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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Antiretroviral therapy (ART) results in suppression of Human Immunodeficiency Virus (HIV) replication, increase in CD4+ T cell count, and partial restoration of immune responses. Yet despite suppressive ART, both transcriptionally silent and transcriptionally active [i.e. cell-associated RNA (CA-RNA)] HIV viruses remain in various CD4+ T cell subsets in persons living with HIV (PLWH) and are proposed to contribute to residual immune activation, lower immune reconstitution and development of comorbidities. Much attention has been given in our field to the clinical significance of continued HIV expression after ART, but we still lack plasma host biomarkers that could illustrate the impact of CA-RNA or could link CA-RNA to future risk for comorbidities. Part of the limitation to address this gap has been that studies attempting to find a correlation between HIV reservoir levels and plasma markers of immune activation have included only a limited number host cellular or plasma variables, have not started with a pre-defined cohort with known reservoir levels, have not linked variables to predefined prognostic biomarkers, and/or have yielded inconsistent results (see background). This R21 now addresses these limitations by studying a cohort with known HIV reservoir levels and by introducing recent advances in Somalogic-based technology inclusive of (a) measuring a large set (at least 7000) of plasma proteins and (b) determining links of predefined host biomarker "signatures" to risk scores for comorbidity outcomes as shown by our preliminary data and other studies. This R21 proposal is possible as a result of the collection through the BEAT-HIV Martin Collaboratory program of plasma and peripheral blood mononuclear cells (PBMC) from 94 ART suppressed PLWH with known distribution of HIV proviral DNA measured by the Intact Provirus Assay (IPDA) which in turn is associated with CA-RNA. Specifically, we hypothesize that in PLWH on suppressive ART the levels of cell-associated HIV RNA will be associated with a) plasma host proteomic biomarkers, and b) pre-defined clinical comorbidity risk scores for cardiovascular, liver/kidney, and metabolic disease following age adjustment. We will test this hypothesis by the following specific aims: (1) identify host plasma biomarkers among 7000 protein measures that will best predict PLWH on ART with higher CA-RNA independently of age, and (2) determine if plasma clinical prognostic scores for comorbidity risks of cardiovascular, liver/kidney, and metabolic disease are higher in PLWH on ART with high CA-RNA when adjusted for age. Completion of this R21 proposal will provide foundational data to further evaluate the usage of biomarker changes in future RO1s describing strategies targeting transcriptionally active reservoirs on ART. The long-term impact of this proposal is its potential to advance cure-directed strategies targeting HIV expressing cells (i.e., immune-based, gag- pol/CARD8 activating, etc.) and to make possible early determinations in biomarker changes of significance to prognosis risk profiles upon a reduction of persistent HIV reservoirs.

NINDS - National Institute of Neurological Disorders and Stroke

Drosophila Neurobiology: Genes, Circuits & Behavior (2026‐2030) ABSTRACT The primary objective of the proposed three‐week course is to provide training in state‐ of‐the‐art and emerging experimental approaches to study the nervous system in one of the most successful invertebrate model organisms, Drosophila melanogaster. The course, titled “Drosophila Neurobiology: Genes, Circuits & Behavior”, is designed to introduce students at all career levels to a wide variety of research topics and techniques, including the latest approaches to study nervous system development, connectivity, and behavior. Daily research seminars present comprehensive overviews of specific subfields of nervous system anatomy and function and/or focus on specific techniques and approaches to study diverse aspects of neurobiology. The course fully leverages the conserved genetics and orthologous morphology of Drosophila to analyze neural development, neuronal physiology, and behavior, thereby emphasizing the relevance of this powerful model system to yield conceptual insights and inspire approaches to advance our understanding of human brain function and dysfunction. There will be a significant emphasis on the disruption and reorganization of neural circuits during the onset of neurological diseases or addiction. Instructors are selected based on their contributions and expertise in the field, with each instructor providing in‐depth knowledge in specific areas that complement each other. Additionally, instructors invite lecturers who have made significant contributions in their fields to provide current updates on the latest developments in research and future directions in their areas of interest. Participants are chosen by the course lead instructors from large pools of applicants and range from advanced graduate students to principal investigators. Because of the short duration of the course, participants can attend and receive intense training in an environment free from other demands on their time and attention. This neurobiology laboratory course thus offers a unique opportunity for scientists to gain expertise in an advanced invertebrate model within neuroscience and to apply the concepts and techniques to their own research interests. Importantly, participants are encouraged to disseminate what they learn in the course at their home labs and institutes. Participant feedback on course modules and instructors is collected each year and the long‐term impact of the course is assessed through tracking of alumni career trajectories. The overall effectiveness of the course is demonstrated by the fact that 64% of course alumni have gone on to lead their own research groups as professors.

Cultural Council of Greater Jacksonville

Project and operating grants for arts organizations and individual artists from Cultural Council of Greater Jacksonville. Supports visual, performing, literary, and media arts.

National Park Service

Researching, planning, documenting and producing interpretive programming for the public in the traditional cultural arts as mandated in park legislation and Comprehensive Interpretive Plans.

U.S. National Science Foundation

The Nation s advanced research cyberinfrastructure (CI) ecosystem catalyzes discovery and innovation across all areas of science and engineering (S&E) research and education. The increasingly complex and rapidly evolving S&E landscape requires an agile, integrated, robust, trustworthy, and sustainable CI ecosystem that will drive new thinking and transformative discoveries in all areas of research and education. The success of this vision depends on the ability of the research community to be able to easily and effectively access and use state-of-the-art research CI resources and services in a timely way. This, in turn, drives a set of requirements on the development, operation, and evolution of the CI ecosystem. First, research CI resources and services must be designed to leverage and drive innovations, and they must be user-centric and interoperable to enable the efficient, flexible end-to-end discovery pathways that are increasingly essential for the conduct of research. Second, the information, expertise, and services needed to maximally utilize the CI ecosystem must be disseminated broadly and concertedly to the research community. The NSF Cyberinfrastructure Centers of Excellence (CI CoE) Program aims to realize the above vision by supporting hubs of expertise and innovation targeting specific areas, aspects, or stakeholder communities of the research CI ecosystem. Supported CI CoEs provide expertise and services related to CI technologies and solutions; gather, develop, and communicate community best practices; and serve as readily-available resources for both the research community and the CI community. A key objective of this program is to support CI CoEs that drive advancements in and positively impact the CI ecosystem through structured but strongly community-engaging and community-serving approaches.Overall, CI CoEs are a means of concentrating resources on a specific area of identified need in support of the broader goal of advancing capabilities and performance of the national CI ecosystem [1]. Activities. Successful CI CoE projects will perform a range of functions such as: Exploring emerging technologies, disruptions, opportunities, and community needs, and developing proactive design and adoption strategies, practices, and other approaches in response; Nurturing communities of stakeholders and experts in their area(s) of focus (foci) with the overall goal of achieving self-sustaining communities of practice; and Providing services, training, and outreach to target communities. Topics and Pathways. NSF anticipates creating such CI CoEs in response to specific needs and gaps. NSF anticipates issuing Dear Colleague Letters to indicate interest in pilot CI CoE proposals on particular focus areas. NSF may initially invest in two-year pilot CI CoE projects which aim to develop concepts and plans and demonstrate feasibility through pilot activities as preparatory precursors to eventual proposals for establishing full-scale CI CoEs. The level of support for pilot CI CoE projects is expected to vary, based on the topic and range of activities proposed. Lifecycle and expected endpoint. CI CoEs are typically expected to operate for five years and may be renewed, subject to the outcome of performance reviews, NSF prioritization, continuing demonstrated need for the CI CoE, and availability of funds, consistent with NSF merit review principles. Guidance to proposers. Individuals interested in submitting a proposal for a CI CoE project are strongly encouraged to discuss their project idea with the cognizant CI CoE Program Director(s) in the relevant areas prior to submission. Additional guidance may be provided in Dear Colleague Letters issued to announce interest in pilot CI CoE proposals on particular focus areas. [1] An example is the NSF Cybersecurity Center of Excellence, Trusted CI, https://trustedci.org.

Daiwa Anglo-Japanese Foundation

Supports UK-Japan collaboration in education, science, arts, and culture.

NHLBI - National Heart Lung and Blood Institute

PROJECT ABSTRACT Congenital heart disease (CHD) occurs in approximately 40,000 infants in the United States each year. The National Heart, Lung, and Blood Institute (NLHBI) launched its Bench to Bassinet Program (B2B) in 2009 to overcome the major barriers in translational research, identify the causes of human CHD, and improve outcomes for individuals with CHD. Through the Congenital Heart Disease GEnetic NEtwork Study (CHD GENES), the B2B program has enrolled over 14,000 participants with CHD and 18,000 family members, conducting genomic sequencing to identify an estimated 25% of previously unexplained CHD cases. Despite these advances, critical gaps persist in our understanding of how genetic variants influence genotype- phenotype correlations and long-term outcomes in CHD. Although not initially designed as a longitudinal cohort, the NHLBI recognized the unique potential of the CHD GENES and directed the coordinating center (CC) to organize deep phenotyping and re-enrollment of a subset of participants for an in-person clinical assessment and to make the data available to the scientific community as the B2B Congenital Heart disease Advancing New understanding in GEnomics (CHANGE) Cohort. The new iteration of the CC is a unique, integrated combination of world-leading cardiovascular and clinical/translational research expertise, advanced infrastructure, outstanding operational support, and state-of-the-art technology. The specific aims are to: 1) Establish and maintain the B2B CHANGE Cohort, 2) Create a unique resource for CHD research by integrating new data sources with the existing clinical and genomic information maintained in the B2B DataHub (HeartsMart) and shared with NHLBI’s BioData Catalyst system, and 3) Ensure the CHD community has the necessary access, tools, and support to translate B2B data into improved health and quality of life for those affected by CHD. B2B CHANGE will be established using a multifaceted and patient-informed cohort outreach and engagement approach incorporating nationally recognized expert leadership and consultation and adaptation to local contexts as appropriate. Innovative clinical assessments and technical advancements to HeartsMart will expand and enrich existing phenotyping approaches, extend the duration of follow-up, and allow for new biological sample acquisition for future mechanistic and translational studies. Through resources including HeartsMart and BioData Catalyst, and extensive outreach, education, and engagement, the CC will ensure the CHD community has access to this vital resource to support rigorous, independently funded, investigator-initiated ancillary studies. The B2B CC has provided excellence in administrative support and coordination for the B2B program for the previous two funding cycles and will continue to be a successful partner with site investigators, the NHLBI, and the CHD community, leading the coordination of knowledge and data for this important cardiovascular research effort.

DE Arts Council

General operating and project support for arts organizations and individual artists in DE. Funds visual arts, performing arts, literary arts, and arts education.

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

Project Summary/Abstract Epigenetic modifiers govern cell fate transition during animal development and their mutations drive multiple human congenital disorders; however, the molecular mechanisms underlying the roles of epigenetic modifiers in these normal and pathological processes remain poorly understood. It is widely believed that epigenetic modifiers function through the epigenetic marks they catalyze. Nevertheless, the discoveries of catalytic- independent role of epigenetic modifiers challenge this view, raising the question about the biological function of epigenetic marks. Mono-methylation of histone H3 at lysine 4 (H3K4me1) is a reliable mark of enhancers that shape cell identity, and its reconfiguration accompanies the differentiation of pluripotent stem cells, suggesting that the regulation of H3K4me1 plays an instructive role in cell fate transition. To examine this hypothesis, we investigated the catalytic function of LSD1 and LSD2, two paralogous histone demethylases targeting H3K4me1, in regulating gene expression during cell fate transition. Using state-of-the-art approaches such as precise genome engineering, epigenetic and transcriptomic profiling, and stem cell differentiation, we demonstrate functional synergism between the demethylase activity of LSD1 and LSD2 in regulating cellular differentiation. Based on these compelling preliminary data, here we propose to dissect the molecular mechanisms underlying how the demethylase activity of LSD1/2 regulates cell fate transition. The results generated from our proposed studies will not only reveal novel molecular mechanisms underlying the roles of H3K4me1 in gene regulation and cell fate transition, but also provide insights into understanding the pathogenesis of diseases driven by LSD1/2 loss-of-function. This research aligns with the NIH mission to advance our understanding of fundamental biological processes and contribute to knowledge relevant to developmental disorders and regenerative medicine.

NIGMS - National Institute of General Medical Sciences

Project summary/abstract. Proteins orchestrate cellular processes as dynamic ensembles of interconverting conformations, characterized by the underlying free energy landscape (FELs). Understanding these FELs is paramount for deciphering biological mechanisms, elucidating disease pathogenesis, and engineering novel therapeutics. However, resolving complete FELs, predicting how they respond to perturbations like mutations or ligand binding, and designing them de novo present formidable challenges, limiting our ability to rationally control protein function. This application seeks to bridge this critical gap by developing an integrated computational and experimental platform for the comprehensive decoding, modulation, and de novo design of protein FELs. I am a postdoctoral researcher in Dr. Anum Glasgow’s laboratory at Columbia University, with a strong background in computational biophysics, protein engineering, and advanced hydrogen-deuterium exchange mass spectrometry (HX/MS) analysis. My development of PIGEON-FEATHER, a state-of-the-art Bayesian framework for deriving site-resolved energetics from HX/MS data, exemplifies my commitment to advancing methods for studying protein ensembles. Building on this foundation, my K99 research will establish a transformative framework for resolving, manipulating, and designing protein FELs, providing fundamental insights and practical tools for protein science, drug discovery, and synthetic biology. Aim 1 will develop PF- MetaD, a novel enhanced sampling approach that incorporates HX/MS-derived protection factors (PFs) into meta dynamics simulations. This will be enabled by two deep learning tools I propose to develop—PFNet and PFBoost—for accurate, residue-level PF determination. Together, these will allow the reconstruction of complete protein FELs. Aim 2 will apply these landscape insights to a critical biomedical challenge by designing state- selective protein binders to modulate the FEL of BRAF kinase, aiming to rationally control its activity in cancer- associated mutants by reshaping its conformational ensemble. Aim 3 will push the boundaries of protein engineering by pursuing the de novo design of a universal, ligand-responsive allosteric protein switch based on the PAS domain scaffold, programming its FEL for custom molecular recognition and regulation. Under the primary mentorship of Dr. Anum Glasgow and Dr. Barry Honig, and with the support of collaborators and the rich research environment at Columbia University and affiliated New York City institutions, I will train in single- molecule FRET, high-throughput screening methodologies, advanced machine learning for integrating multimodal biophysical data, scientific leadership, and grant writing. These skills will enable my long-term goal: an independent multidisciplinary lab at a leading R1 institution, focusing on FEL-guided design of functional and therapeutic proteins. This K99/R00 award is critical for my transition to an independent investigator, transforming our ability to rationally program biomolecular behavior.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Influenza viruses cause seasonal and epidemic outbreaks that pose a recurring burden on global public health systems. Despite annual vaccination efforts, severe influenza virus infections occur each year and disproportionally impact children, the elderly, and those with pre-existing conditions. Influenza-induced lung damage and persistent inflammation are highly variable across infected individuals, with limited understanding of the pathogenic signals that contribute to these processes. This proposal hopes to shed light on the pathogenic signals that promote the development of damage-associated niches in the lung leading to more severe disease outcomes. Prior members of the Thomas laboratory discovered a subset of damage- responsive fibroblasts (DRfibs) that reside in damage-associated lung niches and uniquely contribute to influenza-induced lung damage. DRfibs produce high levels of ADAMTS4, an enzyme that degrades versican, an extracellular matrix component produced in the lung during development and infection. Interestingly, when mice lack ADAMTS4, they are protected from influenza-induced mortality compared to wildtype littermate controls. It was found that a dense versican barrier prevented CD8 T cell: DRfib crosstalk, leading to fewer IFNg-producing CD8 T cells, less lung damage, and improved hypoxemia in ADAMTS4 KO mice. This proposal seeks to exploit ADAMTS4 KO mice as a model of damage-associated niche disruption to elucidate how preventing T cell: DRfib communication affects T cell phenotype, clonality, and specificity using spatial transcriptomic, scRNAseq, and TCR sequencing approaches. Low blood oxygen saturation (hypoxemia) is included as a predictor of poor outcomes in 9 out of 12 influenza and pneumonia severity scores, highlighting a strong correlation between impaired oxygenation and influenza severity. Tissue-level hypoxia in the lungs is also a characteristic of influenza illness. Previous research has shown that a cell’s microenvironment can significantly impact its phenotype; however, the impact of hypoxia on immune and stromal cell subsets in the lungs during and following a respiratory virus infection has not yet been explored. This F32 proposal will employ a unique mouse model to reveal how hypoxia in the lung microenvironment during severe respiratory viral infection influences the phenotypes of T cells and fibroblasts. Successful completion of the proposed will generate a unique atlas of hypoxic cell phenotypes that could have broad implications for the field as many severe respiratory viruses induce hypoxemia and lung damage. Dr. Paul G. Thomas, a well-established influenza immunologist and member of the Center of Excellence for Influenza Research and Response, and St. Jude Children’s Research Hospital will be integral to achieving the goals outlined in this proposal by providing technical training, practice in scientific communication, mentorship experience, on-site access to state of the art resources, and networking opportunities with influenza experts. Completion of the research and training goals outlined in this F32 proposal will unveil novel mechanisms of influenza pathogenesis while supporting the development of the applicant’s independent research career.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT The mammalian heart undergoes profound transcriptional and phenotypical remodeling during postnatal development, a process known as cardiac maturation. However, the molecular mechanisms driving this transition is not fully understood, posing a major challenge in cardiac regenerative medicine, where induced cardiomyocytes from pluripotent stem cell differentiation or non-myocyte reprogramming exhibit an overall immature phenotype that severely limits their application in cell therapy and in vitro disease modeling. In this K99/R00 application, I propose to integrate cutting-edge single cell multiomics with state-of-the-art computational methods to unravel the cell-type-specific gene regulatory networks governing cardiac maturation, and develop a novel dual-reporter system to model and enhance cardiac maturation in vitro and in vivo. During the K99 phase, I will characterize the epigenomic changes of the mouse heart during postnatal development at a single cell resolution using various single cell multiomic technologies (Aim 1), and construct cell-type-resolved gene regulatory networks underlying cardiac maturation using bioinformatic approaches coupled with deep learning (Aim 2). I will also establish cell culture and mouse models with CRISPR-mediated knock-in of dual-fluorescent reporters to track and assess cardiomyocyte maturation (Aim 3a). During the R00 phase, I will experimentally characterize key regulatory elements and novel transcriptional regulators using functional genomic approaches (Aim 3b). I will also leverage these findings to enhance the maturation of in vitro-derived cardiomyocytes for improved therapeutic potential (Aim 3c). The expected outcomes of my proposed research will deepen our understanding of postnatal cardiac development and uncover new therapeutic strategies to improve cardiac function after injury. My career goal is to lead an independent research group that develops and employs innovative technologies to study the regulatory mechanisms underlying cardiac development, regeneration, and disease. In my K99 phase, I will acquire crucial knowledge and skills in advanced single cell genomics and computational biology to complement my previous expertise in developmental biology and cardiac research. My career development will be supported by an exceptional mentoring and advisory committee from UCSD/Salk/HHMI, along with world-class resources, training opportunities, and institutional support at UC San Diego. These elements will provide a strong foundation for my successful transition to an independent tenure- track faculty position.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Although effective therapeutics that target the dysregulated kinase activity of BCR::ABL1 have been developed for patients with chronic myeloid leukemia (CML), acquired resistance remains an important clinical issue. Additionally, problematic side effects plague a considerable proportion of patients who are expected to require lifelong therapy. The first five approved tyrosine kinase inhibitors (TKIs) for CML target the ATP binding pocket of BCR::ABL1 (“orthosteric” TKIs). Asciminib is the first active “allosteric” TKI for CML and was recently approved as a frontline therapy based on high response rates and excellent tolerability. Asciminib is rapidly being adopted as a preferred treatment in all lines of therapy. We have demonstrated that several mutations that confer resistance to orthosteric TKIs unexpectedly confer in vitro and/or clinical resistance to asciminib. We have further demonstrated that a clinical variant of BCR::ABL1 lacking ABL1 exon 2 is uniquely and highly resistant to asciminib. Notably, these isoforms retain asciminib binding affinity, thereby invoking a novel molecular mechanism of resistance. Our central hypothesis is that asciminib will be vulnerable to multiple resistance- conferring mutations that disrupt its allosteric effect on kinase conformation, in addition to a limited number of mutations that impair its ability to bind BCR::ABL1. Our rationale is that pioneering work on orthosteric TKI resistance mechanisms in CML have informed kinase conformational dynamics, optimal CML patient management, development of next-generation TKIs and successful prediction of TKI resistance mechanisms in several other malignancies. We propose to (i) employ orthogonal approaches to identify and validate single point mutants in BCR::ABL1 that can confer resistance to asciminib, and compound (≥2 on one DNA strand) mutants that arise following subsequent orthosteric TKI therapy, (ii) assess their sensitivities to a novel active investigational allosteric inhibitor, combinations of TKIs, and a novel bitopic TKI, (iii) determine mechanisms of resistance through computational and structural studies, (iv) define residues necessary for adoption of the closed ABL1 kinase conformation, and (v) assess the ability of asciminib-resistant mutants to pathologically activate ABL1 kinase activity. The proposed research is significant due to its potential to rapidly impact clinical investigation and optimize patient management, inform understanding of kinase regulation and other malignancies. The proposed research is innovative because it applies state-of-the-art methodologies to comprehensively define and characterize a novel mechanism of resistance to a first-in-class highly clinically active allosteric TKI and thereby establish a new paradigm. Additionally, it will assess the promise of emerging agents, TKI combinations, and an innovative bitopic TKI with best-in-class features for treating asciminb-resistant single and compound mutants.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT People with HIV-1 (PWH) on antiretroviral therapy (ART) are prone to experiencing chronic inflammation despite effective viral suppression. This sustained inflammation has been linked to an elevated risk of developing a variety of age-associated comorbidities, including chronic kidney disease (CKD). Preliminary data supporting this study demonstrates multiple distinct inflammatory endotypes among aging PWH on ART, several defined by levels of chemokine C-C motif ligand 2 (CCL2), a critical mediator and biomarker of kidney injury and disease. However, the precise cellular and molecular inflammatory immune endotypes in PWH that could lead to disease remain undefined. Moreover, how endotypes defined by circulating inflammatory markers impact organ- compartmentalized inflammation and the functional and molecular states of immune cells are unknown. The overall objective of this project is to define the early cellular and molecular signatures of inflammation associated with the progressive development of CKD in PWH on ART in both blood and urine. This will be achieved by comprehensively defining plasma inflammatory endotypes in a retrospective cohort of aging (50+ years) PWH on ART, sampled as they progressed from early to later stage kidney disease, with comparison to PWH on ART with normal renal function. In addition, systems immunology will be used to characterize the soluble and cellular inflammatory profiles of peripheral blood and urine in a prospective cohort of 200 aging PWH on ART. Urine, a readily accessible non-invasive biofluid, contains proteins and viable cells originating from the kidney that can serve as indicators of renal inflammation and overall kidney function. A combination of advanced machine learning approaches, clinical tests, and human kidneys-on-chips models will be applied to define the relationship between systemic, urinary, and renal cell inflammation and dysfunction in PWH on ART that are associated with onset of CKD. This project will test the hypothesis that specific inflammatory immune endotypes can be identified in PWH on ART that promote the activation and dysregulation of immune and kidney cells, contributing to the development of CKD. The hypothesis will be tested, and the overall objective achieved, with completion of three Specific Aims. Aim 1 will define plasma inflammatory endotypes of aging PWH on ART and identify signatures that predict CKD. Aim 2 will identify how plasma inflammatory endotypes impact the cellular, metabolic, and functional programs in blood and urine of aging PWH on ART. Finally, Aim 3 will determine the mechanisms of activation of renal inflammatory programs using kidneys-on-chips. This research will identify specific endotypes of inflammation associated with development pf CKD and uncover pathways driving chronic inflammation in the blood and urine that promote kidney injury and disease. This knowledge will enable the development of CKD risk prediction tools and of therapeutic interventions like CCL2 signaling inhibitors to reduce inflammation-related kidney disease and other comorbidities in this expanding population.

NHLBI - National Heart Lung and Blood Institute

Project Abstract Pneumonia is a leading cause of infectious deaths worldwide; over 2 million people die of pneumonia each year. The leading bacterial cause of pneumonia is Streptococcus pneumoniae (Spn), an opportunistic pathogen that colonizes the human respiratory tract. While there are >100 known serotypes of Spn worldwide, current immunization strategies protect only against a limited few. Recent advances in our understanding of mucosal immunology have identified lung-resident CD4+ memory T (TRM) cells as critical determinants of broad protection against multiple serotypes of Spn. However, despite their clinical value from the public health perspective, little is known about mechanisms that drive the establishment of these CD4+ TRM cells in the lungs. Furthermore, it is unclear whether Spn may alter CD4+ TRM cell formation in the lungs using its own virulence factors. Understanding these mechanisms is instrumental for development of next generation cross-protective immunization strategies against this pathogen. Relevant to this, our preliminary data suggest that the Spn toxin pneumolysin (Ply) and bacterial sensing by NLRP3 are both key to recruitment and establishment of CD4+ TRM cell in the lungs. However, it remains unclear whether pore-forming activity or complement-activating biology of Ply is required for CD4+ TRM cell formation nor is it known how NLRP3 sensing of Spn may coax CD4+ TRM cell formation. In this proposal we will test the hypothesis that Spn drives CD4+ TRM cell formation via Ply’s pore forming activity and induction of macrophage-epithelial crosstalk via NLRP3. This hypothesis will be tested through two specific aims: Aim 1 will determine whether pore formation activity of Ply drives CD4+ TRM cell formation by boosting T cell recruitment, and Aim 2 will determine whether NLRP3 sensing of Spn is required for macrophage-epithelial crosstalk to drive CD4+ TRM cell formation. These studies will be accomplished by using isogenic Spn mutant strains, genetically engineered mice, intratracheal murine infection models, adoptive transfers, spectral flow cytometry, and single cell- and bulk-RNA sequencing. Findings from these innovative studies will guide development of more effective, broadly protective Spn immunization strategies that will prevent life-threatening Spn-pneumonia and subsequent diseases. This proposal will support the applicant with her scientific, technical, personal, professional, and career development which includes courses and workshops, guidance from a strong mentoring team and dissertation advisory committee, opportunities to develop science communication skills, and opportunities to mentor junior students in the lab and classroom. The University of Michigan offers top academic training, connections with esteemed faculty in pulmonology, microbiology, and immunology, and state-of-the-art resources to achieve the proposed aims. Completion of this proposal will also support the applicant’s rigorous training in experimental design, microbiology and immunology techniques, and data interpretation that will usher her towards becoming a successful, independent scientist.

NEI - National Eye Institute

Project Summary: Neurodevelopmental disorders, including syndromic disorders of retinal and brain development, are a major cause of morbidity in children. A subset of these disorders results from abnormal vascular development, and microcephaly and chorioretinopathy (MCCRP) is a recently identified disease that may belong in this category. It is characterized by small head circumference, brain anomalies, developmental delay, and vision loss due to chorioretinopathy and abnormal retinal vasculature. Autosomal recessive MCCRP results from defects in TUBGCP4 or TUBGCP6, which encode components of the gamma-tubulin ring complex (γ-TuRC), a ubiquitous structure necessary for microtubule nucleation and spindle formation in cells. However, γ-TuRC has not previously been implicated in vascular development and it is unknown why defects in γ-TuRC lead to blindness and microcephaly. We demonstrated that Tubgcp4 and Tubgcp6 expression is highly upregulated in murine vascular endothelial cells (EC) from the retina and brain (relative to EC from other tissues), and that murine EC deficiency of TUBGCP4 results in embryonic lethality, indicating a critical role for TUBGCP4 in EC. Our long-term goal is to identify the role of the γ-TuRC in retinal and brain development. The objective of this application is to define the pathophysiology of TUBGCP4 and TUBGCP6-associated MCCRP. We will test the hypothesis that TUBGCP4 and TUBGCP6 serve critical, EC-specific roles in the retina and brain, and that deficiency of these proteins results in MCCRP due to a primary vascular developmental defect. Since retinal and cerebral vascular development is not complete until several weeks after birth, we will use novel conditional knockout mouse models of Tubgcp4 and Tubgcp6 and a tamoxifen-inducible EC-specific Cre recombinase to eliminate expression of these genes in EC postnatally. Ophthalmic studies will demonstrate the necessity of EC-specific TUBGCP4 and TUBGCP6 in retina and retinal vascular development, including optical coherence tomography (OCT), OCT-angiography, electroretinogram, optokinetic response, and retinal histology (Aim 1). Neurologic studies in mice and/or embryos lacking TUBGCP4 or TUBGCP6 in EC will demonstrate the necessity of these proteins in cerebral and neurovascular development, including MRI brain imaging, neurobehavioral studies, and brain immunohistochemistry (Aim 2). Elucidating the pathophysiology of MCCRP will improve our understanding of the genetic mechanisms controlling retinal and brain vascular development, and may reveal new therapeutic targets for more common blinding retinal vascular diseases. The career development objective of this proposal is to develop the mentorship and expertise needed to become a productive independent clinician-scientist and international leader working at the intersection of inherited retinal diseases (IRD) and disorders of vascular development. OHSU is a center of renowned expertise in IRDs, in vivo retinal vascular imaging, and the neurosciences; it provides state of the art resources and world-class faculty to support Dr. Everett’s scientific and career development goals for this proposal.

Delaware Community Foundation

Delaware Community Foundation ($350M in assets) supports nonprofits in DE through grants focused on education, community development, health, arts. Awards range from $2,000 to $100,000.

National Park Service

This Funding Announcement is not a request for applications. This announcement is to provide public notice of the National Park Service s intention to fund the following project activities without full and open competition. OVERVIEW The Demonstration Arts and Cultural Preservation Project seeks to make possible the continuation of a long-held park goal to provide a venue and support for the Native artists to perpetuate and preserve their history, culture and craft through park or Visitors Center studiobased work on art forms including wood carving, metal-smithing, bead work, fiber arts such as weaving, story-telling and other elements of culture. The partner, Sitka Tribe of Alaska (STA) will provide staffing to conceive a detailed plan for the project, to publically solicit applications from Native artists who wish to participate in the project, to select participating artists, to schedule artists studio time, and to monitor and manage artists participation and fulfillment of mission. SITK will provide training for the artists on the park, its history and mission, so that as artists interact with visitors they will be able to provide information not only on their arts, but on the park itself. Park staff will work closely with STA staff on scheduling, training and support, so that the artists in studio are on site during peak visitor periods. The project will run from Maythrough September. STATEMENT OF JOINT OBJECTIVES/PROJECT MANAGEMENT PLAN The goals are to foster the preservation of Native art and culture, and to enhance visitor enjoyment of the park. STA will provide the management of the project, and SITK will provide the venue, training and liaison with the visitors. The two partners will work together to align the artists, the venue, the scheduling of demonstrations and the visitor interaction. Through the selection and presence of active Native artists in the park studios, STA and SITK will jointly make possible the continued perpetuation of a number of Native art forms that are in significant need of support. These art forms have been passed down through generations of artists for several millennia, but the lack of contemporary venues and support for artists threatens the continued existence of these forms of art. With input from SITK, STA will establish a calendar of artists participation in studio space, aligned with visitor flows, and establish a management team to manage the project, including a senior manager with project and budget oversight, and a scheduler who will track and manage artist time and attendance. SITK will designate a member of the Interpretive staff as project liaison. That person will work on scheduling, preparing the studio space for artists, arrange for training artists in SITK and NPS information that will be helpful to visitors, and provide such other support as to make the project run smoothly. Artists will be provided such materials and equipment as are needed to be able to practice their crafts. The artists will be scheduled in-studio during days when the heaviest load of summer visitors is projected, so that their work can be viewed by the largest number of park visitors. STA and SITK will work together on publicizing the demonstration arts project, with a special emphasis on the key goal of preservation of culture and art forms. The partners will have scheduled check-in points through the life of the project to review its progress and to address any problems that may arise. The partners also will do a formal review when the project is completed so that lessons learned about success and challenges can be captured. RECIPIENT INVOLVEMENT STA will manage this project, and that management and associated costs will be funded by this project. STA will assign a senior manager to oversee its execution, including the management of the budget. The manager in turn will hire a part-time scheduler to ensure artists are scheduled at times appropriate to the studio space and visitor influx. The scheduler will track time and attendance, and provide that information to the manager so that the artists can be paid for their time in the studio. Program Point of Contact: Becky Latanich 907-747-0132.

Dentsu Foundation

Funds creative education, arts, and social good communication programs globally.

Tasveer

The Desi Improv Festival will include an improv workshop and a main improv event. The project is designed to introduce participants to the art of improvisation through engaging scenes, games and exercises in a fun, supportive environment. Research shows that improv is a powerful tool for team building and community engagement. By focusing on collaboration, creativity and spontaneous thinking, this workshop aims to break down communication barriers and foster acceptance and understanding. Participants will develop skills in adaptability, active listening and effective communication. Ultimately, this workshop will empower participants to feel more confident, connected, and better equipped to navigate diverse environments.

Tasveer

Tasveer will organize a free nine-day literary and storytelling festival focusing on South Asian culture in January 2019. It will feature presentations and workshops on writing fiction, comedy, screenplays, graphic novels, and other ways of telling a story. The events will take place at Seattle Art Museum Located at 1300 1st Ave and Northwest Film Forum located at 1515 12th Ave.

NHGRI - National Human Genome Research Institute

ABSTRACT Noncoding genetic variation that alters gene regulation is of paramount importance for health, disease, and evolution. Diseases ranging in incidence from the most common to the most rare all have substantial risk associated with regulatory variation; and most of the genetic differences between closely related species are noncoding. Whole genome sequencing can directly identify that variation but to realize its potential to elucidate the genetic determinants of health and disease, will require accurate annotation of this noncoding variation for functionality. In coding sequence, the genetic code allows variants to be annotated to a rough hierarchy of likely functional effects and pathogenicity. In noncoding sequence such annotation is less clear. Perturbation assays, i.e., assays that modify genetic or epigenetic states and measure the effect of those perturbations on regulatory endpoints, offer a possible path to annotating noncoding variation. However, to fully leverage this data, novel and sophisticated statistical and machine learning approaches are required to extract useful information from those assays, to integrate that information across regulatory endpoints, and to extrapolate findings so that annotation of previously unobserved (unperturbed) variation in diverse cell types is possible. The goal of the Duke Prediction Center is to develop the analytic approaches and tools that will allow for the routine annotation of noncoding variation for functionality and ultimately pathogenicity. Aim 1 is to establish best practices in perturbation assay design and analysis. This will allow IGVF characterization centers design their experiments so that, when coupled with optimized analyses, the data produced will be maximally informative for subsequent predictive modeling. Aim 2 is to develop novel mechanistic machine learning approaches for predicting the functional effect of noncoding variation on function in diverse cell-types. Aim 3 is to identify noncoding genomic regions that are subject to functional constraint which will be leveraged in prioritizing variants for pathogenicity. The expected outcomes of this project will be (i) robust estimates of optimal experimental design parameters and recommendations for analysis tools and best practices for the various assays used within the IGVF consortium, (ii) predicted functional effects of observed variation to be shared through the IGVF variant/phenotype catalog as well as a state-of-the-art machine learning method (and associated tools) that can identify previously-unknown interactions among genomic variants, both observed and novel, and predict their functional impact in diverse cell types, and (iii) a list of regulatory elements subject to functional constraint shared through the IGVF variant/phenotype catalog and a principled prioritization framework (and associated tools) for interpreting variation within patient genomes for pathogenicity. Due to the considerable success of genetics, there are thousands of unknown regulatory causes of disease. Each of those causes is an opportunity to improve treatment, diagnostics, or prevention. This project will be a major advance towards unlocking that potential.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This K23 award will facilitate Dr. Grau’s transition into an independent investigator who develops and tests scalable interventions with attention to health disparities to meet the variation in needs among individuals with post-traumatic stress disorder (PTSD) and hazardous alcohol use (HAU). Targeted research and training activities will extend his knowledge and build his expertise in developing and testing scalable interventions that integrate therapist-delivered and digital components to effectively engage and treat patients with PTSD+HAU in under resourced community settings like Federally Qualified Health Centers (FQHCs). Training: Dr. Grau proposes a comprehensive training plan with the following training aims: (1) Develop expertise in mobile health interven-tions, (2) Gain skills in qualitative data collection and analysis and (3) Acquire key skills in and knowledge of optimization trial design and conduct. Context: PTSD is an extremely damaging psychiatric condition when left untreated, especially for individuals with low-income who are served in FQHCs. Brief, modified evidence-based PTSD treatments are effective and feasible in FQHCs; however, co-occurring problems, most notably HAU, negatively impact treatment engagement and effectiveness. As such, there is a critical need to develop scala-ble interventions that treat PTSD+HAU while maximizing engagement in under resourced community settings such as FQHCs. Responsive to the NIMH Strategic Plan, Goal 3 (Strive for Prevention and Cures), Objectives 3.2 (Develop strategies for tailoring existing interventions to optimize outcomes), and 3.3 (Test interventions for effectiveness in community practice settings), the overall research objective is to develop and test a multimodal intervention that integrates therapist-delivered and digital interventions to treat PTSD+HAU in FQHCs. Re-search Plan: Aim 1 will assess the feasibility and acceptability of three stepped care, therapist-delivered inter-vention components for PTSD+HAU in our partner FQHC. Aim 2 will refine the therapist-delivered components and develop digital components (e.g., personalized text messages) in preparation for a PTSD+HAU hybrid ex-perimental design (HED). Aim 3 will assess the feasibility, acceptability, and preliminary effectiveness of a PTSD+HAU HED in FQHCs combining therapistdelivered and digital interventions to maximize engagement in treatment. Aim 3 results will inform a fully powered HED (future R01 submission) to create a multimodal adap-tive intervention for PTSD+HAU with patients in community health settings. Key innovations include state-of-the-art training, PTSD+HAU scalable intervention development with real world patients in community settings, and use of the HED design. Optimization of adaptive interventions for community patients with PTSD+HAU is a critical next step and will have significant impact on PTSD treatment in FQHCs.

NIMH - National Institute of Mental Health

Abstract Despite antiretroviral therapy (ART), HIV-associated brain injury (HABI) persists in over half of people with HIV (PWH), manifesting as chronic cognitive impairment. While HIV-1 primarily infects microglia, driving central nervous system (CNS) neuroinflammation, current preclinical models do not recapitulate the chronic, suppressed infection characteristic of the ART era. Furthermore, they do not capture complex patient genetics and multicellular, glial and neuronal, interactions in a scalable and efficient manner. To address this need for more physiologically relevant models, we propose the development of an AI-guided triculture platform comprising major CNS cell types. This platform will use induced pluripotent stem cell (iPSC)-derived microglia, astrocytes, and neurons, using both morphological profiling and other omics-based profiling to model HABI under ART suppression. AI/machine learning (ML)-driven analysis of cellular morphology, combined with multi-omic data integration, will facilitate rapid classification and prediction of microglial functional states and their impact on neuronal health. Leveraging Modulo's established triculture system, previously successful in yielding therapeutic candidates for amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) currently in Investigational New Drug (IND)-enabling studies, we will construct a scalable HABI model under ART suppression. Our objectives are to (1) develop and validate an HIV-infected, ART-suppressed triculture platform, utilizing AI/ML-driven morphological profiling to classify HABI-specific microglial states; and (2) comprehensively characterize this model through neuroinflammatory profiling, behavioral correlates, and integration with publicly available HABI patient datasets. We hypothesize that our combined computational lab-based triculture system can effectively model HABI pathophysiology under ART conditions, enabling both rapid disease state classification and identification of therapeutic targets. Through the integration of experimental and computational approaches, this platform will provide insights into HABI mechanisms and accelerate therapeutic development. We will disseminate this model to the scientific community through publication and collaboration. Connecting in vitro modeling with patient outcomes offers a powerful tool for investigating neuroimmune dysfunction in HIV and related neurological disorders. Successful implementation will yield a platform for modeling neuroHIV under ART suppression, advancing our understanding of disease mechanisms and facilitating the discovery of novel therapeutic strategies for PWH with cognitive impairment.