWAS); 5) derive methylation risk scores; and 6) leverage advanced machine learning approaches to evaluate multi-level predictive models. Dr. Fischer’s multidisciplinary mentorship team is composed of world-leading experts working within the VA Connecticut Healthcare System and Yale University. The high-quality research and collaborative environment present at these institutions will facilitate Dr. Fischer’s transition into an independent VA researcher and equip him with the tools needed to produce impactful, innovative research that advances the U.S. Department of Veterans Affairs top research and clinical goals: suicide prevention.

NIEHS - National Institute of Environmental Health Sciences

ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their widespread use and adverse effects on human health (e.g., metabolic disease, cancer). Early-life exposure to PFAS is of particular concern as developmental periods are a critical window of vulnerability during which disruptions to the gut microbiota and host metabolism can have long-lasting consequences. Infants and young children are exposed to PFAS through breast milk, formula, and contaminated food or water. Despite the recognition that many environmental pollutants influence the gut microbiota, there is a lack of research assessing PFAS-induced microbiome toxicity using quantifiable and biologically meaningful endpoints. Further, given the essential connection between the host and microbiome, there is a critical need to study the impact of PFAS on the physiology and function of gut microbes and the resulting effects on host health. The proposed studies will address these gaps by elucidating the mechanisms by which PFAS influences host-microbiome interactions. The central hypothesis of this grant is that gut microbes modify PFAS toxicokinetics and mediate PFAS- associated health outcomes via the disruption of host-microbe homeostasis. Herein we present a paradigm- shifting view of bacterial-mediated mechanisms of PFAS toxicity. Two specific aims will test this hypothesis: Specific Aim 1 will evaluate the effects of PFAS on diverse gut microbes to understand microbial toxicity, bioaccumulation, and adaptation in microbial species key to health. For Specific Aim 2, mouse models will be used to determine how early-life PFAS exposure disrupts the host-gut microbiome axis leading to metabolic disorders in adulthood. Our interdisciplinary team combines expertise in perfluorinated chemical toxicology, microbiology, metabolomics, and biostatistics. To comprehensively study how PFAS exposure is linked to detrimental health outcomes, our studies use state-of-the-art technologies (e.g., metagenomics, metabolomics) to explore microbial toxicity and the broader effects of environmental chemicals on gut microbiome and its community structure and function. Results from the proposed studies will provide new and impactful data that will provide for more personalized risk assessment frameworks and support the development of microbiome- centered therapeutic strategies to mitigate the health impacts of PFAS.

NIA - National Institute on Aging

Project Summary/Abstract In humans, the heart function declines due to aging. The prevalence of heart disease increases with age. Aging, even in apparently healthy individuals without overt cardiovascular disease, is associated with damaged heart structure and comprised cardiac function. Aging is an important risk factor for heart diseases. KDM6A is a recently-discovered histone demethylase. Mutation of this gene causes severe defective embryogenesis. The objective of the proposed research is to investigate if KDM6A plays a role in the regulation of normal heart function and further investigate if KDM6A deficiency is involved in the epigenetic determinants of responses to aging-related heart injury. This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address the aging-related heart damage which affects a large population but remains poorly understood. The results will reveal novel molecular mechanisms that mediate the pathogenesis of aging-associated heart failure and remodeling. Completion of this project may provide new insights into preventive and therapeutic strategies for heart aging.

Sand Point Arts and Cultural Exchange

Sand Point Arts and Cultural Exchange will purchase and install equipment that will allow the KMGP 101.1 radio station to provide free community programming. The programming and production equipment will be installed within Warren G. Magnuson Park at 7400 Sand Point Way NE and the station's antenna will be installed at the University of Washington's McMahon Hall located at 4249 Whitman Court. Planning and installation activities will occur during the summer of 2017.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract The presence of a reservoir of cells harboring integrated, replication-competent virus that persists under long-term, fully suppressive antiretroviral therapy (ART) and the inability of the host immune responses to control the initial events of viral replication that follow ART interruption are critical barriers to curing HIV infection. Thus, novel therapeutic strategies to remove these barriers are critically needed. The overarching hypotheses of ERASE HIV are: (i) decreased and/or dysfunctional CD8+ T and NK cell antiviral functions, combined with the recently-described CD8+ T-cell-mediated transcriptional silencing of HIV, favour HIV persistence under ART and prevent the control of viremia if ART is stopped; and (ii) novel approaches to elicit effective CD8+ T-cell, NK cell, and antibody-dependent cellular cytotoxicity (ADCC) functions while inhibiting the CD8+ T-cell-mediated virus silencing will promote remission and/or eradication of HIV. The overarching goal of ERASE HIV is to identify novel mechanisms of HIV persistence and to test them in the most relevant pre-clinical animal models through mechanistically-oriented, community-supported therapeutic strategies that can be ultimately translated to cure HIV infection in humans. ERASE HIV includes three highly integrated Research Foci (RFs). RF1 is aimed at identifying the molecular and cellular mechanisms underlying the two distinct antiviral activities of CD8+ T-cells: the MHC-restricted, Ag-specific response that directly eliminates virus-infected cells, and the non-MHC restricted, non-cytolytic silencing of HIV transcription. As such, RF1 will provide the conceptual basis for the interventions tested in RF2 and RF3. RF2 will use animal models of ART-treated HIV infection to (i) restore CD8+T and NK cell function with an α-IL-10 and IL-15 superagonist (N-803) strategy; (ii) target rebounding virus by using a CD4-mimetic compound (CD4mc) to enhance antibody recognition of cells expressing HIV Env and their elimination via ADCC; and (iii) determine if improving CD8 T and NK cell function via α-IL-10 and N-803 synergizes with CD4mc to clear infected cells. RF3 will determine if suppression of the latency-promoting activity of CD8+ T-cells, coupled with N-803 and interventions to promote apoptosis (Bcl-2 inhibitors) or immune-mediated removal (CD4mc) of cells that have reactivated virus, will reduce the reservoir size. In all, we will exploit the synergy between the mechanistic data generated in RF1 and the in vivo interventions in RF2 and RF3 to validate a strategy that targets both HIV persistence during ART and HIV recrudescence after ART interruption. ERASE HIV is supported by experts in HIV advancements (SisterLove); recognition and killing of HIV Env-expressing cells (Finzi/Sodroski); T and NK cell biology (Sekaly/Ribeiro/Deleage/Parsons); reservoir assays and latency models (Kulpa/Jones/Litchterfeld/Howell); pre-clinical animal studies (Paiardini/Silvestri/Garcia/Saez-Cirion/Keele/Kumar); mathematical modelling (Davenport); and therapeutics development (Merck and ImmunityBio) for HIV cure. We believe that the proposed mechanistically-oriented pre-clinical work will inform strategies that can be translated in clinical trials to achieve prolonged viral remission in PWH.

Erie Community Foundation

Erie Community Foundation ($300M in assets) supports nonprofits in PA through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

Eritrean Association of Greater Seattle

The Eritrean Association of Greater Seattle will organize an Eritrean Independence Day Celebration at Seward Park on May 25, 2019. The family-friendly event will feature Eritrean singers and musicians, local Eritrean children and youth performing traditional dances, poetry readings, drama, and a showcase of visual arts. There will be a soccer tournament the preceding weekend, May 18-19. Several thousand people are expected to attend the festival and tournament.

Esmee Fairbairn Foundation

45M+ GBP/year across arts, children & young people, environment, and food. One of UK's largest independent funders.

NCI - National Cancer Institute

Project Summary The postnatal development of the mammary gland is dependent on a multitude of cellular programs that are orchestrated by steroid and peptide hormones as well as locally produced cytokines. Two Janus kinases, JAK1 and JAK2, are obligatory intracellular signaling mediators of many peptide hormones and cytokines that have essential functions for the growth, differentiation, and survival of the mammary epithelium. Previous work from several laboratories including our own has established that JAK1 and JAK2 have non-redundant functions for the activation of specific Signal Transducers and Activators of Transcription (STATs) in normal and neoplastic epithelial cells. Important roles of these canonical JAK/STAT signaling cascades during mammogenesis are generally thought to be limited to the differentiation and remodeling of alveolar cells during the gestation cycle. In contrast to this notion, our team has discovered that JAK1 and JAK2 synergistically control the postnatal development of the mammary epithelial ductal tree. We uncovered that STAT proteins are activated in a compensatory manner in ductal epithelial cells, but the collective results from several genetically engineered mouse models revealed that the cooperative functions of JAK1 and JAK2 are not facilitated by their downstream STATs. Unlike in JAK1/2 mammary-specific double knockout mice, the growth and survival of mammary epithelial cells do not require the expression and/or activation of the seven known mammalian STAT proteins. We, therefore, propose that the biologically relevant functions of JAKs during postnatal mammary gland development are facilitated by noncanonical molecular signaling mechanisms of JAK1 and JAK2. Additional preliminary findings also raise the issue of whether the significant biological roles of JAKs are solely dependent on the functionality of their tyrosine kinase domains. To interrogate the noncanonical functions of JAK signaling, we will first establish whether the JAK1/2-dependent signaling mechanisms that govern the development of a mammary gland are dependent on the kinase and/or scaffold functions of JAKs (aim 1). Next, we will investigate the activation of JAK substrates that are currently known and use state-of-the-art genomic and proteomic approaches to identify novel targets and pathways that rely on JAK1 and JAK2 without the expression and activation of STATs (aim 2). Since JAK1/2 kinase inhibitors were clinically ineffective in treating advanced breast cancers, we will investigate the significance of noncanonical JAK signaling in mammary tumor cells and the effects of pharmacologically targeting JAK1/2 for degradation in human-relevant breast cancer models (aim 3). The collective outcomes of this project are expected to provide substantial new insights into the central roles of peptide hormone and cytokine signaling in mammary gland development. The anticipated results from the three aims will elucidate novel molecular mechanisms by which Janus kinases signal within normal and neoplastic epithelial cells beyond the activation of STAT proteins and establish whether pharmacologically targeting JAK1/2 for degradation is a suitable strategy for the treatment of breast cancer.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY A functional cure for HIV that maintains lifelong suppression of viremia without antiretroviral therapy (ART) remains an urgent unmet need. Broadly neutralizing antibodies (bnAbs) can control HIV, but vaccines have failed to induce them because they require unusual structural features that are not readily generated by natural B cell maturation. Genome engineering now allows mature bnAb genes to be inserted into the immunoglobulin heavy chain (IgH) locus of primary B cells, where they function as antigen receptors capable of undergoing germinal center maturation and forming memory responses. In mice, IgH-reprogrammed B cells generate durable bnAb titers near therapeutic levels after vaccination. However, the in vivo behavior of genome-engineered human B cells has not been tested due to the lack of an appropriate model. The recently developed Truly Human Xenograft (THX) mouse supports robust antigen-dependent human B cell responses and thus provides a unique opportunity to establish a preclinical platform for engineered B cell therapies. In Specific Aim 1, we will determine whether IgH-reprogrammed human B cells can participate in germinal center reactions and generate memory and long-lived plasma cells following vaccination in THX mice. In Specific Aim 2, we will establish an HIV infection and treatment model in THX mice, adapting mucosal challenge, ART suppression, and analytical treatment interruption protocols to evaluate viral rebound and reservoir establishment. Completion of these aims will demonstrate feasibility of eliciting vaccine-responsive bnAb memory responses from genome-engineered human B cells in vivo, while also establishing the THX mouse as a physiologically relevant platform for HIV infection and treatment studies. Together, this work will provide a critical foundation for advancing engineered B cell vaccines as a potential functional cure for HIV.

NIMH - National Institute of Mental Health

ABSTRACT The long term goals of these studies are to identify motor imitation as a biomarker of autism spectrum disorder (ASD) to both deepen understanding of brain and behavioral mechanisms for comorbid conditions and improve diagnosis with a cost-effective, objective, and reliable assessment method we developed. Although ASD is defined by core deficits in social-communicative functioning and restricted interests and repetitive behaviors, an ASD diagnosis is often accompanied by clear impairments in motor control and learning that present early and persist through childhood and into adulthood. Prominent among these ASD-associated motor impairments is difficulty imitating others’ actions (i.e., motor imitation). Imitation is crucial to social-communicative development, and impaired imitation has long been recognized as a likely contributor to the core difficulties in ASD. Crucially, while movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including attention deficit hyperactivity disorder (ADHD) and intellectual disability (ID), current literature suggests that deficits in motor imitation may distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Efforts to establish imitation as a biomarker of ASD have been hampered by a lack of objective, reliable assessment, with studies thus far applying labor intensive methods that require subjective assessment by highly trained researchers/clinicians. Our team has pioneered the development of an automated Computerized Assessment of Motor Imitation (CAMI) to quantify ASD-associated imitation deficits with better diagnostic discrimination ability than traditional methods. A remaining challenge in developing motor imitation as a phenotypic biomarker is to establish the specific neural mechanisms contributing to imitation deficits. Previous fMRI studies on motor imitation in ASD have shown mixed results, possibly due to the significant limitations in assessing naturalistic motor imitation in the fMRI scanning environment, where there are substantial constraints on motion. To address this challenge, our team develops high-density diffuse optical tomography (HD-DOT) that enables fMRI-comparable image quality in an open setting. Herein, we propose to establish the specificity of motor imitation impairments (Aim 1) as well as the brain mechanisms underlying such impairments (Aim 2) of ASD relative to ADHD and ID. Our proposed study, by integrating state-of-the-art methods for quantitative, objective motor imitation assessment and concurrent identification of ASD-specific underlying neural correlates, has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children. ASD-specific neurobehavioral biomarkers identified through our proposed CAMI and HD-DOT methods may advance clinical subtyping of ASD and opportunities for individualized treatment, refine monitoring response to intervention, and inform underlying neurobiological mechanisms.

NHLBI - National Heart Lung and Blood Institute

Project Summary Hereditary cardiomyopathies including dilated (DCM) and hypertrophic (HCM) forms can lead to increased mortality and morbidity. A new class of drugs called myotropes has been developed to target thick filament dysfunction in the heart, and one has recently been FDA-approved for a specific cardiomyopathy. This small molecule drug, however, does not possess the same efficacy for cardiomyopathies that arise from pathogenic variants that disrupt cardiac thin filament (cTF) function. Based upon this strong precedence, we seek to identify cTF structural elements that modulate cardiac performance that are within “cardiomyopathy mutation hotspots” and may serve as new actionable targets for the treatment of cardiac diseases. This proposal addresses key understudied functional regions of cardiac troponin C (cTnC), the Ca2+ binding subunit of the troponin complex, which regulates Ca2+ dependent myofilament activation. These regions include the N-helix of the N-domain (which is only present in vertebrate cardiac and skeletal TnC and absent in all other members of the EF-hand Ca2+ binding protein family) and the C-domain that contains high affinity Ca2+ binding sites. Aim 1 will utilize newly developed knock-in (KI) cTnC -I4M (DCM) and -ΔN (rationally engineered N-helix deletion) mice to evaluate the specific hypothesis that the N-helix of cTnC promotes the transition from the Ca2+-free to Ca2+-bound partially activated and Ca2+-bound fully activated state during cardiac muscle activation. Relatedly in Aim 2, newly developed KI cTnC -D105A and -D141A (rationally engineered to abolish Ca2+ binding to sites 3 and 4, respectively) mice and -D145E reconstituted assays will test the hypothesis that Ca2+ ions bound to the high affinity sites of TnC C-domain stabilize its structure and, therefore, contribute to the allosteric coupling that exists between the two TnC domains. Additionally, this Aim will investigate the physiological role of these cTnC Ca2+ binding sites in myofilament Ca2+ buffering function. Preliminary data with cTnC -I4M and -ΔN mice revealed a reduction in heart contractility and impaired myofilament activation, suggesting that the N-helix acts as a regulator that augments cardiac contraction by slowing down crossbridge kinetics. Echocardiographic analysis of cTnC - D105A and -D141A mice also showed reduced cardiac contractility and pathological remodeling. Embryonic studies will be performed for mouse models that homozygous pups cannot be obtained. These studies will be augmented with reconstituted assays containing the HCM cTnC-D145E protein, which was shown to virtually abolish Ca2+ binding to the high affinity sites. Preliminary studies utilizing Cryo-Electron Microscopy (cryo-EM) show that the cTnC N-helix and the C-domain are directly involved in the activation pathway of native cTF. We will leverage multiple physiology-based and state-of-the-art structural biology techniques, such as cryo-EM and small angle X-ray diffraction. We have improved our cryo-EM capabilities to achieve the highest resolution ever (3.8Å) for cardiac troponin within the native cTF. These studies will allow us to uncover new mechanisms governing contractile regulation in the heart and identify novel specific targets to modulate cardiac contractility.

NCI - National Cancer Institute

Project Summary The overall goal of this application is to establish the University of Arizona Cancer Center (UACC) as a Network Lead Academic Participating Site (LAPS) for the NCI’s National Clinical Trials Network (NCTN). As the only NCI-Designated Comprehensive Cancer Center headquartered in the state of Arizona, the UACC currently provides significant leadership and mentorship in the development and conduct of important translational and therapeutic clinical trials for cancer patients across the state. This application will enhance participation and bolster the UACC’s infrastructure capabilities to continue to provide scientific leadership in the development and conduct of clinical trials and substantial accrual to clinical trials across the state and entire NCTN while simultaneously training the next generation of clinical investigators in state-of-the art clinical trials for the treatment of adult cancer patients. Specifically, this will support the UACC’s infrastructure to increase clinical research activities, protocol development, investigator leadership and junior faculty mentorship. UACC has a strong track record of past and present leadership and participation in the NCTN Program and will continue this participation as a LAPS site. We will achieve our goal through the following Aims: 1) to develop, lead, and participate in scientifically and clinically relevant NCTN clinical trials; 2) to support robust accrual, timely and accurate data reporting and internal monitoring for NCTN trials; 3) to support accrual at satellites sites across the state of Arizona as part of the Arizona Clinical Trials Network; and 4) to serve the community by utilizing a Clinical Trials Oncology Navigation program to assist with trial education and enrollment and retention of patients reflective of our catchment populations and the state of Arizona. We plan to do this through creating a LAPS Leadership Committee for oversight and mentoring, by working with the Clinical Trials Navigator to educate patients on clinical trials, and specifically targeting sites with access to rural and other underserved populations.

Estelita's Library

The project will fund the Grand Opening of Estelita's Library, located at 241 MLK Jr Way S Seattle WA 98144 in the Central District. The funds will be used for community engagement activities to introduce local organizations, businesses, and individuals to our work and the new site; a new deck and ADA public restroom expansion; landscape design and native plant installation; and creative programming including art curation, events and workshops on themes of social justice and community organizing. The anticipated project completion date is November 30, 2021.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Tuberculosis (TB) in humans results from infection with members of the Mycobacterium tuberculosis complex (MTBC). The disease is endemic in many parts of the world. So is bovine tuberculosis (bTB) - a well-recognized zoonotic disease of bovine species (cattle and buffalo) also caused by infection with members of the MTBC. India has the world’s highest TB burden in humans, with more than 2M new cases and 400,000 TB-related deaths each year. India also hosts the largest bovine herd on the planet (~300M animals), and our recent studies suggest that more than 22M of those animals may suffer from bTB. Yet the risk of zoonotic TB (zTB) resulting from transmission of MTBC from bovines to humans in India and other high-TB burden settings is unknown. This is a major knowledge gap, and elimination of TB will be considerably more difficult if there is spillover from a domestic livestock reservoir to humans. This is of particular concern in countries such as India where the frequent consumption of unpasteurized milk and close contact with infected animals likely present additional elevated risks for zoonotic transmission. Because of this, the World Health Organization (WHO) and other supranational organizations have developed a "Roadmap for zoonotic TB" that calls for the establishment of a stronger evidence base to improve understanding of the burden and risk pathways of zTB to guide an effective response. To fill these knowledge gaps, we propose studies with the overall objective of estimating the risk associated with zTB in a high-TB-burden setting. We will accomplish this by applying rigorous quantitative risk assessment augmented by state-of-the-art whole-genome sequence (WGS)-based molecular epidemiology and multi-host transmission modeling. Performed at well-established study sites in Vellore and Tiruvallur districts in Tamil Nadu, India, our Specific Aims are to: 1) Estimate the risk of human TB associated with exposure to cattle, buffalo, or the consumption of raw milk in ~1,750 human cases and ~3,500 controls; 2) Apply WGS-based approaches to define the genetic diversity and molecular epidemiology and perform phylodynamic and phylogeographic analysis of MTBC lineages circulating in human TB cases, sympatric cattle and buffalo, and locally sourced raw milk; and 3) Perform multi-host transmission modeling to quantitatively assess zTB risk to humans and the potential benefits of control. These studies involve the application of innovative and powerful nested case-control epidemiological surveys with WGS-based genotyping and mathematical modeling. The results of our studies will inform and refine estimates of zTB risk, enable identification of transmission chains at a local scale, and transform our understanding of spillover and circulation of MTBC strains between human and bovine hosts. In the long-term, our findings will provide sustained positive impact through the development of evidence-based approaches to quantify and reduce risk of zTB in support of the global efforts to end TB.

East African Arts & Cultural Association

The East African Arts & Cultural Association will celebrate Seattle Ethiopians' Week with a 5 day public celebration to be held July 2-6, 2017. It will take place at King's Hall located at 2929 27th Ave S. The celebration will convene the Ethiopian community to express their heritage, engage Ethiopian youth in relevant community issues, showcase Ethiopian performing and visual arts, and strengthen mutual understanding and respect between a wide variety of cultures.