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NIAID - National Institute of Allergy and Infectious Diseases

Abstract CD8+ T cells are unique in effective sensing and killing of intracellular pathogen-infected cells and tumor cells. Because current vaccines are designed to induce high titer pathogen-specific antibodies for host protection, new vaccines focused on promoting effective memory CD8+ T cells are needed. Since a single naive CD8+ T cell has the potential to give rise to multiple types of progenies, it is essential to understand how naive T cells are primed to form distinct effector and memory cells. It is generally accepted that the strength of cognate antigen (Ag) stimulation determines the size of the primary response and of the memory cell pool, and that strong cognate Ag signals coupled with robust co-stimulation and cytokines altogether drive naive CD8+ T cells towards an effector rather than a memory cell fate. The current dogma also states that cognate Ag stimulation does not lead to functionally distinct subsets of memory CD8+ T cells. In contrast, however, we recently discovered that the strength and the stability of cognate Ag/MHC interactions with the T cell receptor (TCR) determine the development of memory cell functional characteristics, in particular stem-cell associated characteristics, through epigenetic imprinting. Stem cell memory CD8+ T (TSCM) cells have been shown to exhibit superior functional features, progeny potential, self-renewal capacity and longevity. Using state of the art conditional mouse models, high dimensional spectral flow cytometry, lentiviral-based inducible gain or loss of function experiments, and computational modeling approaches, we will define the features of T cell epitopes, key TCR structural modes of recognition, TCR signaling pathways, genetic and epigenetic regulators that enhance the differentiation of TSCM cells in vivo. We will validate our findings in models of chronic infections and tumors. This research directly impacts the rational design of more effective vaccines and adoptive T cell transfer therapies.

NIEHS - National Institute of Environmental Health Sciences

Preterm birth (PTB) affects 10% of pregnancies globally, with rates rising 12% between 2014-2022, incurring healthcare costs exceeding $25 billion annually in the US alone. While inflammation is a known trigger of PTB, the environmental factors driving this inflammatory response remain poorly understood. A critical knowledge gap exists in understanding how emerging environmental contaminants, particularly micro- and nanoplastic (MNP) particles, associate with PTB and alter placental immune function. Our preliminary data provide compelling evidence that MNPs bioaccumulate in human placentae at concentrations 23.9 times higher than in blood. Using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), we found significantly elevated MNP levels in preterm versus term placentae (224.7 vs 175.5 µg/g tissue; p=0.0032), with specific polymers showing 17-157% higher concentrations in preterm cases. The long-term objective of this research is to establish how environmental MNP exposure correlates with adverse pregnancy outcomes and identify modifiable risk factors for PTB prevention. Leveraging our completed longitudinal pregnancy cohort study (the Bacteria and Birth Study; BaBs Trial, n=585; PTB=103, term=367) with comprehensive maternal-infant biospecimens collected from first trimester through 6 weeks postpartum (>93,000 samples), we will: Aim 1) Define temporal patterns of MNP accumulation by quantifying 12 environmentally relevant polymers in maternal blood, urine, placental tissue, and cord blood (n=3,500 specimens) using Py- GC/MS, while integrating data on other environmental toxicants to establish exposure signatures that predict PTB risk; and Aim 2) Characterize the pathophysiology of MNP-associated placental dysfunction through systematic analysis of inflammatory markers (n=1,200 samples), histopathological changes (n=351 placentae), and immune cell distributions mapped by spatial transcriptomics (n=30 placentae). This comprehensive molecular and cellular characterization will establish the foundation for future mechanistic studies using animal models and in vitro systems. This research is innovative in challenging current paradigms of PTB etiology while introducing state-of-the- art methods to track environmental exposures during pregnancy. Our unique approach combines advanced analytical capabilities (Py-GC/MS- submicron plastics detection) with high-resolution spatial profiling to reveal how MNP exposure correlates with altered maternal-fetal immune balance. Success will establish: 1) The first longitudinal assessment of MNP accumulation patterns during pregnancy; 2) Novel biomarkers for identifying at- risk pregnancies; and 3) Key molecular and cellular changes associated with MNP accumulation in human placentae. These findings will directly inform the design of future mechanistic studies while directly providing evidence-based guidance for reducing harmful exposures during pregnancy, particularly benefiting vulnerable populations disproportionately affected by PTB.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY A substantial fraction of the HIV reservoir that persists in the face of antiretroviral therapy (ART) actively expresses a multitude of HIV proteins, yet the mechanisms by which they avoid detection and/or elimination by the immune system is unclear. The features of these “translationally-active” HIV reservoir cells have remained elusive due to lack of tools to identify and characterize them at the single-cell level. In this proposal, we leverage three new technologies we have pioneered and/or adapted to both better understand these cells, as well as to target them therapeutically. The first technology, HIV-prex, is a single-cell sequencing technology we developed to simultaneously characterize the transcriptomes of translationally-active HIV reservoir cells from ART- suppressed people with HIV (PWH). The second technology is MIBI-TOF, a high-parameter imaging method enabling in-depth analysis of translationally-active reservoir cells in their local tissue microenvironments. The last technology is TRACeR, a bioengineered platform we developed to identify and target translationally-active HIV reservoir cells on the basis of their cell-surface presentation of HIV peptides bound to MHC class I (MHC-I). These approaches will be applied across three aims, using both banked and prospectively-collected blood and tissue specimens from the UCSF SCOPE cohort of PWH. In Aim 1, we will establish the transcriptional and proteomic features of translationally-active reservoir cells – including the HIV peptides presented by MHC-I on their cell surfaces – from ART-suppressed PWH, and compare their features to reactivated latent reservoir cells. The features of the active reservoir cells will be tracked longitudinally over the course of 2-20 years of suppressive ART, and be compared between men vs. women. In Aim 2, we will compare the features of translationally-active reservoir cells from blood and multiple tissue compartments (gut, lymph node), as well as establish the spatial context of these cells in the gut, the main site of HIV persistence. In Aim 3, we will develop a novel method to eliminate translationally-active reservoir cells, through re-engineering of the top HIV TRACeRs into BiTE therapeutics, the test their efficacy using in vitro models as well as ex vivo using specimens from PWH. Elimination of translationally-active reservoir cells has important translational value as it can diminish the chronic inflammation linked to co-morbidities in ART-treated PWH. Furthermore, it can help achieve HIV remission given the potential of these cells to cause immune dysfunction and lead to viral rebound upon ART interruption. Collectively, our aims will improve our understanding of translationally-active HIV reservoir cells – an important but poorly understood component of the HIV reservoir – and develop targeted strategies to directly eliminate them.

NIGMS - National Institute of General Medical Sciences

Project Summary The University of Mississippi Medical Center (UMMC) is home to the State’s only academic health science center and has a rich history of high-level biomedical research. As the States only level 1 trauma facility, level IV NICU, Children’s Hospital and Cancer Care Program, Sickle Cell Anemia Program, Transplant Program, and Bone Marrow Transplant Unit, our Hospitals and Clinics treat the most critically ill in Mississippi. In addition, the population of patients consists of the most at risk socioeconomic backgrounds. There is a great need to increase the number of physician scientists trained on the front lines where social and economic determinants greatly impact the health care of our residents. Therefore, the goal of this proposal is to establish and grow the University of Mississippi Medical Center MSTP in order to have a long-term impact to increase clinician scientists uniquely trained to tackle the most challenging problems that our health care system faces. Recognizing the exceptional resources, faculty, and environment at UMMC, leadership heavily invested in the MD/PhD program, setting the groundwork for support of the next generation of MD/PhD students. Over the last 5 years, 10 MD/PhD students have graduated from a variety of graduate programs supported by the School of Graduate Studies that include Cellular and Molecular Biology, Microbiology and Immunology, Experimental Therapeutics and Pharmacology, Neuroscience, Physiology, Biomedical Materials Science, and Population Health. Nearly 80 program faculty provide perspectives from all backgrounds and range from junior to established investigators that have trained over 300 PhD students. State of the art equipment, infrastructure, and research cores established largely by NIGMS funded Centers for Biomedical Research Excellence and the Mississippi Center for Clinical and Translational Research provide an optimal training environment where students can learn whole animal physiology, -omics approaches to understanding disease mechanisms, cell and molecular biology techniques, population health and more. Finally, recruitment strategies and geographical location make UMMC the ideal home to meet NIH goals to train physician scientists that represent a wide range of socio-economic backgrounds.

NIAID - National Institute of Allergy and Infectious Diseases

The University of North Carolina (UNC) Global HIV Prevention and Treatment Clinical Trials Unit (CTU) has a well-established record of high quality, innovative clinical research, strong network and scientific leadership. The CTU engages with critically important populations infected with and at high risk of HIV in southeastern US, southern Africa and southeast Asia. Our CTU is led by three experienced principal investigators (Joseph Eron MD, Mina Hosseinipour MD and David Wohl MD) and will support all four NIH Clinical Trials Networks (CTN); Adult Therapeutic Strategies, HIV Prevention, Vaccine Prevention and Pediatric, Adolescent and Maternal Therapeutic Strategies. Our four experienced Clinical Research Sites (CRS) include Chapel Hill CRS (Adult Strategies, Prevention and Vaccine CTN) led by Dr. Wohl, Greensboro CRS (Adult Strategies, Prevention and Vaccine CTN) led by Cornelius Van Dam MD, Malawi CRS (all four CTN) led by Lameck Chinula MD and Vietnam CRS (Adult Strategies, Prevention and Vaccine CTN) led by Vivian Go PhD. Participants with HIV include those newly diagnosed (including with acute infection), PWH stably suppressed on therapy, PWH with adherence challenges to care or medication, and PWH with drugresistant HIV. We will enroll PWH at risk for comorbidities and PWH or without HIV including those with co-epidemic pathogens such as tuberculosis (TB) and Hepatitis B virus (HBV) which affect USA populations but the higher disease prevalence in Malawi and Vietnam allows research efficiency. We have skilled, experienced clinical and translational investigators working hand-in-hand with junior investigators in US and international settings, who will engage and execute the network scientific agenda. A globally representative set of senior scientists and public health leaders on our Scientific and Strategic Advisory Group advise the CTU leadership team. The CTU administration has a highly organized structure that is responsive to our research teams and CRSs. Each CRS engages the communities representing the affected populations in an interactive, openminded way. State-of-art communication and experienced, outstanding and well-organized laboratory, pharmacy, regulatory, quality and data management support the CTU, CRSs. Using this robust framework the UNC Global CTU is positioned optimally to continue our scientific, and network leadership and clinical trials support to all four NIH HIV networks, contributing to the elimination of HIV and significant co-infections in the USA and globally.

U.S. National Science Foundation

The URO program provides support for operations, technical enhancements, scientific investigations, and student training at university-based radio facilities. A primary function of funded University Radio Observatories is to provide focused research environments that foster hands-on student involvement in state-of-the-art radio astronomy instrumentation. UROs also serve the general astronomical community by providing open access to a substantial fraction of available telescope time.

Friends of Uptown Art Walk

The friends of Uptown Art walk will be launching from May 2nd to May 30th, 2025, a transformative gallery show and community activation revitalizing the Uptown arts scene while championing fat liberation, mutual aid, and inclusion—particularly for QTBIPOC individuals. Through strategic outreach, partnerships with local businesses/arts organizations, and promotion, this project will strengthen participation in Third Thursday Art Walks, fostering a thriving arts ecosystem. FAT, a fat liberation gallery show hosted at The Fishbowl Gallery, located at 323 2nd Ave W will feature artwork, discussions, and interactive programming that challenge societal norms and celebrate fatness. Programming includes an opening reception, vendor market, movement session, speaker event, clothing swap, healing arts workshop, community discussion, and closing reception—empowering attendees to embrace body autonomy and liberation. The event is free and open to the public.

Uptown Arts & Culture Coalition

Uptown Arts & Culture Coalition (UACC) seeks funding for a community movie night at Counterbalance Park on September 19, 2024. This event will engage the neighborhood with a free, family-friendly screening of short films during Uptown Artwalk. Specific event goals: attract 150+ attendees; engage 5+ local businesses for partner promotion; increase Uptown Artwalk attendance; highlight Uptown arts & culture organizations; demonstrate Counterbalance Park's potential as a public, outdoor event venue. Seattle Parks & Recreation will provide A/V; SIFF will provide film curation; Uptown Alliance, Tidy Uptown, Uptown Artwalk, & UACC will share planning and promotion. We hope to purchase ADA-accessible planking to ensure wheelchair access to the gravel-covered park. We seek support for event insurance, film licensing fees, and complimentary refreshments. We respectfully request $3,000 to support this community-led event to benefit residents, artists, and businesses in Uptown.

Shunpike

Shunpike will carry out a three-phase public art project that starts with artist residencies on the former site of Teatro Zinzanni, continues with the Artists of Color Expo & Symposium (ACES) in the Armory at Seattle Center on November 17-18th, and concludes with community-generated and youth-created murals surrounding the Seattle International Film Festival's Uptown Cinema. Resident artists will show their work and speak of their experience at ACES. This will inform the public art intended for the Uptown Cinema murals, ensuring community and youth engagement through a racial equity lens.

Human Impacts Institute

A new round of health and art fellows will work to explore the concept of a �just transition� to make environmental health data and sustainable advancements more accessible to the public.

Human Impacts Institute

A new round of health and art fellows will work to explore the concept of a �just transition� to make environmental health data and sustainable advancements more accessible to the public.

ACC APG - Natick

The Soldier Center is seeking solutions in the following scientific and technical areas: Combat Feeding & Equipment Ration development, field feeding systems Soldier Protection & Survivability Headborne protection, modular armor, chemical/biological protection, nanotechnology Modeling & Simulation Soldier effectiveness, operational survivability Human Performance & Biomechanics Body-worn systems, hand-held devices, soldier-centric sensors Expeditionary Maneuver Support Energy efficiency, EMI/EMP protection, battlefield mobility Aerial Delivery Advanced airdrop systems for personnel and cargo Simulation & Training Technology Medical training, AI-based battlefield visualization, cyberspace warfare training This Broad Agency Announcement (BAA) is intended to fulfill requirements for scientific study and experimentation directed toward advancing state-of-the-art technologies and/or increasing knowledge and understanding as a means of eliminating current technology barriers. This BAA DOES NOT focus on specific systems or hardware solutions. This BAA identifies DEVCOM SOLDIER CENTER research/exploratory development areas of interest and provides prospective offerors information on the preparation of proposals along with proposal evaluation factors. The Government may award purchase orders, contracts, grants, cooperative agreements, or other transactions against this BAA. Read the Full BAA & Submission Guidelines: On SAM.gov https://sam.gov/opp/e8c7609f0f154df4afda846595bca888/view

National Endowment for the Humanities

USA-250: CELEBRATING JOHN PHILIP SOUSA IN SOUTH DAKOTA [IN CELEBRATION OF AMERICA?S 250TH ANNIVERSARY, THE SOUTH DAKOTA STATE UNIVERSITY (SDSU) SCHOOL OF PERFORMING ARTS AND THE OSCAR LARSON PERFORMING ARTS CENTER IN BROOKINGS, SOUTH DAKOTA PROPOSE A DYNAMIC AND HISTORICALLY GROUNDED TWO-DAY PUBLIC SYMPOSIUM AND CONCERT PROGRAM TITLED "USA-250: CELEBRATING JOHN PHILIP SOUSA IN SOUTH DAKOTA." THIS INITIATIVE WILL ILLUMINATE THE ENDURING LEGACY OF JOHN PHILIP SOUSA, WHOSE MUSIC PLAYED A PIVOTAL ROLE IN SHAPING AMERICAN PATRIOTIC IDENTITY.]

NIH

Background: How can we apply the community health worker (CHW) model to help both care partners and Veterans with serious illness in rural areas? Little is known about this approach. We will test a VA-supported intervention successfully piloted in the Durham VA and surrounding rural communities in 2021. VA’s Office of Rural Health, Caregiver Support Program and National Social Work Office are aware and support this work. Significance: Clinically, this work will help improve care for rural Veterans with serious illness by supporting care partners in their caregiving role in the community thus bolstering the care of Veterans receiving primary support from care partners in rural areas. A strength of our intervention is that it adapts and extends a successful model of individualized support commonly used outside of the VA. This approach maximizes the potential for sustainability, broad dissemination, and care delivery impact across the VA. This work will be generalizable. Strategically, this SDR proposal responds to the National Academies report recommending all health systems, including VA, develop processes to routinely identify, assess, and support needs of care partners. Our project meets rural health access, long-term care/aging, engagement science, and caregiving HSR priorities for investigator-initiated research focused on rural populations. Additionally, our proposed efforts fit squarely with the VA’s Rural Health State of the Art conclusion that we must expand VA partnerships in the community and help Veterans and their families understand their options for care and support in the community and at the VA. Innovation & Impact: This project is innovative because of its focus on social and practical needs of care partners, advances the science of community engagement in VA care and support, and situates a care partner- focused community health worker model squarely in the VA system for the first time. The entire project is guided by a Community Advisory Board (CAB) composed of social service, serious illness care, and rural care experts plus Veterans and care partners with lived experience. Specific Aims: Aim 1. Determine CHW effectiveness in reducing care partner burden, increasing Veterans' well-being, and increasing care partner-Veteran satisfaction with VA care in the intervention group compared with the usual care (CSP) group: We will apply our feasible CHW intervention to a larger sample, randomized control trial. (Hl) Care partners randomized to the intervention group will have lower mean Zarit-12 scores at 6 months compared to the control group. (H2) Care partners and Veterans randomized to the intervention group will have higher mean 1-item CAHPS Global Satisfaction scores at 6 months compared to the control group. (H3) Veterans randomized to the intervention group will have higher mean Warwick Edinburgh Mental Well- Being scores at 6 months compared to the control group. Aim 2: Following intervention, explore Veterans' and care partners' experience of care and support using subgroup semi-structured interviews in the intervention group. We then facilitate CAB Delphi Method sessions (including study Veterans, CHWs, and care partners) exploring Aims 1/2 data using equity-focused intervention mapping for wider implementation. Aim 3: Conduct budget impact analysis from the VA perspective to evaluate cost-drivers and assess feasibility to inform adaptation and implementation of the intervention within Durham VA Health Care System. Methodology: Two-arm randomized control trial using validated measures. We follow this using qualitative exploration with participants plus a Delphi method exploring implementation with the community advisory board and participants. We end with a unique business impact analysis of the intervention. Next Steps/Implementation: We are supported/advised by VA’s Office of Rural Health and Caregiver Support Program in Durham, NC with additional advisement from National Social Work Office, Chaplaincy, Palliative Care, county Veteran Services and Area Agencies on Aging (see LOS). If successful, this intervention can be added to the options available from CSP to support rural care partners and their seriously ill Veterans.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

This study aims to develop new methods for detecting pre-cancerous dysplasia on colonoscopy and histology in patients with inflammatory bowel disease (IBD). IBD is associated with a higher incidence of colorectal cancer compared to the general population. However, IBD dysplasia is more difficult to detect on colonoscopy because lesions are flat, irregular in shape, and coincide with inflammation. In efforts to combat visualization problems, most gastroenterologists continue to perform random mucosal biopsy for increased sensitivity of dysplasia detection on colonoscopy. Accessory measures to help enhance dysplasia detection including high- definition endoscopy, dye chromoendoscopy, and narrow band imaging require extensive expertise, increase procedure duration, and have not been definitively shown to improve dysplasia detection rates. In addition to difficulty detecting dysplasia on colonoscopy, pathologists face similar ambiguity when evaluating dozens of biopsies provided from every colonoscopy. Beyond reviewer fatigue, pathologists are challenged to separate inflammation from dysplasia and the grade of severity, typically requiring referral to experts at high volume centers for second opinion review. Machine learning and computer vision methods are well suited to address clinician limitations in detecting visual features of IBD-related colonic dysplasia. Our multi-disciplinary team’s prior work developing methods to improve endoscopic disease activity assessments and quantify histologic imaging using machine learning will be adapted and applied to dysplasia detection in this proposed project. We will pursue three aims to achieve our goal of determining whether computer vision models can match or exceed the diagnostic ability of experts for detecting dysplasia on colonoscopy and histology. Aim 1 will build computer vision models trained to infer histologic ground truth using endoscopic imaging for detecting the presence of dysplasia on standard colonoscopy video from multiple centers. Methods will incorporate both still image classifier pipelines and new generative diffusion-based model architectures for full video analysis. Aim 2 will evaluate the performance of both experts and new FDA-approved AI assistant tools in colonoscopy for detecting dysplasia on colonoscopy, comparing results to best performing video-based dysplasia models. Finally, Aim 3 will apply computer vision quantitative histology to predict the presence of dysplasia on routine colonic biopsy, leveraging state-of-the-art histologic image segmentation methods for both enhanced pathologist annotation and modeling. Optimized dysplasia model performance will be tested and piloted in a real-world digital pathology workflow to evaluate the feasibility and performance of automated dysplasia detection in clinical practice. We expect these advancements will transform IBD dysplasia assessment by eliminating the need for cumbersome mucosal interrogation methods, improving accuracy of dysplasia detection, personalizing dysplasia surveillance and management, and providing a deployable technologic solution to elevate the quality of IBD care rendered by less-experienced clinicians.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) represent a major quality of life burden due to persistent symptoms, including abdominal pain, diarrhea, malnutrition, weight loss, and depression. Multiple factors cause IBD including lifestyle choices (e.g., poor diet), genetics, and the gut microbiota. To improve the detection and treatment of IBD there exists a critical need to increase understanding of the reciprocal relationship between diet, gut microbiota function, and inflammation. The candidate, J. Alfredo Blakeley-Ruiz, is a PhD scientist with extensive expertise in the use of the multi-omics approaches metagenomics and metaproteomics. Using integrated metagenomics-metaproteomics it is possible to observe overall shifts in microbial metabolism, while also measuring the responses of the immune system through the quantification of host proteins. Thus, integrated metagenomics-metaproteomics represents a powerful tool for untangling the relationship between diet, gut microbiota function, and inflammation. The candidate's long-term goal is to develop metaproteomics tools to identify the dietary components and microbiome functions that contribute to inflammation in IBD patients, so that dietary recommendations can be made to ameliorate inflammation in patients suffering from IBD and other intestinal diseases. This proposal builds on the candidate's expertise by providing training in the skills needed to connect his metaproteomic data to the host's intestinal immune response. The protected time provided by this proposal will allow the candidate to focus on training in (1) techniques for profiling GI physiology, (2) translatable models of IBD and the evaluation of their pathology, and (3) the husbandry of in vivo models. This training will allow the candidate to investigate the mechanisms behind how diet induced changes in microbiome function negatively impact the immune system leading to increased IBD pathology. The central hypothesis is that the digestibility and glycan conjugates of dietary proteins synergize with complex carbohydrates (e.g., starch and fermentable fiber) to change gut microbiome metabolism. This affects susceptibility to IBD via microbial metabolism mediated changes in the local immune cell landscape and colonic barrier integrity. This hypothesis will be investigated by feeding wild type and IL-10-/- mice with conventional or humanized microbiomes different combinations of fiber and protein diets, evaluating their colonic immune cell landscape, intestinal barrier integrity, and IBD pathology. These readouts will be linked to microbial and host protein quantities of metaproteomes to tease apart the mechanisms behind how diet-induced changes in microbiome function lead to IBD. NCSU is the perfect institutional environment for this research and training plan. The College of Veterinary Medicine gives access to the clinician scientists, core facilities, animal research facilities (NCSU gnotobiotic core), and didactics needed to fulfill the training plan of this proposal. NCSU has state of the art mass spectrometry (METRIC) and sequencing facilities (Genomics Sciences Laboratory) needed to conduct metagenomic and metaproteomic measurements.

NHLBI - National Heart Lung and Blood Institute

Our primary goal is to acquire new insights into chronic GVHD (cGVHD) pathobiology to create new therapies to limit fibrosis. We’ve shown that T:B cell engagement can initiate cGVHD by causing pathogenic αhost immunoglobulin (Ig) deposition that exacerbates tissue injury, recruits monocytes (monos) and TGFβ-secreting macrophage (Macs), and stimulates fibroblast/myofibroblast/endothelial cell pro-fibrinogenic cytokines. Our central hypothesis is that developing effective αfibrotic therapies requires greater elucidation of tissue cellular mechanisms and dynamic evolution processes that culminate in cGVHD. We will use state-of-the-art techniques in valid mouse models to expose cGVHD vulnerabilities. Tissues will be obtained at an early and late timepoint from cGVHD mice with bronchiolitis obliterans (BO) or scleroderma (Scl) to assess cGVHD progression in lymphoid and cGVHD organs. In an innovative, scientifically and technologically unprecedented, approach we will interrogate cGVHD mechanisms in BO and Scl models by spatially and temporally resolving and integrating proteomics with whole genome transcriptomics at a single cell resolution within histopathological regions of interest. This will result in a spatiotemporal atlas mapping how specific cells drive cGVHD disease progression in both lymphoid and target tissues; an invaluable tool for future studies. Our specific aims will test the hypotheses that: Aim 1. Interrogating T cell:B cell crosstalk at cGVHD tissue sites will lead to novel therapeutics and individualized applications. During the mechanistic discovery phase, we will infuse bifunctional (suppressive and cytolytic) αCD19 scFv chimeric antigen receptor (CAR19) Tregs to preclude B cell support of pathogenic IgG secretion, leveraging our murine cGVHD/BO cell atlas to assess the means by which these cells disrupt cGVHD progression. Aim 2. cGVHD tissue injury recruits monos that evolve into αinflammatory, pro-fibrinogenic Macs and engagement with fibroblasts/myofibroblasts to initiate fibrosis. Coupling mono and Mac reporter and deleter donor mice with spatiotemporal multi-omics, we will define the mechanisms by which monos and Macs enter cGVHD tissues and pro-fibrotic cytokines are produced, leading to new and key therapeutic targets. To halt fibrosis, mannosylated lipid nanoparticles with TGFβ1 siRNA will be given to selectively bind CD206+ Macs linked to murine cGVHD/BO and Scl. Aim 3. Mac communication with fibroblasts/myofibroblasts causes fibrosis that can be halted by fibroblast activation protein (FAP) CAR Tregs. Utilizing our first of its kind cell atlas of disease progression, we will elucidate the nature of crosstalk between profibrogenic TGFβ-producing Macs, fibroblasts, myofibroblasts and endothelial cells culminating in tissue fibrosis. We show FAP upregulation in cGVHD lung (BO), skin (Scl) and cGVHD/Scl patients and will infuse FAP CAR Tregs to eliminate damaged cells. We will fill cGVHD pathophysiology knowledge gaps for mechanistic insights focused on T:B and Mac: fibroblast/myofibroblast/endothelial cell (fibrosis) crosstalk, test novel therapies in clinically relevant models and, with mature data, assist Dr. Pavletic to lead cGVHD CAR trials at the NIH Clinical Center using intramural funds

Utah Community Foundation

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

Utah Division of Arts and Museums

General Operating Support grants sustain Utah arts and museum organizations through funding for core operations, enabling consistent programming, exhibitions, and community engagement that enrich cultural life across the state.

Utah Division of Arts and Museums

Project grants fund specific arts and museum initiatives in Utah including exhibitions, performances, festivals, and educational programs that bring arts experiences to diverse communities and underserved populations.

Sanctuary Art Center

Utility boxes are a necessary part of the urban streetscape as the provide the essential controls to our trafic lights, however they are simply there for ?Utility? and to a passer by amount to nothing more than a large grey obstruction. This project aims to build community through the transformation of the Utility Boxes in the U District from ordinary obstructions into a community assets that contribute to both placemaking and wayfinding.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract The human immunodeficiency virus (HIV) remains as an incurable pandemic pathogen that lacks an effective vaccine. While antiretroviral therapies (ART) can effectively suppress HIV replication, it does not eradicate the virus. As a result, people living with HIV (PLWH) remain vulnerable to AIDS in part due to viral immune evasion strategies. The HIV accessory protein Nef plays a crucial role in this process. Nef enhances viral replication and immune evasion by altering the trafficking and promoting the degradation of immune receptors. One of Nef’s most well characterized functions is the disruption of the major histocompatibility class I (MHC-I) trafficking to target it for lysosomal degradation. This Nef function prevents cytotoxic T lymphocyte (CTL) recognition and clearance of infected cells thereby enabling evasion of the immune response. While some pathways targeted by Nef are well studied, the full breadth of Nef’s host interactions— especially in the context of other HIV accessory proteins— remains poorly understood. One approach to address this gap in knowledge is unbiased proteomic analysis of Nef-host protein interactions. Three prior studies have utilized proteomic approaches to investigate Nef functions. However, their conclusions have been limited by using systems that express Nef in isolation, the use of potentially disruptive affinity tags, and failure to block degradative pathways, utilized by Nef. Our preliminary data as well as the work proposed here address these limitations. In our preliminary studies and proposed aims we will use both T cell lines and primary T cells expressing all HIV accessory proteins (Vif, Vpu, and Vpr, Rev and Tat) and a novel functionally validated tagged Nef protein. Using this system, we identified the Nef interactome in a T cell line in the presence and absence of lysosomal inhibition by TMT-based quantitative proteomics. Furthermore, with our approach we have identified novel Nef binding proteins associated with inflammatory, innate immune response and viral sensing pathways. Subsequent analyses have confirmed these novel interactions in both a T cell line and primary T cells. Based on our strong preliminary data, we will test the overarching hypothesis that novel Nef interacting proteins that have not previously been reported will reveal new pathways targeted by Nef that promote viral pathogenesis. We will evaluate our hypothesis with the following aims. In Aim 1, we will confirm our preliminary data and extend the characterization of the Nef interactome to primary T cells, and we will identify the Nef binding domains responsible for novel Nef-host protein interactions. Furthermore, in Aim 2, we will determine the functional significance of novel Nef interactions with inflammatory and antiviral pathways. The work proposed in this study will provide a complete, unbiased characterization of the Nef interactome as well as reveal pathways that are essential for HIV pathogenesis. Furthermore, these findings hold promise for identifying novel therapeutic targets for HIV infected patients.

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY Peripheral nerve injuries (PNIs) are surprisingly common, yet effective and reliable biomarkers for their diagnosis and prognosis remain an unmet clinical need. Traditional clinical examinations, standard neurophysiological tests, and current imaging methods often lack objectivity, depend heavily on clinician expertise, and have limited prognostic value. To address this gap, we propose a phased R61/R33 study to develop and validate [18F]3F4AP, a novel PET radioligand, as a biomarker for PNIs. In the R61 phase, we will test the hypothesis that [18F]3F4AP—an investigational PET tracer available at Massachusetts General Hospital for human research—can reliably detect overexpressed potassium channels in demyelinated axons, a hallmark of incomplete PNIs. Specifically, we will evaluate the pharmacokinetics and imaging protocols of this tracer in patients with upper or lower limb PNIs, radiculopathies, and plexus injuries, using state-of-the-art PET/MRI and high-resolution, high-sensitivity organ-specific PET scanners. This phase aims to establish optimal imaging parameters and assess the tracer’s initial diagnostic accuracy in well-characterized incomplete PNIs. In the R33 phase, we will expand the study to include a broader patient cohort, including individuals with PNIs of uncertain diagnosis or prognosis. This phase will focus on validating the radioligand’s ability to detect PNIs across a range of severities and chronicities and will assess whether [¹⁸F]3F4AP PET offers superior diagnostic performance compared to existing tools. By the conclusion of the R33 phase, we aim to establish [¹⁸F]3F4AP PET as a reliable diagnostic modality for PNIs, positioning it for further analytical and clinical validation. This project addresses a critical need for improved PNI diagnostics, with the potential to reduce unnecessary surgeries, enhance treatment planning, and ultimately improve patient outcomes, making a significant impact on public health.

OD - NIH Office of the Director

PROJECT SUMMARY/ABSTRACT This proposal requests funds to acquire a LUMICKS C-Trap Dymo300 microscope to support NIH-funded investigators across multiple schools at Vanderbilt University. The C-Trap combines the ability to exert forces on molecules and cells through optical tweezers with the ability to visualize structures through confocal imaging with the sensitivity to detect single molecule fluorescence. The instrument is highly automated and capable of handling complex calibrations and work-flow scripts, facilitating access for a broader scientific community. The instrument also includes a microfluidic laminar flow platform that aids in assay construction and protocol refinement. This microscope will be located within, and maintained by, the Vanderbilt Center on Mechanobiology – an initiative that serves faculty labs within the School of Engineering, the School of Medicine Basic Sciences, and the College of Arts and Sciences. All three schools have provided matching financial commitments that will fully cover the service contract for the instrument. Multiple scientific thematic areas have been identified that will specifically benefit ~19 major and minor users from all three schools. Among these themes, Vanderbilt has a strong community of investigators focused on advancing our understanding of DNA repair, replication and gene regulation. These researchers will use the microscope to observe how purified multiprotein machines process and maintain the information encoded within DNA through binding, translocation, and remodeling events. A second theme supports Vanderbilt’s robust cytoskeletal and cell mechanics research programs. In this area, the C-Trap is ideal for visualizing and manipulating actin and microtubule filaments, along with their associated proteins and molecular motors. These studies will provide access to a whole new frontier for Vanderbilt investigators who can deeply probe complex associations among cellular machinery. A third theme will investigate the mechanobiology of T-cell receptor-antigen quality and T-cell activation, as well as other receptor- ligand associations and conformational motions. Additional areas of research involve membrane dynamics, biomolecular condensates, forces associated with phase separation and colloids, and studies of AAA+ protein machines that carry out a multitude of cellular processes. The microscope will serve as a regional resource and bolster teaching across all three schools. The C-Trap will be housed in a space where Vanderbilt has purposefully clustered mechanobiology faculty labs and positioned other core resources. Management, support of the microscope and projects, and long-term operation and maintenance of the system will be led by Dr. Matthew Lang, who has over two decades of experience in optical tweezers and single-molecule studies. Collectively, Vanderbilt is ideally positioned to make rapid and significant use of these new capabilities, extending our research scope across a broad range of NIH-sponsored studies.