Johns Hopkins University

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Peripheral nerves possess a remarkable ability to regenerate after injury; however, this regenerative capacity declines significantly with age, leading to prolonged or permanent functional impairments in older adults. This age-related deficit has been linked to dysfunction in Schwann cells and macrophages, two cell types critical for nerve repair. Glutamate carboxypeptidase II (GCPII) is a membrane-bound enzyme that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG), releasing glutamate. GCPII is expressed in both Schwann cells and macrophages, and its expression is markedly upregulated following peripheral nerve injury (PNI) across species—including mice, rats, swine, and humans—with even greater increases observed in aging. Given that GCPII directly regulates glutamatergic signaling in peripheral nerves and that excessive glutamate is implicated in nerve injury, we investigated GCPII inhibition as a potential therapeutic strategy. Our preliminary data shows that treatment with the prototype GCPII inhibitor 2-PMPA significantly enhances remyelination and functional recovery in aged mice following PNI. However, critical barriers must be overcome to advance this strategy toward clinical translation. Specifically: (1) 2-PMPA is highly charged, with poor oral bioavailability and limited tissue penetration, necessitating pharmacological optimization; (2) the underlying mechanisms by which GCPII inhibition improves regeneration remain undefined; and (3) while elevated GCPII expression has been observed in multiple human PNI samples, additional data are needed to characterize its temporal dynamics and the influence of age and sex, which are critical for translation. To address these important gaps, we assembled an interdisciplinary team of preclinical and clinical investigators with expertise in preclinical PNI models, clinical treatment of PNI patients, and drug discovery and development. The team will complete the following 3 aims. AIM 1: Evaluate the efficacy of the new orally bioavailable GCPII inhibitor, tetra(ODOL)-2-PMPA, in aged mice following PNI using electron microscopy, electrophysiology, and behavioral assays to assess morphological and functional recovery. AIM 2: Elucidate the molecular mechanisms underlying GCPII inhibition–mediated recovery using glutamate receptor antagonists, GCPII knockout mice, and spatial transcriptomics in Schwann cells and macrophages. AIM 3: Using human tissues from PNI patients and iPSC Schwann-neuron co-cultures, examine GCPII expression and activity by age, sex, and time post-injury. Myelination outcomes in the co-culture model will also be utilized to assess the functional impact of inhibition. Successful execution of these aims will result in an orally available GCPII inhibitor ready for IND-enabling studies to support future clinical studies aimed at improving recovery from PNI, particularly in the aging population.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Peroxisomes are essential organelles that play pivotal roles in diverse biochemical pathways, from lipid metabolism and homeostasis to reactive oxygen detoxification. Peroxisome activities are intimately linked with other organelles, both functionally, coordinating metabolic pathways, and physically, through membrane contact sites that allow direct transport of metabolites between sub-cellular compartments. Recently, peroxisomes have been recognized for acting as signaling platforms, with key roles in immunity. Thus, a pathogen’s ability to modulate peroxisome biology could have profound impacts on numerous host cellular processes. However, the role of peroxisomes in bacterial pathogenesis remains largely unexplored. Recent findings indicate that bacterial pathogens exploit peroxisome biology to subvert host defenses. Many intracellular bacterial pathogens reside within membrane-bound compartments, shielding the bacteria against recognition and killing by host immune surveillance pathways. Maintaining the integrity of these replication vacuoles is critical for pathogen survival and virulence. Recently, we discovered an unprecedented link between bacterial pathogens and peroxisomes in which mutations that render peroxisomes metabolically inactive restrict replication vacuole expansion, induce vacuole rupture and limit bacterial replication. In the case of Legionella, we found that this pathogen actively manipulates host peroxisomes, altering the relative abundance of peroxisome metabolic enzymes, and recruiting peroxisomes to its replication vacuole. These processes are dependent on the bacterium’s Type IV secretion system, implicating Legionella secreted effector proteins in peroxisome modulation. However, the effectors involved remain unknown. The goal of this proposal is to elucidate how Legionella manipulates host peroxisome biology and to define the role of peroxisomes in Legionella pathogenesis. We will identify and characterize the bacterial effectors responsible for altering peroxisome metabolic programming and location, providing critical insight into the virulence strategies employed by Legionella. By uncovering novel effector functions and host targets, this work will advance the molecular understanding of bacterial pathogenesis and host cell manipulation. Moreover, this research will address a critical gap in our understanding of how bacterial pathogens exploit host organelles to establish infection. Given the emerging evidence that other intracellular bacterial pathogens - Salmonella, Mycobacterium and Chlamydia – also exploit peroxisomes, our studies are expected to reveal broadly relevant virulence strategies.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Prostate cancer is a top cause of cancer death, but many more men are diagnosed with it than those who die from it. Accurate at-diagnosis risk stratification among men with prostate cancer, both for cancer death and for cardiovascular disease, has remained imprecise. Prostate cancer does not need to remain enigmatic if tackled in a collaborative fashion. Notably, few studies have investigated differences based on molecular subtypes of prostate cancer so far, and no epidemiology consortium exists that has linked tumor tissue biospecimens. By using molecular tumor subtyping, this project will lay the foundation for precision prevention efforts. This project will establish the new Prostate Cancer Cohort Consortium (PC3) within the NCI Cohort Consortium. We will include ten of the most powerful cancer epidemiology cohorts with long-term outcome data: the NIH-AARP Diet and Health Study (AARP), Agricultural Health Study (AHS), Atherosclerosis Risk in Communities Study (ARIC), Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, Campaign Against Cancer and Heart Disease (CLUE), Health Professionals Follow-up Study (HPFS), Kings County, WA (KCWA) study, Physicians’ Health Study (PHS), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and Southern Community Cohort Study (SCCS). With 72,494 prostate cancer cases and 8,160 prostate cancer deaths, PC3 data will have unprecedented precision, specifically for high-risk groups of Black men, older men, and men with high comorbidity. We will establish data sharing, create central analytical datasets and open-source R packages, and pool tumor biorepositories. In Aim 1, we will evaluate the potential for precision prevention informed by tumor subtype to improve outcomes after cancer diagnosis. We hypothesize that ETS fusions, enhanced by PTEN loss, are particularly sensitive to the hormonal effects of adiposity and physical activity in their progression to fatal outcomes. In Aim 2, we will improve risk stratification for post-diagnosis prostate cancer survival. We will identify the best- performing existing prognostic tool for death from prostate cancer, integrate information about the patient into a novel risk classifier to improve prediction, and use counterfactual prediction approaches to create models that are informative under different treatment patterns. In Aim 3, we will recalibrate risk prediction for cardiovascular events among men with prostate cancer to account for their competing risk of cancer death. The impact of this project will be establishing a novel consortium, PC3, that closes the gap between prostate cancer and other cancer types. PC3 will represent the first U.S. population-based comparative validation of at-diagnosis risk classifiers for the two most common outcomes, cancer death and cardiovascular events. The project will be the steppingstone for future research based on PC3 infrastructure created that can leverage the molecular subtyping data, harmonized data sets, and software created for additional research.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY HIV prevention is under-resourced and under-researched in women across the lifespan. Emtricitabine/tenofovir disoproxil fumarate (F/TDF) is the only approved and most widely available form of biomedical HIV pre- exposure prophylaxis (PrEP), yet remains underutilized among women. Recommended F/TDF PrEP dosing in women is limited to daily dosing. There are conflicting data and significant knowledge gaps in the efficacy of event-driven or on-demand (“2-1-1”) F/TDF PrEP for women. Modeling data suggest that a “2-2-2" regimen may be more protective for women, but the pharmacokinetics/pharmacodynamics (e.g., HIV susceptibility) (PK/PD) of this regimen has not been evaluated. Little is known regarding the impact of reproductive aging and associated shifts in systemic hormone levels and in the inflammatory biomarkers and microbiome of the female genital tract (FGT) on PrEP efficacy. Quantification of PrEP concentrations at the sites of sexual exposure (i.e., FGT and rectal mucosa) is key to understanding F/TDF PrEP prevention efficacy, particularly with less than daily dosing. As such, we hypothesize there will be reproductive age-mediated differences in F/TDF pharmacologic parameters in the FGT of women over the lifespan, and PrEP concentrations associated with 2- 1-1 event driven dosing in the FGT will not confer adequate protection from HIV acquisition, but 2-2-2 dosing will be adequate for women across the lifespan. Given the sparseness of pharmacologic data in the FGT for event-driven PrEP and the unknown consequences of reproductive aging-mediated changes in cervicovaginal immunomodulatory markers on F/TDF PK/PD, we propose the On-Demand HIV Prevention Across the Lifespan: The OPAL Study. The OPAL study evaluates the PK/PD of daily and event driven F/TDF PrEP in women across the lifespan and if an increase in F/TDF dosing for event-driven PrEP from 2-1-1 (standard of care in men) to 2-2-2 (proposed for women) is required for effective HIV prevention in women. The following aims address the significant knowledge gaps in our understanding of the relationship between reproductive aging and F/TDF PrEP PK/PD in anatomic sites of HIV viral transmission: (1) Characterization of the pharmacologic dynamics of F/TDF in the FGT and rectum in women across the lifespan. (2) Interrogation of F/TDF pharmacologic differences in the FGT and rectum between daily oral and event driven PrEP regimens, specifically the currently utilized 2-1-1 regimen and the proposed 2-2-2 regimen. (3) F/TDF population PK (popPK) analysis and simulations to refine current models and to evaluate the significance of reproductive aging on HIV vulnerability in the FGT and rectum. The proposed work is a critical steppingstone in understanding the biological and pharmacologic dynamics of on-demand PrEP products for women across the lifespan and in meeting the ending the HIV epidemic goals.

NIH Research Projects · FY 2026 · 2026-05

Project Summary The auditory cortex is the central hub for sound processing, with the thalamus serving as the “gateway” for conveying auditory information to the auditory cortex. Proper maturation of the thalamocortical circuit depends on sensory experience. In cases of congenital deafness, the absence of auditory input to the thalamus leads to alterations and remodeling of this circuit. However, our understanding of these changes at the thalamocortical level remains limited, as most research has focused on peripheral and cortical alterations. Also, the timing of cochlear implantation or gene therapy significantly influences hearing outcomes, suggesting that other ascending auditory structures may have passed their period of plasticity and may become less responsive to certain aspects of auditory processing. Our long-term goal is to define the developmental window during which the thalamocortical circuit remains plastic, thereby achieving optimal treatment outcomes. The objective of this project, which is the foundation for the long-term goal, is to establish a foundational understanding of the development of auditory thalamocortical circuits and how they are altered in deafness. The central hypothesis of this project is that, in deafness, topographic organization is preserved while tonotopic features are lost, due to the retention of ectopic non-lemniscal projections and the absence of lemniscal input. The rationale for this study is that elucidating the early developmental stages of auditory thalamocortical axonal growth from the thalamus to the cortex is crucial for understanding how the brain reorganizes in deafness and hopefully lays the foundation for a potential therapeutic approach. This project will address two specific aims: (1) to identify the developmental trajectory of the auditory thalamocortical circuit, both anatomically and functionally, and (2) to investigate these changes in deafness. To achieve Aim (1), we will use transgenic mice with targeted gene expression in the lemniscal and non-lemniscal thalamic nuclei to track neuronal trajectories across various developmental stages, from their generation to the innervation of their final target regions. For Aim (2), we will use a genetically modified virus tagged with a fluorophore or encoded calcium indicator to target the MGBv and MGBd, studying their respective anatomical and functional changes in the auditory cortex of deaf mouse models (Otoferlin-knockout mice). This study is innovative, as it will be the first to specifically map the development of the lemniscal and non-lemniscal auditory thalamocortical circuits and examine the changes in a deaf mouse model. The findings will be significant because they will provide insights into how the early auditory thalamocortical circuit develops and how it is rewired in deafness. Ultimately, these findings could guide the development of more effective treatments for individuals with hearing deficits.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Maternal immune activation (MIA) during pregnancy, particularly from viral infections like SARS-CoV-2 (SCV2), poses significant risks to fetal development, resulting in long-term immune dysfunction in offspring. Our findings suggest that maternal SCV2 infection predisposes offspring to chronic inflammatory lung diseases, such as asthma, through the formation of prenatal lung epithelial immune memory linked to epigenetic modifications in key inflammatory genes like IL-33. This project aims to define the mechanisms by which prenatal lung epithelial immune memory is established and contributes to chronic inflammatory lung diseases. We hypothesize that maternal SCV2 infection disrupts the SDF-1/CXCR4 axis in fetal lung mesenchyme via maternal IL-6, leading to epigenetic changes in fetal epithelial cells, including increased chromatin accessibility at inflammatory genes such as IL-33. To test this, we will (1) investigate how the timing of maternal SCV2 infection impacts immune memory formation, (2) examine mesenchymal-epithelial cell interactions in immune memory formation, and (3) explore signaling pathways that mediate SDF-1/CXCR4-driven epigenetic changes. The results of this research will uncover novel mechanisms of non-immune cell immune memory and provide insights for developing preventive strategies for chronic inflammatory lung diseases in offspring exposed to maternal viral infections.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT/PROJECT SUMMARY The International Society for Environmental Epidemiology (ISEE) North America Chapter (NAC) was formed in 2019 focusing on promoting research collaborations across North American institutions. Since then, it has grown to host 1055 members from or residing in the United States (US), Bermuda, Canada, and Greenland. Although ISEE Global hosts an annual international meeting, this meeting is held on different continents each year, and visa issues and travel expenses often inhibit attendance by students, trainees, and early career researchers. Therefore, the ISEE-NAC started hosting regional meetings in 2023 to accommodate members with barriers to attending the global meeting when the location is not in America. Given the success of our previous regional meeting, recent changes in institutional funding allocation, and travel restrictions for international students and trainees and federal employees, we have experienced an increased interest in hosting the ISEE-NAC meeting in 2026. This meeting will enhance the mission of ISEE-NAC by providing a venue for environmental health and epidemiologic researchers, practitioners, and government personnel located in North America to network with potential new collaborators. The 2026 ISEE-NAC regional meeting will be held with a theme of “translating environmental health research to inform public health practice” and will be critical to moving our field forward. Meeting planning is already underway. Together with the organizing committee, we are planning a 2.5 day in-person meeting in Baltimore, MD (June 1-4, 2026) at the Johns Hopkins University Homewood Campus. The purpose of this meeting is to: provide networking and professional development opportunities for students, trainees, and early career scientists in environmental epidemiology (Aim 1); illuminate environmental epidemiology research throughout North America (Aim 2); and highlight research related to environmental health and epidemiology intervention, translational research, and community engagement (Aim 3). By focusing on community engagement, translation, and implementation, this meeting supports NIEHS Strategic Plan 2025-2029 items related to solutions-focused research and translation, building collaboration and partnership, and supporting training and workforce development through increasing public access to important environmental health findings.

NIH Research Projects · FY 2026 · 2026-05

Project abstract Late-onset unexplained epilepsy (LOUE) is a chronic condition affecting more than 250,000 older adults in the U.S., and people with LOUE are at high risk of developing dementia within 5 years of epilepsy diagnosis. The current proposal will add DNA methylation and chronic risk factor data to the ongoing multicenter Epilepsy of Late-onset Unknown etiology as a risk factor for Cognitive Impairment and Dementia (ELUCID) study, following 600 adults with LOUE and collecting medical history, MRI, and EEG data as well as longitudinal cognitive testing. The central hypotheses are that lifetime exposures contribute to LOUE and cognitive performance, and that distinct epigenetic markers will be identified associated with LOUE and with cognitive impairment in this group. Three distinct, complementary, independent aims will be pursued: 1) Define the epigenetic markers of LOUE, particularly differentially methylated regions and “epigenetic age,” and compare how epigenetic age is related to “brain age” calculated from MRI and EEG; 2) Define the chronic health drivers associated with LOUE, and how these factors affect the relationship between vascular risk factors and LOUE; and 3) Determine the relationships between epigenetic markers and chronic risk factors in people with LOUE, and how these affect cognition in people with LOUE. This study will establish fundamental knowledge to inform dementia prevention in this high-risk group.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium that causes chronic lung disease, often leading to rapid lung function decline and incurability. There are no FDA-approved treatments, and only a few antibiotics, including imipenem and cefoxitin, are repurposed for this disease. These drugs belong to the most prescribed antibiotics class in the world, namely β-lactams. The lack of understanding of how M. abscessus develops resistance to these commonly used antibiotics significantly hampers our ability to diagnose and treat this emerging disease effectively. This proposal aims to identify genetic markers for imipenem and cefoxitin resistance in M. abscessus. Basic research, like the study proposed here, identified mutations in the rpoB gene as the cause of Mycobacterium tuberculosis resistance to rifampicin. This crucial discovery paved the way for the development of rapid and accurate molecular tests for tuberculosis. In Specific Aim 1, We will identify genes and mutations that confer imipenem and cefoxitin resistance in M. abscessus using clinical isolates from US hospitals and lab-generated mutants from reference M. abscessus strain. Whole genome sequencing and comparative genomics will be employed to identify potential resistance markers, which will then be validated by recreating mutations in a drug-sensitive reference M. abscessus strain and testing for resistance. In Specific Aim 2, we will assess a radical strategy based on simultaneous use of two β-lactams to treat β-lactam-resistant M. abscessus. In summary, this study aims to provide identify specific mutations that enable M. abscessus to evolve to become resistant to β-lactam antibiotics in the clinical setting, such as during treatment with these drugs and to treat such infections.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Solid organ transplantation remains the definitive treatment for end-stage organ failure, but is limited by the adverse effects of lifelong immunosuppression and the risk of chronic rejection. Blockade of the CD154/CD40 costimulatory pathway has shown unparalleled efficacy in preclinical models, but clinical translation has been hampered by complications and the need for complex multi-component interventions to achieve maximal efficacy. Separately, regulatory T cell (Treg) therapies offer promise but face challenges including high costs, complexity, and concerns about durability in inflammatory environments. This exploratory proposal addresses these limitations through an innovative high-risk, high-reward approach that integrates these two therapeutic strategies into a single recombinant biologic: β-Tol, a multifunctional fusion protein combining anti-CD154 and one or more immunomodulatory moieties. The central HYPOTHESIS is that this novel fusion protein will synergistically inhibit pathogenic effector T cell differentiation, while promoting their conversion into protective Treg. Preliminary data demonstrate that CD154 blockade synergizes with the immunomodulatory moiety to dramatically enhance mouse Treg conversion, while suppressing effector differentiation, and that initial β-Tol constructs outperform conventional anti-CD154 treatment for Treg induction in vitro. The research design employs a multidisciplinary approach combining protein engineering, immunological characterization, and preclinical validation. Specific Aim 1 will define the regulatory identity of Treg induced by different β-Tol candidates using profiling and functional suppression assays to identify optimal construct architecture. Specific Aim 2 will assess therapeutic potential using stringent mouse skin transplant models combined with fate-tracking of alloreactive T cells. Pharmacokinetic studies will inform dosing strategies, while pathological examination will assess safety profiles. By leveraging modular protein engineering and interdisciplinary collaboration, this exploratory proposal seeks to develop a next-generation immunotherapeutic platform for transplantation. Success would provide foundational proof-of-concept for a clinically translatable strategy to induce immune regulation with precision, reduced toxicity, and in the form of a streamlined monotherapy – all aligned with NIH's mission to improve health through innovative biomedical research.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Cell survival and function depend on the ability to detect and respond to various environmental cues and intercellular signals, a process governed by complex, dynamic signaling networks. Our research seeks to understand how these networks are regulated, how they encode information through temporal and spatial dynamics, and how they drive critical cellular processes such as growth, migration, metabolism, and survival. To address these questions, we will pursue two complementary research directions. First, we will develop robust, high-throughput tools for tracking signaling network dynamics using highly multiplexed imaging of various genetically encoded fluorescent biosensors. By integrating approaches from synthetic biology, chemical biology, and computational modeling, we aim to investigate how cells interpret and integrate multiple signals to regulate growth, migration, and metabolism. We will also examine how heterogeneous signaling responses across individual cells collectively shape population-level behaviors. Second, we will explore the molecular mechanisms and functional roles of self-organized signaling activities, with a focus on the Ras-PI3K- ERK network. This network exhibits features of excitable systems, such as wave-like propagation of activity across the cell surface, and plays critical roles in proliferation, metabolism, migration, and survival. Dysregulation of this network contributes to developmental disorders, metabolic diseases, and cancer. We will examine how the distinct dynamics of PI3K isoforms relate to their specific functions, and how cell adhesion regulates self-organized signaling behavior. Together, our research takes a multidisciplinary approach to uncover fundamental principles governing signaling network dynamics, mechanisms, and functions. The experimental and computational tools developed through this work will have broad utility across the field of cellular signaling.

NIH Research Projects · FY 2026 · 2026-05

Project Summary: The pending introduction of the 1536 channel probe Neuropixels 2.0 Quad Base in Q2 2024 followed by the much smaller 1536 channel Neuropixels NXT Probe (developed entirely with support from NIH U01 NS115587) will open a path to brain wide electrophysiology recording. However, the challenge of chronically implanting 4-8 such probes on a single animal and recording data at rates of 1.3 to 4.0 Terabytes/hour outside the ability of most groups. To maximize the scientific impact of this new technology, this application will simplify, speed up, and make more reliable the use of multiple 1536 channel probes for brain wide recording in freely moving animals. Three critical elements will be enhanced: multi-probe implantation, large-scale data acquisition, and large-scale data digestion. These will be benchmarked against a challenging scientific application, brain wide recording of spiking activity and local field potentials in a complex freely moving rodent navigation task. Implanting many probes in an animal significantly extends the time and risks of the implantation surgery. We will develop freely available tools for robot assisted surgery in mice and rats. Our goal is 8 probes implanted in less than 8 hours with no more than two attending scientists. In comparison, for those few labs that attempt so difficult a surgery, a 14-18 hour surgery is typical. Reliability of inserting each probe is also critical because failures are prohibitively costly, especially in heavily trained animals. Our surgeries will be reliably planned with a combination of Pinpoint anatomy-based targeting software and software we will develop to model the probe and probe fixtures outside the skull while projecting the paths of probe shanks inside the brain. The probe fixtures will be adapted allow for flexible positioning and angling of the shanks. SpikeGLX, developed in our lab, is currently the highest bandwidth GUI for stable data acquisition from Neuropixels probes. We have successfully recorded from > 12000 channels simultaneously in preliminary testing. We will confirm capacity to > 18,000 channels for the newest probe types, create a new graphical representation of ongoing signals across all probes for assessment and channel selection, and enable selective data saving based on behavioral epoch or external experimental factors (e.g. a trigger). Data analysis of recordings that may exceed 10 terabytes require fundamentally new approaches as manual curation is impractical. We will develop a pipeline for automated spike sorting of the raw data into spikes from individual neurons, including filtering for sorted neuron quality based on region specific properties. We will benchmark this new suite of capabilities against a complex navigation task in rodents. Navigational signals are known to be distributed across many brain regions. Therefore, rather than study one or a few regions at a time as is standard, an 8 probe, 32 shank, 12,000 channel brain wide recording will gather data from 25-40 brain regions simultaneously, allowing estimation of large-scale information flow.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Gene editing offers the prospect of directly modifying any nucleotide(s) in the genome, including correction of pathogenic variants underlying disease. These technologies could form the basis of cures for currently untreatable genetic conditions. The work proposed in this application aims to identify genome editing strategies to prevent aortic pathology in Marfan syndrome (MFS). MFS is the most prevalent hereditary connective tissue disorder and is associated with significantly increased morbidity and mortality due to life-limiting thoracic aortic aneurysm and dissection. MFS is caused by heterozygous pathogenic variants in FBN1, the gene encoding the main structural component of extracellular microfibrils, fibrillin-1. Microfibrils are essential for providing structural elasticity and resilience, in addition to having a signaling role, and defects in both features are thought to contribute to elastic lamina fragmentation and aortic wall weakness. We hypothesize that gene editing correction of FBN1 pathogenic variants or genome editing-based upregulation of the structurally related protein FBN2 within aortic vascular smooth muscle will reduce risk of aortic root dilation and dissection, thereby limiting the major cause of morbidity and mortality in this disease. In the first aim, the candidate will identify a prime editing strategy to correct the Fbn1 C1041G pathogenic variant in aortic vascular smooth muscle of a murine model of MFS and will test this therapeutic strategy by monitoring aortic aneurysm. In the second aim, a machine learning model will be used to identify promoter variants, putative enhancers, and transcription factor binding site motifs within the FBN2 promoter region that are predicted to augment FBN2 expression. These elements will be functionally evaluated in a massively parallel reporter assay (MPRA). Finally, in vivo genome editing will be used to introduce an optimized FBN2 upregulatory strategy established through these analyses in the Fbn1C1041G/+ mouse model of MFS for correction of aortic pathology. In addition to establishing potential gene editing treatment strategies for aortic aneurysm in Marfan syndrome, these studies will enable the candidate to obtain expertise in the design and application of state-of-the-art gene editing tools that can be used to generate disease models and investigate therapies for many different genetic disorders, which he plans to pursue throughout his career as a physician-scientist.

NIH Research Projects · FY 2026 · 2026-05

Pulse oximeters are used extensively in medical settings to monitor acutely ill patients, but testing is only required on healthy volunteers in laboratory settings to attain Food and Drug Administration (FDA) clearance for clinical use. This project’s investigators have led the contemporary re-evaluation of pulse oximeter accuracy, showing that pulse oximeters overestimated true oxygen saturation three-fold more frequently among critically ill Black patients and that these inaccuracies resulted in delayed delivery of care and significantly higher rate of readmissions among patients with COVID-19. As a consequence, the FDA held two advisory committee meetings to re-evaluate regulatory requirements for pulse oximeters, culminating in updated draft guidance released in January 2025 requiring greater diversity of skin pigmentation among pulse oximeter testing subjects but maintains that laboratory testing in healthy volunteers is adequate, which continues to assume – without evidence – that pulse oximeters are accurate in acutely ill patients with common physiologic derangements that cannot be simulated in laboratories. Following up on compelling preliminary studies, this project investigates pulse oximeter accuracy and its impact on clinical outcomes among hospitalized patients with shock (organ hypoperfusion) and acute exacerbation of COPD (AECOPD) in whom severe hypercarbia (elevated blood CO2) is common. Shock will be accurately characterized based on vasopressor dose or low cardiac output in a very large retrospective cohort using a unique high-frequency repository of vital sign and waveform data to precisely match pairs of concurrent pulse oximeter readings (SpO2) with gold-standard arterial oxygen saturation (SaO2) and determine cardiac output by applying an algorithm from an FDA-cleared device to stored arterial catheter waveforms. Pulse oximeter accuracy in shock, its interaction with race, and impact on 3-month mortality and rehospitalization will be investigated. A prospective study will enroll 150 hospitalized patients with AECOPD to obtain arterial blood gases and test whether high levels of partial pressure of CO2 (pCO2) impact accuracy (SpO2- SaO2) of four FDA-cleared pulse oximeters, interact with objectively measured dark skin pigmentation to worsen accuracy, and if pulse oximeter error in AECOPD is associated with clinical outcomes such as hospital length of stay and 3-month rehospitalization for AECOPD. Additionally, we will evaluate and refine the performance of a prototype continuous non-invasive oxygen monitoring device in three sub-cohorts, each of 25 acutely ill patients with either shock, hypercarbia, or pure hypoxemia. This prototype measures partial pressure of diffused oxygen (PtcO2) while forgoing skin heating and harsh adhesives required of traditional PtcO2 devices and uses methods that are hoped to mitigate skin pigmentation-related inaccuracies of pulse oximetry. If our hypotheses that shock and hypercarbia significantly impact pulse oximeter performance are confirmed, clinician approaches to the management of patients will be directly impacted and the need to test existing and new devices in real patients rather than relying on healthy volunteers in laboratory settings will be confirmed.

NSF Awards · FY 2026 · 2026-05

The “2026 International Category Theory Conference (CT)” and “Discoveries and Vistas: Life, the Universe, and Higher Categories (DV)” are tandem conferences scheduled for July 13–18 and July 20–22, 2026, respectively, at Johns Hopkins University in Baltimore, MD. The events are official satellites of the International Congress of Mathematicians in Philadelphia and will attract top researchers from around the world. CT is part of an annual series, and this is the first time in its several decades old history that it will take place in the United States. These events will both showcase and stimulate cutting-edge research in category theory in the United States. NSF funding will broaden participation by supporting travel for U.S.-based graduate students and early-career researchers. Both conferences will feature invited speakers who will deliver one-hour lectures on their work. CT will also feature submitted participant talks, selected in a competitive process by the scientific committee. DV is shorter and more specialized with invited talks given by a carefully curated selection of excellent international researchers with an explicit focus on higher-dimensional categories. Information about both conferences can be found at ct2026.com This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-05

Summary The goal of this R21 NIH Exploratory/Developmental Research project is to advance development of rodent models of drug discrimination, drug-seeking and self-administration of vaporized cannabis extract to facilitate future medications development for cannabis use disorder (CUD). There are no FDA-approved medications for CUD, and development of effective pharmacotherapies is hindered the lack of appropriate rodent models demonstrating the reinforcing effects of cannabis (CAN) or its primary psychoactive cannabinoid, Δ-9- tetrahydrocannabinol (THC). The majority of studies in rodents examining IV self-administration of THC have failed to demonstrate reliable reinforcing effects. There is a critical need to continue development of reliable self- administration models in rodents to increase our understanding of CAN/THC reinforcement and to test novel pharmacotherapies for CUD. The primary route of use for CAN use in humans is via inhalation. Inhalation models using vaporization technology have been validated in rodents using combusted CAN and THC, and may be useful for advancing CAN/THC self-administration models. We will build on lessons learned from these prior studies and leverage our experience with cannabis and its phytocannabinoids to examine the discriminative stimulus effects and reinforcing effects of vaporized CANTHC. Aim 1 will utilize drug discrimination procedures to establish CANTHC vapor discrimination in comparison to intraperitoneally (IP) administered THC, including dose- and time course effects of discriminative stimulus effects. Importantly, we will then identify sufficient and optimal CANTHC vapor training doses for drug discrimination. The resulting data will inform optimal CANTHC vapor doses for self-administration under a second order schedule of reinforcement. We hypothesize that CANTHC vapor will produce discriminative stimulus effects in rats trained to discriminate IP THC and that rats will acquire CANTHC vapor discrimination from vehicle vapor. We expect that the time course of discriminative effects of CANTHC will be more rapid than IP injection and will be associated with plasma levels of THC and metabolites. We also expect the discriminative stimulus effects of CANTHC vapor will be blocked by administration of cannabinoid type-1 receptor antagonist. Aim 2 will evaluate the reinforcing efficacy of CANTHC vapor under a second order schedule of reinforcement in which responding is maintained not only by the CANTHC vapor delivery, but also by contingent presentation of drug-paired stimuli that serve as conditioned reinforcers. We hypothesize that CANTHC vapor will maintain seeking and self-administration responses greater than vehicle under a second order schedule of reinforcement and will result in significant levels of THC and its active metabolites. Development and validation of a translationally relevant CAN vapor drug discrimination and self-administration in rodents is critical to understanding the reinforcing and subjective effects of CAN. Establishing these models provides a necessary platform for the evaluation of novel pharmacotherapies for the treatment of CUD.

NIH Research Projects · FY 2026 · 2026-05

Project Summary. Multiple Myeloma (MM) is a disease characterized by the expansion of malignant plasma cells in the bone marrow. MM patients frequently demonstrate clinical responses to treatments consisting of proteasome inhibitors and immune modulatory drugs, hematopoietic bone marrow transplant, and monoclonal antibodies targeting several cell surface antigens, but all MM patients will eventually relapse, and disease eradication remains elusive. Central to this devastating trend is the persistence and evolution of therapy-resistance malignant plasma cells that arise following multiple therapies and the lack of effective non-invasive detection methods to assess disease status in the whole body. One rational approach to overcoming the intrinsic resistance seen with MM is to deliver a drug that is impervious to resistance directly to the tumor cells, such as targeted alpha-emitter therapy (TAT). TAT uses alpha-emitting radionuclides and causes largely irreparable double strand breaks that leads to selective cytotoxicity in cancer cells. However, there are substantial gaps in tools and knowledge in implementing TAT in MM as only few studies have examined the potential of TAT in MM and none with a focus on developing low molecular weight (LMW) theranostics, which show tractable pharmacokinetics than biologicals. Positron emission tomography (PET) is currently used to determine response to treatment and provide prognostic information in MM patients but more molecularly targeted imaging agents are needed to address the needs of MM patients. To address these unmet needs, our hypothesis is to develop a peptide-based first-in- class LMW theranostic pair for MM that targets cluster of differentiation 38 (CD38) protein, which is expressed uniformly and with high density in MM. Accordingly, our objectives are to create an 18F-labled PET imaging agent for improved prognostication of MM, and a potent actinium-225 (225Ac)-TAT to treat MM, in a single hybrid molecule. We will test our hypothesis in the following specific aims: 1) Develop the diagnostic component of a CD38 theranostic pair that fits within the standard clinical workflow; 2) Develop the therapeutic component of a CD38 theranostic pair; and 3) Characterize the therapeutic efficacy of CD38 TAT to control MM tumor growth. The proposal is innovative because it pursues the development of a first-in-class CD38 binding LMW theranostic pair and takes advantage of 18F for improved detection sensitivity and 225Ac for irreparable cell death. The proposed research is significant because it aims to develop imaging agents with potential to reduce unnecessary biopsies and treatments while also enhancing the prognostic value of minimal residual disease negativity and predicting clinical outcomes in MM. Moreover, this research also aims to develop complementary interventions to enhance existing therapeutic combinations by exploring new therapeutic agents that are highly specific, fundamentally different from current therapies, and overcome the resistance seen with current therapies.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Gamma-delta T-cell leukemias and lymphomas (GD T-cell cancers), affect ~1000 patients in the United States each year. Patients with GD T-cell cancers respond poorly to chemotherapies, with some patients experiencing a median survival of only 10 to 15 months. Significant challenges in improving survival for these patients are our poor understanding of the genomic mutations that drive GD T-cell cancers and our inability to selectively kill the GD T-cell cancer cells without harming the normal cells. Recent studies performed by multiple groups including ours have identified genomic mutations in critical signaling pathways that converge on the oncogene MYC. MYC is required for cell proliferation and survival in normal cells and increased MYC activity has been linked to the development of multiple solid cancers. Thus, we surmise that the mutations observed in GD T-cell cancers lead to an overactive MYC signaling which may be driving tumorigenesis in GD T-cell cancers. In addition, we postulate that selective inhibition of MYC activity in GD T-cell cancers will kill the cancer cells without harming the normal cells. For Aim 1, we propose to establish a mechanistic link between the genomic alterations observed in GD T-cell cancers and MYC-driven oncogenesis. We will engineer the mutations in normal cells and quantify how these changes lead to increased MYC activity leading to increased cell proliferation that ultimately leads to cancer. To selectively deliver drugs to block MYC activity in GD T-cell cancers, we developed an antibody that targets the GD T-cell receptor, which is only expressed in GD T-cell cancers and normal GD T cells. We coupled the antibody with drugs that block MYC activity and demonstrated that the antibody-drug conjugate (anti-GD ADC) selectively blocks MYC, leading to the death of cancer cells and normal GD T cells. We previously used similar methods to generate ADC to target other T-cell cancers and the ADC is scheduled to enter a phase 1 clinical trial (Nichakawade et al., Nature 2024). As normal GD T cells are a minor percentage (~5%) of immune cells, their loss is expected to be well tolerated in patients. For Aim 2, we will test the anti-GD ADCs in mouse models that closely resemble the human GD T-cell cancers. However, as such mouse models are currently unavailable, we will implant patient-derived and cell line-derived GD T-cell cancers in mice to closely replicate the diverse phenotypes and genomic profiles of GD T-cell cancers observed in patients. We will then test the safety and efficacy of the anti-GD ADCs in our mouse models. Lastly, most cancers treated with ADCs tend to develop resistance leading to cancer relapse. Thus, for Aim 3, we will identify possible resistance mechanisms that may develop in cancer cells to our anti-GD ADCs. We will then generate methods to counter the resistance and test the methods in our mouse models. Our studies aim to establish the mechanism by which normal GD T cells turn into cancer cells. In addition, the studies will provide the pre-clinical validation required to initiate a clinical trial of anti-GD ADCs and may improve the survival of patients with GD T-cell cancers.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Biomolecular condensates have become the subject of intense interest across the biological, biophysical, and biomedical communities because they represent an elegant form of higher-order organization that cells can use to create dynamic compartments; they also are connected to a wide range of diseases, particularly those related to ageing and neurodegeneration. However, we lack a detailed structural model for any natural biomolecular condensate. Mapping the architecture of these assemblies is challenging because they are heterogeneous, liquid-like, prominently feature intrinsically disordered regions (IDRs), and are exquisitely sensitive to their environment. Crosslinking mass spectrometry (XL-MS) is uniquely suited to map the architecture of biomolecular condensates because it can freeze structural information about proteins when they are in their native cellular context and is equally adept at probing folded and disordered regions. In vivo XL-MS has not yet been applied to map native condensates in situ. The investigator has a unique combination of technical expertise in XL-MS and background in protein folding and biophysics; hence, is particularly well suited to this task. This proposal consists of three broad thrusts. Firstly, we seek to advance tools and methodology to map condensate structure, by (i) expanding the capacity of existing methods to capture protein-RNA interactions through photo-crosslinking and (ii) developing computational workflows that combine artificial intelligence, crosslinking data (as experimental restraints), and molecular dynamics for integrative/hybrid modeling of large assemblies. The other two thrusts focus on two specific condensate systems, the Caulobacter crescentus PopZ granule and the mammalian nucleolus. PopZ forms a polar 150-nm microdomain that regulates cell division and physiological changes during Caulobacter's lifecycle. We aim to understand how this condensate's structural properties evolve over the course of cellular development, and hypothesize that structural models of this assembly will provide a molecular basis to the processes responsible for differentiating the cell's two poles. The nucleolus is a larger, more complex condensate responsible for ribosome biogenesis in eukaryotes. Whilst some proteins within it are well-understood, including the structured ribosome assembly factors and a few high-abundance scaffolding proteins, many of its proteins are quite disordered and poorly characterized. We will obtain high- coverage crosslinking maps of the nucleolus with a range of techniques that will additionally focus on rRNA- protein crosslinking. These experiments will also characterize interactions among ribosome assembly intermediates and the whole host of nucleolar proteins, thereby uncovering potentially new ribosome biogenesis factors and functional roles for IDRs. A further goal is to map contacts between scaffold proteins (fibrillarin and NPM1) to other nucleolar proteins to interrogate the role of heterotypic interactions in supporting the organelle's unique tripartite substructure. To summarize, the PI seeks to lead efforts to apply structural proteomics to build high-resolution models of native biomolecular condensates. The PI anticipates this will represent a third of his research program, with other complementary efforts on protein folding biophysics and aging/neurodegeneration.

NSF Awards · FY 2026 · 2026-05

With the support of the Chemical Catalysis Program of the Division of Chemistry, Professor Timothy H. Warren of the Department of Chemistry at Michigan State University is studying how to add function to molecules through normally unreactive carbon-hydrogen (C–H) bonds using copper-based catalysts. This research aims to create more efficient, environmentally friendly, and cost-effective ways to build important chemical structures, such as those found in medicines and materials. By developing new methods to modify the most abundant types of carbon-hydrogen bonds in organic molecules, this project will help scientists streamline the synthesis of complex molecules and explore new chemical space. The broader impacts of the work include hands-on training for high school students, undergraduates, and graduate students enhanced through collaborations with industrial and academic partners. Outreach activities that include science festivals and mentorship programs will help inspire the next generation of scientists. This project will establish new catalytic protocols to transform strong, unreactive sp3 carbon-hydrogen bonds in molecules and materials to carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-carbon bonds. These C–H functionalization methods provide access to areas of chemical space that are difficult to reach using traditional synthetic approaches. Copper catalyzed radical relay approaches will enable new synthetic methods for C-H arylation, alkylation, and vinylation reactions with broad applicability. Copper nitrene-based methods will allow metal-centered control over site selectivity in C-H amination, allowing functionalization of stronger, more accessible primary C–H bonds even in the presence of weaker secondary and tertiary ones. Mechanistic studies of reactive copper intermediates – including underexplored copper(II) alkyl species - serve as a unifying foundation, informing the development of more efficient and selective catalytic systems. This project expands the synthetic toolbox for late-stage molecule diversification and polymer functionalization and informs broader catalytic strategies in organic chemistry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Reproductive disorders affect >10 million U.S. women annually, result in >$200 billion in healthcare and lost productivity costs and increase chronic disease risk. Recognized and suspected endocrine disrupting chemicals (EDCs) in hair products, like phthalates and certain volatile organic compounds (VOCs), may play a role. However, data on EDCs’ effects on women’s reproductive health remain limited, particularly in groups experiencing chronic elevated exposures, hampering the development of effective public health interventions. Understanding knowledge, attitudes and behaviors (KABs) associated with EDC exposures is critical to develop feasible and effective interventions. The role of increased workplace EDC exposures on women’s reproductive health reflects a major avenue for public health interventions. Over 700,000 U.S. hairstylists, largely low-income, reproductive-aged women, are an at increased risk of elevated EDC exposures that pose a major reproductive concern. Emerging studies show increased EDC exposures in salon workers, but many lack objective measures, and none focused on salons serving women of color, despite hair products marketed to this demographic posing an elevated exposure risk. We developed a robust community partnership with salon owners, stylists, and a non-profit organization with vast community outreach expertise, to conduct pilot studies in salons. Our pilot found that hairstylists serving women of color have elevated EDC exposures of reproductive concern and report a higher prevalence of reproductive problems compared to office workers, representing a “canary in a coal mine”. We will recruit stylists in salons primarily serving women of color, situating this study at the intersection of social and environmental factors. Our main goal is to identify and prioritize avenues for intervention to mitigate exposures and reproductive health risks in this high-risk workforce by: 1) assessing the role of recognized and suspected EDCs (VOCs, phthalates and their replacements) on reproductive health indicators; and 2) understanding knowledge, attitudes, and behaviors among hairstylists associated with EDC exposures to inform future exposure interventions. To accomplish this, we will: 1) determine if exposures to target EDCs are associated with menstrual cycle length; 2) determine if target EDC exposures are associated with diminished ovarian reserve; and 3) assess if results report-back improves KABs related to EDC exposures in hairstylists. This translational study, motivated by concerns among hairstylists and co-designed with our community team will yield novel data on EDC exposures, reproductive health risks, and their prevention in a high-risk group. Findings will lead to a community-driven public health action plan that integrates the social ecological model with the occupational hierarchy of controls to mitigate exposures and improve health. By focusing on highly exposed women, we will more clearly identify health impacts to inform policies, interventions, and personal choices to reduce exposures and protect health.

NSF Awards · FY 2026 · 2026-05

This grant funds a workshop to bring together Designing Materials to Revolutionize and Engineer our Future (DMREF) and the Materials Innovation Platform (MIP) awardees as well as DMREF partners from the National Institute of Standards and Technology (NIST), the Air Force Research Laboratory (AFRL), the Department of Energy (DOE), the Office of Naval Research (ONR), and various other federal agencies. The meeting discusses challenges and successes in materials research and provides an assessment of the current state of the scientific ecosystem on materials discovery and development. This workshop also serves as a platform for collaborative work leveraging rapid growth in data, data-driven Artificial Intelligence/Machine Learning, and community-wide infrastructure development. This meeting includes technical presentations by attendees, poster sessions, and breakout sessions on overarching topics. Questions on workforce training are also discussed. Results from the workshop are to be made available to the broader materials community and the public in the form of an electronic Conference Proceeding booklet. DMREF emphasizes a deep integration of experiments, computation, and theory; the use of accessible digital data across the materials development continuum; and strengthening connections among theorists, computational scientists (including data scientists), and experimentalists, as well as those from academia, industry, and government. A venue is provided for researchers to discuss the trials and successes of their individual projects with their colleagues to facilitate their research efforts. This meeting helps promote advanced materials design within the materials community and address the challenges and gaps in the application of new Artificial Intelligence tools and systems. The workshop is to be held in downtown Washington, DC, in August 2026, following a series of successful workshops, the latest of which was held in July 2024. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-05

This award is funded in part under the American Rescue Plan Act of 2021 (Public Law 117-2). The nature of dark matter is one of the most fundamental open questions of modern science. As searches for the dark matter have advanced, axions - that arise naturally from model solutions of what is known as the strong-CP problem - and axion-like particles have emerged as particularly compelling candidates. The search for these particles opens an experimental window into physics at ultra-high energy scales, up to the Planck-scale, and discovery of axion-like dark matter would provide potential insight into the earliest evolutionary stages of the Universe. This CAREER award supports the development of a precision laboratory experimental platform based on solid-state electron and nuclear spin ensembles and magnetic sensing to advance the search for axions and axion-like particles with sensitivity in the nano-electronvolt to pico-electronvolt mass range. The award will develop an outreach program directed toward young students and the general public with a focus on developing non-standard problem-solving skills of complex real-world challenges. This program will partner with the Boston University GROW and MIT BLOSSOMS programs to develop novel online content with connections to the study of the cosmos and dark matter, and will focus on building connections with schools in the Boston-area with large populations of students. This award leverages the established technical achievements of the Search for Halo Axions with Ferromagnetic Toroids (SHAFT) experimental platform. Specifically, the platform realizes a magnetic field sensitivity of 150 aT per square root(Hz) over a range of 10 kHz to 1 MHz, representing the most sensitive magnetic field measurement with a broadband magnetometer technology. Two primary measurements are planned as a part of the awarded activities. The first will operate the apparatus’ SQUID sensors within a dilution refrigerator at 0.1K temperature to improve the sensitivity to the electromagnetic coupling of axion-like dark matter to approximately 3e-12 GeV near 20 pico-electronvolt mass. This measurement would represent more than an order of magnitude improvement over current experimental sensitivities. The second complementary measurement will be made possible by integrating into the magnetic sensing apparatus solid crystals that host ensembles of nuclear spins, optimized for searches for time-varying nuclear electric dipole moments (EDMs) induced by the EDM interaction of axion-like dark matter. The search will involve high-resolution optical spectroscopy and measurements of the nuclear spin relaxation parameters, with the goal of achieving 20 percent nuclear spin polarization by direct optical pumping. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure and its incidence continues to rise. HFpEF disproportionately affects women after menopause and has a high mortality rate. Due to the lack of well-characterized mechanisms and targeted therapy, treatment of this underappreciated disease remains focused on symptoms and does not address the underlying structural changes of cardiac remodeling that are key to disease progression. I propose to identify the mechanisms underlying the primary structural cardiac changes that occur in HFpEF in a sex specific manner. Specifically, in this study, I propose that Thrombospondin-1 (TSP-1) is an attractive target in cardiac remodeling noted in HFpEF. Mechanistically, myocardial TGF-β activation is a common element in HFpEF. However, TGF-β inhibition is impractical due to the associated toxicity, necessitating the search for other options to influence this pathway. TSP-1 is a matricellular protein that has no structural role, but modulates cell-cell and cell-matrix interactions by interacting with growth factors and surface receptors. Moreover, it is induced in metabolic syndrome, activates TGF-β1, and inhibits metalloproteinase activity in the heart, which could modulate fibrotic pathways. My central hypothesis is that is that TSP-1 is a key matricellular protein and local mediator of TGF-β1-induced cardiac fibrosis whose expression and activation in cardiac fibroblasts is modified by sex hormones, resulting in augmented collagen deposition and crosslinking. I will investigate the effect of biological sex on TSP-1 activation, TGF-β signaling, and subsequent dysregulation of cell behavior, tissue mechanics, and ventricular function. I will also determine the therapeutic potential of targeting TSP-1 in a rodent model of HFpEF. In Aim 1, my goal is to determine the regulatory mechanisms of TSP-1 and downstream consequences of TSP-1 induction in cardiac fibroblasts. Using human cardiac fibroblasts cells, I will identify the mechanisms by which hypoxia and hyperglycemia induce TSP-1, which then activates TGF-β1 and fibrosis. In Aim 2, my goal is to determine if a gain of androgen signaling boosts TSP-1 expression. Using human cardiac fibroblasts, we will describe the relative gain of androgen signaling post-menopause TSP-1 levels in relation to TGF-β activation. In Aim 3, my goal is to establish TSP-1 as a targetable enzyme in HFpEF. Using an in vivo rat model of HFpEF we will test if TSP-1 inhibition prevents or reverses HFpEF ex vivo and in vivo. This study will establish 1) the therapeutic potential for TSP-1 inhibition in HFpEF, 2) that the ratio of estrogen to androgen modifies cardiac remodeling (as opposed to absolute hormone levels), and 3) introduce a new therapeutic approach and a new target to treat HFpEF by addressing matrix remodeling. In addition, completion of this project will allow me to align my clinical expertise as a cardiac anesthesiologist with my research focus and fully transition me to an independent investigator.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Cognitive impairment persists even with highly effective antiretroviral therapy (ART) in people with HIV (PWH). Persistent neuroinflammation is one of many factors that contributes to ongoing cognitive impairment in virally suppressed (vs)PWH. However, there is a critical gap in understanding the underlying cause of neuroinflammation and, as a result, no available therapies to target it. Long-acting broadly neutralizing antibodies (bNAbs) are considered the next generation of therapy for PWH. Currently, there are 50+ trials that involve bNAbs. Despite this substantial effort, there are no funded NIH studies focusing on if bNAb therapy in combination with ART may reduce neuroinflammation and improve cognitive function. As the mechanism of action for bNAbs is the rapid neutralization of virus and clearance of infected cells via engagement of the immune system, a downstream effect of this therapy may be lower levels of inflammation, as is observed with other Ab therapies. We have evidence that HIV-specific antibodies (Ab) play a protective role in the CNS, and others have shown that bNAb therapy enhances host Ab immunity to HIV and simian immunodeficiency virus (SIV). Therefore, our central hypothesis is that bNAb therapy will reduce neuroinflammation in the CNS, by directly eliminating infected cells capable of trafficking to brain resulting in a smaller CNS reservoir, neutralizing virus within the CSF, and indirectly by reducing peripheral inflammation, resulting in improved cognition. To test our hypothesis, we will use the SIVmac251 rhesus macaque model of HIV and an SIV-specific bNAb (ITS103). The SIV-infected ART-suppressed NHP model will allow us to assess the effects of bNAbs on CNS inflammation, reservoir, and cognition. Additionally, this model will allow us to determine if bNAbs have a direct effect on the CNS or indirect effect through altering peripheral inflammation. AIM 1: Determine if bNAb therapy during ART initiation reduces neuroinflammation. To model ART-naïve PWH receiving bNAb therapy simultaneously with ART, we will treat SIV-infected macaques with ITS103 at the time of ART initiation. We will assess the effect of acute ITS103 therapy on 1) brain macrophage transcription, 2) CNS reservoir size, and 3) cognitive performance after 1 year of suppression compared to ART alone. AIM 2: Determine if bNAb therapy during chronic ART reduces neuroinflammation. To model vsPWH receiving bNAb therapy combined with ongoing ART, we will treat SIV-infected macaques with ITS103 after 36 weeks of ART suppression and assess the effect of chronic bNAb therapy on the same outcomes as in Aim 1. AIM 3: Determine if bNAbs have a direct or indirect effect on neuroinflammation. To determine if ITS103 plays a direct role in the CNS we will assess 1) ITS103 concentrations in the CSF, 2) viral decay rates in CSF, 3) central vs. peripheral inflammation and 4) plasma and CSF Ab neutralization capacity with and without bNAb therapy. Our in vivo study utilizing a native SIV and SIV-specific bNAb is highly innovative as it will be the first to study on the effects of bNAb therapy on neuroinflammation and evaluate if this is a viable treatment for PWH.