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NIBIB - National Institute of Biomedical Imaging and Bioengineering

Abstract Multispectral fluorescence imaging enables simultaneous measurement of many molecular targets in situ, but quantitative interpretation is limited by spectral unmixing under photon-count noise. Most current pipelines, adapted from spectral remote sensing, assume Gaussian noise and continuous intensities; fluorescence mi- croscopy instead yields discrete, often overdispersed photon counts. This model–data mismatch reduces accu- racy, sensitivity to weak markers, and reproducibility. This R03 project will establish statistically principled, reproducible models for quantitative biological imaging by developing and validating a count-aware unxming framework that aligns with photon-count physics. The first aim of the project is to develop a unified, likelihood-based framework for spectral unmixing using count data dis- tribution models with structured regularization. The second aim is to validate and benchmark the framework on simulated and experimental datasets against state-of-the-art approaches, demonstrating improved signal accu- racy, localization, and biological interpretability. The expected outcome is a computationally efficient, statistically rigorous approach to count-based modeling that improves unmixing accuracy, robustness in low-photon regimes, and cross-session reproducibility. This new technology lays a robust foundation and pushes the boundaries of quantitative and reproducible spatial biology. By improving the precision and reproducibility of multispectral fluorescence imaging, this project directly supports the NIH mission to advance fundamental knowledge and develop tools that enhance biomedical research, disease diagnosis, and translational discovery.

NCI - National Cancer Institute

PROJECT ABSTRACT / SUMMARY The ribosome is a fine-tuned regulator of gene expression through multiple layers of regulation, including post- transcriptional RNA modifications. Cancer cells have “hijacked” the translation machinery to exert rapid and selective translational control of the cancer proteome in a matter that is distinct from normal cells. Changing the landscape of the hundreds of modifications in the catalytic core of the ribosome may be one of the strategies cancer cells use to reprogram their translatome. Work from our labs has been the first to demonstrate a functional link between rRNA modifications and cancer etiology. We have discovered that one of the most deregulated oncogenic signals, RAS, directly controls the expression of multiple snoRNAs, which are small non-coding RNAs that guide rRNA modifications. As a paradigm example, we have shown that one of the snoRNAs, SNORA24, plays a pivotal role in bypassing oncogene-induced senescence (OIS), a critical tumor-suppressive mechanism. We attribute this profound effect of a snoRNA on cancer progression due to its role in controlling lipid metabolism, a key feature of cancer development. This is reinforced by our findings that SNORA24 controls the translation of lipid metabolism transcripts, which is recognized as one of the hallmarks of liver cancer. We further show that additional snoRNAs driven by RAS expression are critical for cell fitness of colon cancer cells and have opposing roles on control of global protein synthesis. In cancer, the dysregulation of these modifications has been increasingly recognized as a contributor to tumor development, progression, and drug resistance. However, a systematic analysis of snoRNA function in cancer biology, the mechanistic and biochemical basis for their function as well as the breadth of these modifications for distinct human cancers is lacking. Here we will combine the expertise of our two labs as well as collaborators to (1) mechanistically dissect the biochemical and structural basis for rRNA modifications on control of cancer metabolism, (2) use state-of-the-art CRISPR screen to directly assess snoRNA function in different steps of tumorigenesis in-vivo and whether this is guided directly by rRNA modifications, as well as (3) create an atlas of all RNA modification changes in primary human prostate cancer and their impact on the cancer translatome. In addition, here we will build off of a novel technology known as Pan-Mod-Seq that can simultaneously measure all known rRNA modifications in dozens of cancer samples at the same time. We will be in a strong position to further analyze the prospective and retrospective associations of these modifications on cancer progression, metastasis and therapeutic response. Understanding the role of rRNA modifications in cancer will provide insights into disease mechanisms and open new avenues for diagnostic biomarkers and therapeutic interventions.

National Park Service

Complete the work of historians who began documenting the history of Tuskegee Institute,train Tuskegee University students and members of the community on the art and science of collecting oral history.

European Commission - HORIZON

Creative alliances: Fostering global partnerships in cultural policies and CCI innovation. Call: Culture, Creativity and Inclusive Society 2026. Programme: HORIZON. Keywords: Digitalisation/ICT and cultural heritage, International relations, Policy development, Policy making and economics, Social innovation, Social sciences, interdisciplinary, Visual arts, performing arts, design. Open call from the EU Funding & Tenders Portal.

Creative Growth, Inc

Support for a program of studio arts instruction, gallery exhibition and promotion for 152 adult artists with developmental, physical, and emotional disabilities.

Creative Saskatchewan

Creative Saskatchewan supports the province's creative industries including film, music, publishing, and visual arts through grants and market development funding.

Creative Time

Grants for public art projects that challenge social conventions and push the boundaries of art in public spaces.

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.

OD - NIH Office of the Director

Summary The California NanoSystems Institute (CNSI) at the University of California, Los Angeles (UCLA), is committed to pioneering nanobiology and biomedical research. Central to this mission, the Electron Imaging Center for Nanosystems (EICN), established in 2007, provides cutting-edge cryogenic electron microscopy (cryoEM) instruments and specialized expertise to elucidate the mechanisms of molecular machinery at the nanometer scale. A previous NIH S10 award was pivotal in installing the world’s first operational Titan Krios in 2008, a landmark achievement that fueled the cryoEM revolution of the past decade. This instrument produced data for one of the earliest near-atomic-resolution single-particle cryoEM structures and played a critical role in Moderna’s groundbreaking mRNA vaccine development. Building on this success, a second NIH S10 award enabled the acquisition of a Titan Krios G4 in 2024, equipped with advanced technologies for both cryoEM imaging and cryogenic electron tomography (cryoET) tilt series acquisition. These state-of-the-art instruments support hundreds of registered UCLA users, facilitating atomic-level structural analysis of isolated or enriched biological complexes for a wide range of research applications. While EICN’s cryoEM and cryoET capabilities meet current user needs, the lack of a cryogenic focused ion beam (cryoFIB) instrument significantly restricts our large user base from conducting in situ structural studies within cells and tissues using cryoET. Most cells, exceeding 1 µm in thickness, are too dense for electron penetration and require precise milling into lamellae of 200 nm or less to enable high-resolution cryoEM or cryoET imaging. This application seeks funding to acquire an Aquilos 2 cryoFIB instrument, which will empower NIH-supported biomedical research across 38 user laboratories (including 26 major users) within EICN’s extensive user community. The proposed cryoFIB will substantially enhance EICN’s cellular cryoET capabilities, advancing federally funded research in critical areas such as viral and microbial infections, neurodegenerative disorders, tumorigenesis, therapeutic development, drug design, and vaccine delivery systems, as well as the PI continuous cryoEM/cryoET method development. The Aquilos 2 cryoFIB will benefit from robust institutional support, including dedicated staff, ongoing instrument maintenance, and operational resources, ensuring long-term impact and accessibility. The instrument will be managed by EICN’s highly experienced core facility team, which has successfully operated the facility for 18 years since its inception. The principal investigator, managing director, facility technician, and user coordinator possess the technical expertise and operational experience necessary to ensure the cryoFIB’s seamless integration and productive use. This high-end S10 instrument will immediately bolster NIH- funded biomedical research across UCLA’s colleges of natural sciences, engineering, and the David Geffen School of Medicine, driving transformative discoveries in structural biology and beyond.

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.

NCATS - National Center for Advancing Translational Sciences

SUMMARY This National Research Service Award (NRSA) Institutional Research Training Grant Proposal (T32) aims to support a research year for pre-doctoral medical students with a focus on Healthcare Artificial Intelligence (AI) and Technological Innovations. The program's primary objective is to identify and train potential physician scientist leaders in the fields of AI-assisted diagnostics, clinical decision support tools, personalized medicine prognostics, and biomedical instrumentation. Our program will provide support for a dedicated research year embedded within our newly launched 3-year medical school curriculum, providing comprehensive research exposure, advanced technical skill development and career training within 4 years of training. This initiative is the first institutional training program aimed at supporting dedicated research time for medical students and the first focused on this rapidly evolving discipline. This T32 program capitalizes on NYU Langone Health's strengths in foundational AI research, clinical decision support implementation, healthcare innovation, and implementation science. These strengths are complemented by indispensable support from our Clinical and Translational Science Institute (CTSI), educational partners within NYU Grossman School of Medicine and Vilcek Institute of Graduate Biomedical Sciences, and our faculty’s world renowned clinical and research expertise. Our program will provide trainees with the skills needed to lead and execute research projects using state-of-the-art approaches; training in relevant technical skills in computation, statistics and biotechnology; and career support to ensure their future success. The training program will also equip trainees with data literacy, multidisciplinary communication skills, a systems-based approach to research and clinical practice, and a deep understanding of the considerations required when developing novel healthcare technologies. We see the greater impact of this as being two-fold. First, this training grant will foster a new category of physicians who are not only experts in their clinical specialty but also pioneers in translational AI research and innovations. In the wake of the ongoing AI revolution, it is imperative for physicians to comprehend and contribute to the ever-growing role of predictive and large language models in the context of disease prevention and improved patient outcomes. Secondly, our T32 will help to address the continuing shortage of physicians participating in biomedical research, particularly in this burgeoning field. By providing dedicated research time for medical students without requiring a PhD-level commitment, the program aims to lower the barriers of entry and increase research competence across a larger cohort of trainees. In conclusion, this T32 program is poised to create a new generation of AI and technologically literate physician researchers and by integrating this program with existing CTSI training programs and research initiatives, we will create a unique educational platform that will ensure our scholars are future leaders in translational medicine and healthcare.

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.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Sjögren’s disease (SjD) is a systemic autoimmune disease in which destructive lymphocytic infiltration of the salivary (SG) and lacrimal glands leads to chronic dry eyes and mouth. It is one of the most common autoimmune diseases and causes significant disease morbidity but lacks approved disease modifying therapy. A hallmark histologic feature of SjD is dense immune infiltrate of the SG called focal lymphocytic sialadenitis (FLS). The CXCR3 chemokine signaling is an essential system for recruiting T cells to tissues and regulating their behavior. We and others show increased expression of the CXCR3 ligands, CXCL9 and CXLC10, in the SG in SjD, primarily in fibroblasts, endothelial cells, and antigen presenting cells. In this proposal, we will examine the mechanisms by which CXCR3 signaling controls the recruitment, maintenance, and activation of T cells in the SG. We hypothesize that CXCL9 and CXCL10 production by different cell types within the SG plays distinct roles in the formation and maintenance of FLS. The proposal will focus on understanding 1) which cells express CXCL9 an CXCL10 through the course of disease and 2) how different cellular sources of CXCL9 and CXCL10 influence T cell behavior and phenotype in the SG. We will perform complementary studies of human SG biopsies and mouse models of SjD to make mechanistic insights into disease-relevant immunopathogenesis. Dr. Yockey will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at the Massachusetts General Hospital (MGH) under the mentorship of Dr. Andrew Luster, an expert in chemokine signaling, and Dr. Cory Perugino, an expert in human immunology. The CIID is a state-of-the-art multidisciplinary research center focused on investigating the mechanisms of immune-mediated inflammatory diseases. Dr. Yockey has developed a career development plan with four objectives to acquire: 1) Skills in tissue imaging and spatial transcriptomics, 2) Expertise in human T cell biology, 3) Knowledge of chemokine signaling and stroma-immune interactions, 4) Proficiency in histologic assessment of the salivary gland. Dr. Yockey has assembled a Training Advisory Committee and team of collaborators with unmatched and complementary expertise in key areas including SjD biology and computational biology. By completing these research and training plans, Dr Yockey will establish the intellectual and technical skills necessary to become an independent investigator. Importantly, she will develop expertise to conduct parallel studies using mouse models and patient samples to be able to ask human- relevant, fundamental questions about autoimmunity pathogenesis. She plans to use these important skills to spend the rest of her career advancing the care of patients with SjD and other autoimmune diseases by deciphering mechanisms of immune-mediated tissue damage.

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.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Optimizing safe perioperative opioid use is a critical priority. Despite being intended for short-term use, a significant number of patients who are first exposed to opioids (opioid-naïve) following surgery continue using them longer than the typical recovery period (i.e., 3months). This prolonged exposure is termed new persistent opioid use (NPOU). To date, the existing literature has heavily focused on identifying pre-existing risk factors. However, to better inform practice and facilitate actionable interventions, there is a critical need to discern which patients are at higher risk and characterize trajectories of post-operative opioid use that develop into unhealthy opioid use (i.e., misuse, abuse, and addiction). Thus, the proposed work has two specific aims: (1) to develop an optimal prediction model to identify patients at risk for NPOU, and (2) to determine the extent to which NPOU reflects unhealthy opioid use and identify patient characteristics associated with such use. To achieve these aims, we will analyze electronic health records from a large academic health system that serves diverse sociodemographic populations using state-of-the-art analytic methods, including machine learning and natural language processing. Complementing the proposed training plan, the overall objective is to promote the safe perioperative use of opioids among opioid-naïve patients by generating insights to prevent the transition from acute to chronic opioid use, and to discern chronic opioid use that reflects unhealthy use. This proposed research and training will be strongly supported by structured training activities, an interdisciplinary mentorship team consisting of experts in medicine, nursing, health informatics, and computer science, as well as robust research resources from the University of Pennsylvania. Supporting NIDA’s strategic priority of preventing prolonged drug use, addiction, and related adverse consequences through data science, the proposed research training proposal will provide the applicant an essential foundation for a sustained research career focused on identifying mechanisms underlying the continuum from initial opioid use to addiction, informing the development of novel, effective, and timely interventions to mitigate opioid-related harms, specifically among the large and growing population of opioid-naïve patients undergoing arthroplasty.

United Indians of All Tribes Foundation

Daybreak Star houses Indigenous Art the Sacred Circle Gallery and also hosts large community events such as Seafair Indian Days Powwow and Indigenous Peoples' Day. Daybreak Star's restrooms are not ADA-compliant. This project will develop a design to turn a closet into a universal, accessible, single restroom on the upper level of the building and modifications for the lower level restrooms to comply with current accessibility codes. This project will be completed by February 2019.

West Seattle Community Orchestras

We will provide free concerts for the West Seattle community in December 2024. The first concert will be held on December 9, 2024 at 6pm at Chief Sealth High School located at 2600 SW Thistle St, Seattle, WA 98126. This program promotes the arts in our community through supporting children's musical education as well as local artists conducting the ensembles.

NIA - National Institute on Aging

Project Summary/Abstract Pneumonia is the leading infectious cause of morbidity and mortality in older adults. The incidence of pneumonia increases exponentially with age, resulting in over 3 million US emergency department (ED) encounters and 1 million hospitalizations per year in individuals ≥65 years of age. Although aspiration pneumonia has traditionally been considered a distinct clinical entity, there is an emerging consensus that pneumonia should be considered on a continuum as aspiration of organisms from the oropharynx is a shared pathogenic mechanism for nearly all pneumonias. Oral hypofunction and dysphagia (swallowing dysfunction) are geriatric syndromes and established factors in oral dysbiosis and pneumonia risk. However, the prevalence and interaction between them has not been well characterized as it relates to the pathogenesis or microbial etiology of pneumonia in older adults. This knowledge gap represents a patient safety threat as diagnostic misclassification of pneumonias can result in poorly targeted antibiotic therapy and failure to refer for swallowing and/or oral rehabilitation. There is an urgent need to comprehensively characterize profiles of oral hypofunction and dysphagia in older adults with pneumonia of various bacterial etiologies and evaluate their role in pneumonia pathogenesis. Previous studies examining oral and swallowing profiles in adults with pneumonia are limited due to a lack of objective diagnostic evaluations or consideration of the upper airway microbiome. To address these knowledge gaps, we propose an observational study of older adults presenting to the ED with pneumonia that involves comprehensive assessments of both oral and swallowing function in combination with cutting edge metagenomic analyses and application of saliva to a microphysiological lung model of aspiration. Our overarching objective is to significantly advance the understanding of oral hypofunction and dysphagia in pneumonia pathophysiology in older adults as a foundational step towards reducing diagnostic error, improving targeted antibiotic therapy, optimizing referral to oral and swallowing rehabilitation, and reducing the significant morbidity and mortality observed in this population. Our multidisciplinary team of experts will achieve this objective via the following specific aims: 1a. Determine the prevalence and profiles of oral hypofunction and dysphagia among a cohort of older adults with pneumonia; 1b. Compare prevalence and severity of oral hypofunction and dysphagia between older adults with and without pneumonia and between patients with pneumonia due to normal respiratory flora vs. respiratory pathogens; 2. Compare microbiome profiles in older adults with pneumonia based on the presence of oral hypofunction and dysphagia; 3. Identify targetable mechanisms of saliva-induced lung bronchial epithelial injury in a lung microphysiological system. The proposed work is highly innovative as it will be the first to comprehensively assess oral and hypofunction to elucidate relationships with pneumonia development; include state of the art microbiome characterization of upper and lower respiratory sites; and utilize a microphysiological lung model to examine the impact of salivary characteristics on host response mechanisms.

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 Cells optimize their functional capacity in response to extracellular signals to meet metabolic demands and maintain cellular and organism-level homeostasis. Endoplasmic reticulum (ER) is a central hub for protein folding, trafficking, lipid synthesis and secretion. ER also regulates the function of other organelles by exchanging ions and other hydrophobic molecules through inter- organelle contact sites. The structure of the ER is highly dynamic with specialized subdomains such as ER sheets, tubules, 3-way junctions and exit sites. ER exhibits complex architectural configuration related to cell’s functional capacity. However, whether and how different ER subdomains play a role in optimizing the functional capacity of the cell in response to metabolic demand is unclear. Moreover, the upstream signals that regulate ER shape dynamics are not known. In this proposal, we aim to use state-of-the-art metabolic flux approaches to investigate how the structural regulation of ER controls lipid and glucose fluxes in cells. Additionally, by using enhanced Focused Ion Beam Scanning Electron microscopy and super-resolution fluorescent microscopy, we will interrogate the ER’s architectural response to nutrient sensing and signaling pathways. Lastly, we will perform CRISPR-Cas9 screens, coupled with high-content imaging and deep learning-based analysis to discover novel regulators of ER shape and function. This work will provide novel insight into how organelle shape and dynamics regulate cellular function and health. It will introduce a new perspective to the field by incorporating subcellular architectural remodeling as a new layer of metabolic regulation.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY HIV infection is the second leading cause of viral infection-related mortality in the United States. Furthermore, the inability of the immune system to clear the virus renders this chronic infection a major driver of inflammation- associated co-morbidities, including cardiovascular disease and neurological disorders. This emphasizes the need to understand mechanisms that contribute to immune-mediated control of infection and how these could be exploited to develop cure strategies. Natural Killer (NK) cells help control infection by killing infected cells; their function is tightly regulated by a balance of activating and inhibitory receptors present on both the NK cell and the target cell. NK cell killer-cell immunoglobulin-like receptors (KIRs) interact with different members of MHC-I proteins and regulate the activation or inhibition of NK cytotoxic activity. Population studies have identified combinations of KIR and MHC-I alleles associated with slower HIV disease progression. Among them, KIR3DS1 (whose sequence is relatively conserved compared to other KIRs) was the first to be associated with delayed disease progression. KIR3DS1 interacts with the nonclassical MHC-I molecule, HLA-F, which is also relatively conserved compared to classical MHC-I molecules that bind to KIR2 and KIR3 proteins. This interaction triggers NK cytotoxicity towards HIV-infected cells. Our recently published work suggests that this KIR3DS1/HLA-F interaction can be augmented by IL-15 and retinoids. While these are clinically approved for cancer therapy and are safe in ART-suppressed people with HIV, the mechanisms that contribute to this augmentation, with the potential for further manipulation are unknown. The overall goal of this proposal is to decipher the mechanisms that regulate the HLA-F/KIR3DS1 interaction in the context of infection, cytokines, and retinoids. Our central hypothesis is that the pathways that regulate the KIR3DS1/HLA-F interaction can be exploited to enhance NK cell-mediated control of infection in vitro and in vivo. In Aim 1, we will evaluate the contribution of human genetic polymorphisms, viral subtype, and HIV accessory genes on HLA-F expression. In addition, we will assess the effects of various cytokines and new retinoids on HLA-F expression. In Aim 2, we will evaluate the interplay of KIR3DS1 and HLA-F in controlling HIV infection in vitro. This will include assessing the effects of the cytokines and retinoids described in Aim 1 on NK cell phenotype and function. In addition, a custom CITE-Seq panel and single cell metabolomic profiling will be used for a comprehensive analysis of KIR3DS1-expressing vs non- expressing NK cells to determine whether pathway differences between these populations could be exploited to expand or enhance the function of KIR3DS1+ NK cells. In Aim 3, using samples from two clinical trials, we will assess the in vivo effects of the IL-15 superagonist, N-803 (ACTG A5386), and the retinoid, isotretinoin (ACTG A5323), on CD4+ T cell HLA-F expression, NK cell phenotype/metabolomic, and whether these associate with reservoir dynamics. Together, our studies will yield insights into the pathways that modulate the KIR3DS1/HLA- F interaction that could help develop cure strategies with FDA-approved biologics and small molecule inhibitors.

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.