Johns Hopkins University

NIH Research Projects · FY 2026 · 2025-03

Herpesviruses are major human pathogens that cause life-long persistent infections and result in clinical manifestations that range from a mild cold sore to cancer. Herpes simplex virus (HSV) is among the most frequently encountered pathogen by the general population. Infection with HSV-1 often results in oralabial disease but it can also cause ocular disease (keratitis) that can lead to blindness or encephalitis, which can be fatal. Type-2 infections are characterized by genital ulcerative disease and infections of the newborn. There is a concerted effort to develop new compounds that block the replication of the virus or a vaccine that can prevent disease. Drugs are being developed that not only target the DNA replication enzymes but also other aspects of the virus life cycle that are amenable to inhibition. The herpesvirus virion is comprised of four structural components: an icosahedral capsid, which encloses the viral DNA genome; an electron dense asymmetrically distributed material, which immediately surrounds the capsid and is termed the tegument; and an outer membrane or envelope, which encloses the tegument and capsid and in which are embedded the viral glycoproteins. Maturation of the capsid into an infectious particle is an essential process and thus potentially a step that can be blocked using a drug or inhibitor. The UL36 gene product is the focus of this proposal. The pUL36 protein, which is resident in the inner-tegument is essential for virus maturation, in its absence, capsids are packaged with genomic DNA and even exit the nucleus (primary envelopment) but subsequently fail to undergo secondary envelopment. This large protein of 336 kDa encodes multiple functions and activities and the protein domains of many of these functions have been mapped and examined in detail. The premise and impetus for undertaking this study, is the observation in preliminary experiments of mutations in UL36 that allow virion morphogenesis. These completely enveloped particles are non-infectious. We will rely on our strength and experience in molecular genetics and cell biological approaches to begin to delineate the impact of these types of mutations on pUL36 activities. Hence, the goal of this proposal is to delineate sites of this protein that could shed light on how pUL36 functions beyond cytoplasmic envelopment. This project is limited to completion of these studies for an important viral protein and satisfies the criteria of an R03 small grant format. The Specific Aims proposed to achieve these goals are: Specific Aim 1: Discover mutant sites in pUL36 that result in the formation non-infectious enveloped virus. Specific Aim 2: Discover how pUL36 functions post-morphogenesis.

NSF Awards · FY 2025 · 2025-03

Bacterial protein Cas9, part of the CRISPR-Cas immunity system, has emerged as a transformative gene editing tool with applications in basic research, agriculture, and healthcare. However, despite its widespread adoption in biotechnology, many questions remain regarding how Cas9 functions in nature. Cas9 main biological function is to protect bacteria from viral invaders known as bacteriophages, or phages for short. These CRISPR-Cas9 systems acquire memories, in the form of DNA fragments, from prior phage infections, allowing bacterial cells to rapidly kill the same phage when it is encountered again in a later infection. This project will explore the hypothesis that a class of phages called “temperate phages” that are often neglected in CRISPR-Cas studies hold the key to understanding CRISPR-Cas memory acquisition. These results will inform new generations of Cas9 technologies, including molecular recording devices, and highlight how CRISPR-Cas systems and temperate phages together influence the evolution of bacterial communities. The project also details an educational plan that will provide undergraduate students an opportunity to learn more about the arms race between bacteria and their phages and careers in microbiological research. A central question in CRISPR-Cas memory creation is how cells survive a lytic phage infection long enough to create a new memory and utilize it for defense. Intriguingly, many CRISPR systems target temperate phages, which are capable of entering a program called ‘lysogeny’, in which their DNA is inserted into the bacterial chromosome, where it may remain in a dormant form. This proposal tests the hypothesis that CRISPR-Cas systems can exploit the temperate lifecycle by acquiring memories about those phages under non-lytic conditions. Specifically, the proposal examines whether new memories can be made during the initiation of lysogeny (aim 1) and/or after lysogeny has occurred and the phage has integrated into the chromosome as a prophage (aim 2). Finally, the proposal tests whether prophages can influence the ability of CRISPR-Cas systems to acquire memories from other infecting phages (aim 3). Temperate phages are understudied in CRISPR-Cas laboratory experiments, because the rates of lysogeny are significantly higher than spacer acquisition. This proposal will employ new genetic tools to thoroughly dissect the interactions between CRISPR-Cas systems and their natural temperate phage targets, revealing a new paradigm for how CRISPR-Cas immunity is established. 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 2025 · 2025-03

Project Summary/Abstract We propose to hold an International Society for Magnetic Resonance in Medicine (ISMRM) Workshop entitled "Perfusion MRI: Found in Translation" in Pamplona, Navarra, Spain. Perfusion MRI provides important diagnostic biomarkers in many diseases throughout the body, beyond those available from standard anatomic MRI. The significance of Perfusion MRI has been extended to all specialties of medicine. The purpose of the proposed ISMRM Perfusion MRI Workshop is to bring together scientists and clinicians interested in technical research and application-oriented innovations in perfusion MRI. The Workshop has three aims: Aim 1 is to organize an interdisciplinary international workshop highlighting the opportunities and challenges of perfusion MRI; Aim 2 is to discuss the key questions and gaps in the Perfusion MRI field to guide future research and clinical applications; Aim 3 is to promote harmonization of imaging protocols and disseminate existing tools for the analysis of perfusion data and training resources related to perfusion imaging techniques. This workshop will be of great interest to the clinical community, such as neurology, psychiatry, oncology, cardiology, nephrology, pulmonology, hematology, and orthopedics. The organizing committee consists of a diverse group of scientists and clinicians with inclusion of women and underrepresented minorities as well as a mixture of junior and senior investigators. A diverse panel of world renowned scientists and clinicians will present their research in methodologies and applications of perfusion MRI. The Workshop will be CME accredited. The Workshop will employ several novel approaches. Scientific presentations will be combined with new socializing and networking methods to provide ample opportunities of discussion, collaboration, and brainstorming. To maximize the impact of the Workshop on the scientific community and to move the perfusion MRI field forward, we will set concrete goals. Therefore, the 2025 Perfusion MRI Workshop will be a timely event to unify and further publicize recent efforts in perfusion MRI, and to disseminate open source tools for perfusion image processing and analysis. By holding panel discussions with industry vendors, we expect to set much-needed standards for the implementation of perfusion protocols across platforms.

NSF Awards · FY 2025 · 2025-03

Non-technical Abstract Earth’s solid outer layer is made up of either continental or oceanic crust. In Earth’s past, the continents had different arrangements to what we are familiar with today. The theory of plate tectonics, which emerged in the 1960s and was formalized in the 1970s, explains the changing face of Earth in terms of the opening and closing of oceans (i.e., creation and destruction of the oceanic crust that floors them). The coming and going of oceans act to fragment and separate continents then bring them back together in new formats. With over 50 years of scientific inquiry since the discovery of plate tectonics, geologists still do not understand the exact processes responsible for the birth and death of oceans. The Atlantic Ocean is 180 million years old and has not yet shown any signs that it is closing. Geological evidence suggests that a previous ocean existed in a similar region to the Atlantic of today; the Iapetus Ocean, named after the father of Atlas in Greek mythology. Geological constraints on the birth and death of the Iapetus Ocean suggest that it began closing less than 80 million years after it opened. Why the divergent fates of these two oceans? The answer to this question may lie in the respective processes that birthed the Atlantic and Iapetus. This project will test the idea that the process of ocean formation—the style of continental rifting—can impart differential susceptibility to subsequent closure of the ocean basin that forms. Research will proceed via geological, geochemical and geochronological study of fragments of the Iapetus Ocean preserved at five locations between western Scotland and Arctic Norway. Work will focus on the apparent spatial coincidence of records of Iapetus Ocean opening and closing, and implications for the setting in which the closing process was seeded. The project includes public outreach that will benefit local urban population in Baltimore. Summer research internships will provide opportunities for local high school students to get involved in hands-on research. The team will also lead field excursions to explore the “Baltimore Ophiolite’ – a rare sliver of ancient oceanic crust preserved in an urban setting. Technical Abstract The Wilson Cycle is a cherished concept in plate tectonics. However, an enduring issue with the model is the inherent strength of passive margins, which should resist the implied process of passive margin collapse to initiate subduction. Supra-subduction zone (SSZ) ophiolites of the Scottish and Norwegian Caledonides record the first instance of subduction initiation across approximately 2,000 km of the Wilson Cycle’s archetypal ocean, the Iapetus. Seeding work on these SSZ ophiolites suggests a potentially ubiquitous association between records of rifting to open the Iapetus Ocean and those of subduction initiation to close it. These associations provide tantalizing clues that margin structure/litho-architecture inherited from rifting may leave certain passive margins more susceptible to subduction initiation via passive margin collapse. This project will explore the idea of passive margin susceptibility to subduction initiation by testing two hypotheses: (1) Iapetan subduction initiation occurred in regions that also experienced Ediacaran rifting of Rodinia, and (2) Iapetan subduction initiation occurred in an oceanic setting proximal to the Laurentian margin. Testing Hypothesis 1 will involve geochemical characterization and zircon U-Pb dating of enigmatic metavolcanic packages adjacent to the SSZ ophiolites of Unst, Scotland, and Karmøy and Leka, Norway. Testing Hypothesis 2 will involve geochemical and detrital zircon characterization of metagraywackes from the cover sequences of the Karmøy, Leka and Lyngen SSZ Ophiolites, Norway. 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 · 2025-02

Project Summary The goal of this proposal is to optimize the efficacy of CAR T cells against pancreatic tumors using engineered, synthetic cytokine receptors (velocity receptors, VRs) that enhance CAR T migration speed and tumor infiltration. We will test the motility and cell-killing capability of these new CAR T cells in vitro and select the ten most promising VR constructs for testing and validation in mouse models of pancreatic cancer. In 2024, an estimated 66,440 Americans will be diagnosed PDAC and 51,750 will die of the disease – the highest mortality rate of any major cancer. The five-year survival rate for pancreatic cancer patients (90% of whom have pancreatic ductal adenocarcinoma, PDAC) is just ~12%, yet the standard of care has not changed in years. CAR T cells express engineered chimeric antigen receptors (CARs) that bind specific antigens on cancer cells to trigger anti-tumor effects. They have shown exceptional clinical success for patients with hematologic malignan- cies; however, conventional CAR T cells show low specificity and poor infiltration for patients with solid tumors, especially pancreatic tumors. We hypothesize that a key reason for the lackluster performance of CAR T therapy (as well as molecular therapies) for patients with pancreatic tumors is the stromal matrix, which constitutes a major barrier to the infiltration of CAR T cells and hinders their interaction with target tumor cells. Our therapeutic approach focuses on the largely unaddressed challenge of crossing the stromal matrix. We recently engineered and expressed synthetic cytokine receptors (velocity receptors, VRs) on mesothelin CAR T cells (CAR TV cells) that enhance the migration speed of control CAR T cells 3- to 6-fold in vitro and prompt these cells to infiltrate solid tumors 10 to 50 times more than control CAR T cells in preclinical mouse models of PDAC. This enhanced infiltration correlates with tumor growth inhibition and prolonged survival, at doses for which control CAR T cells show little infiltration and no effect on tumor growth. This activation results from interactions between the engineered VR receptors and inflammatory cytokines secreted by the CAR T cells, including interleukin-5 (IL-5), IL-8, interferon γ (IFNγ), and tumor necrosis factor α (TNFα). As a proof of principle, we tested five different VR receptors that induced enhanced migration in vitro in PDAC mouse models. Our overall hypothesis is that hyper-migratory CAR TV cells lead to greater inhibition of solid tumor growth due to increased tumor infiltration. We propose to optimize the tumor-infiltration efficacy of CAR TV cells by enlarging the repertoire of VRs via a modular design based on the hinge, transmembrane, and signaling domains of the receptors for cytokines IL-5, IL-8, IFNγ, and TNFα. Our approach is “CAR-agnostic”; to compare with previous work, we will keep the (mesothelin) CAR construct unchanged. We will test the motility and cell-killing capability of these new CAR TV cells in vitro and select the ten most promising VR constructs for testing and validation in several mouse models of PDAC.

NIH Research Projects · FY 2026 · 2025-02

PROJECT ABSTRACT Our overall goal is to redefine screening for early detection of pancreatic cancer. Currently, endoscopic ultrasound and magnetic resonance imaging (MRI) is used to survey individuals at high risk of pancreatic cancer. These tests are costly, not easily accessible and of variable yield even in high-risk populations. Using state of the art methods, we will develop a highly specific blood based early-detection pancreatic cancer test with sensitivity and specificity appropriate for high-risk individuals. We will couple this with innovative approaches which will further leverage imaging, risk factor and germline genetic data to further stratify risk. We will integrate these diverse data to more precisely guide the management of high-risk patients. The specific aims of this project are: 1) To develop a blood based early detection screening test, PancSEEK, for populations at higher risk of PDAC. 2) To develop PDAC risk models that integrate clinical, genomic, molecular, and imaging data to enable personalized surveillance management plans for individuals at higher risk of PDAC. 3) To prospectively evaluate an integrated risk model, PancDetect, and the blood-based screening test, PancSEEK, in a population at higher risk of PDAC.

NIH Research Projects · FY 2026 · 2025-02

Modified Project Summary/Abstract Section Project Summary. Mental illness is common, impairing, and associated with heightened suicide risk among youth, but access to proper care is sorely limited. Despite known barriers to accessing mental health services (MHS) being well known, there has not been consistent improvement in MHS access over time, and many youth in need of MHS do not receive them.1 Thus, innovative strategies to improve access to care is imperative and has potential to have a profound public health impact. Brief, accessible interventions to improve access to and engagement in quality MHS among MHS-referred youth are understudied. This proposal seeks to address this critical gap in knowledge and promote access to children’s MHS delivery by developing and piloting a virtual group intervention for caregivers of patients who have been referred to MHS by a pediatric community primary care center in Baltimore, Maryland (the Caregiver-Informed Treatment Engagement [CITE] Program). For Aim 1, we will form a CITE Steering Committee of community partners (caregivers and community mental health & primary care providers) to develop CITE for youth referred to MHS. The Steering Committee will convene to guide each subsequent stage of CITE development and piloting. First, the Steering Committee will develop questions to asked in in-depth interviews (IDIs) of community stakeholders, including caregivers in the local community and community mental health and primary care providers; IDIs will assess stakeholder views on appropriate foci for a brief, virtually delivered access-promoting intervention as well as MHS access barriers and facilitators. We will use these data to inform the targets of the CITE intervention to ensure that CITE appropriately addresses the needs of the intended audience. For Aim 2, we will conduct a pilot RCT of CITE recruiting caregivers of youth referred to MHS by their primary care provider. Youth will be randomized to CITE or to facilitated MHS referral. We will examine program feasibility, acceptability, and CITE fidelity. Additionally, youth will be assessed at the start of the study, at the end of the intervention and at 60- and 90-days post-intervention to examine whether CITE improved youths’ psychiatric symptoms, caregiver stress, and families’ access to and engagement in MHS. Finally, for Aim 3, we will examine mechanisms contributing to improved treatment initiation, engagement, and psychosocial outcomes among CITE participants. Specifically, we will explore whether social connectedness, MHS related knowledge, CITE acquired cognitive behavioral and parenting -skills, and parenting stress are associated with CITE engagement and with more favorable mental health outcomes.

NSF Awards · FY 2025 · 2025-02

This new three-year REU Site: Research on Sustainable Energy Technology and Systems (ROSETAS) project is hosted by Johns Hopkins University. The broad societal-wide threat of climate change, driven by the use of fossil fuels for energy, requires innovation and implementation of sustainable energy technology and systems. This Site provides undergraduates with opportunities to engage in research and policy on creating and implementing clean, renewable, and sustainable energy technologies. Participants will select research projects in one of four areas: carbon capture and transformation to reduce the carbon dioxide in the air; energy storage technology for energy on-demand; wind energy technology; and electricity grid management for energy delivery. Students will also participate in a professional development program focused on specific research skillsets, industry and commercial opportunities in this sector, and future STEM career opportunities. ROSETAS provides community college and students from underserved/underrepresented populations to become part of the research community developing novel sustainable energy solutions. The ROSETAS REU program is located at the Ralph O’Connor Sustainable Energy Institute (ROSEI) at Johns Hopkins University will recruit ten students per year in the interdisciplinary areas of energy technology and systems. The objectives are to 1) recruit underserved student populations, particularly those from community colleges and minority-serving institutions, 2) engage students in the energy policy, commercialization, and industrial context surrounding their research, and 3) impact society by building and inspiring the next-generation skilled workforce in the transition to a clean energy economy. Participants will engage in an extensive professional development program (i.e., in-person weekly workshops, off-site visits, a culminating research symposium). ROSETAS REU students will work within integrated research teams to help develop novel solutions and tackle critical problems. For example, projects will feature topics such as direct air carbon capture and sequestering carbon through upcycling, innovations in energy storage emphasizing non-rare earth metals, scale-up and next generation control solutions for wind energy; and transforming infrastructure, control, markets and policy for the electric grid. REU students will participate in research that addresses the technical and issues that can drive innovation and build an advanced workforce in this area of national need. 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 · 2025-02

Inhibition of glutamine metabolism or glutaminolysis is an exciting therapeutic strategy for glutamine-dependent cancers. Such a strategy may potentially avoid the complex upstream signaling pathways and directly prevent cancer cells’ energy production and required building blocks, starving them to death. Altered glutaminolysis is widespread across the disease spectrum of prostate cancer (PC) and renal cell carcinoma (RCC). The first step of glutaminolysis is mediated by glutaminase, which produces glutamate (Glu), an essential precursor for the biosynthesis of amino acids, nucleic acids, and energy production. In radiotherapy, where DNA damage is the central mechanism of cell death, cancer cells undergo metabolic reprogramming to enhance Glu utilization. Inhibition of glutaminolysis (Glni) has been increasingly used with radiotherapy to overcome radioresistance. However, the effect of targeted radiopharmaceutical therapy (RPT) on glutaminolysis remains unknown. To fill this gap, we will systematically evaluate the effect of prostate-specific membrane antigen (PSMA)-based radiopharmaceutical therapy (PSMA-RPT) on glutaminolysis using apporved, 177Lu-/225Ac-PSMA-RPT in experimental models of PC and RCC to deliver a mechanism-driven combination therapy. Since metastatic castration-resistant PC (mCRPC) is associated with high PSMA expression and PSMA is a Glu producing enzyme, PSMA has a critical role in mCRPC metabolism by utilizing a glutamine-independent metabolic pathway. Also, metastatic RCC is highly glutamine-dependent, and glutamine-deprived tumor neovasculature likely overexpresses PSMA to generate additional Glu to meet their high metabolic demand. Our preliminary data show that glutaminolysis is differently regulated in PSMA+ RCC tumors to address 225Ac-L1-induced DNA damage for their proliferation and growth. Additionally, our data revealed that Glni may upregulate PSMA levels in PSMA+ tumor models. Based on our preliminary data, we hypothesize that PSMA-RPT will significantly affect the glutaminolysis of PC and RCC, and Glni will expand the therapeutic window of PSMA-RPT. We have two Aims. In Aim 1, we evaluate the effect of PSMA-RPT on glutaminolysis as monotherapy and in combination with pharmacological (Aim 1a) and with genetic inhibition in PC and RCC cell lines (Aim 1b) to determine its role in DNA damage. In Aim 2, we will evaluate the effect of PSMA-RPT in selected preclinical models of PSMA+ PC and RCC in immunodeficient mice (Aim 2a) and immunocompetent mice (Aim 2b) as monotherapy and in combination with two selected inhibitors targeting the glutaminolysis pathways from Aim 1. We have established several human and mouse PSMA+ RCC and PC isogenic cell lines and a stable patient-derived RCC model for the proposed research. We will take advantage of our established PSMA-based research within our cancer center to expand the scope of PSMA-RPT for prostate and non-prostate malignancies. If successful, this project will uncover new insights into RTP-induced metabolic changes associated with DNA damage and will deliver mechanism-driven combination therapy beyond the existing paradigm.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Pulmonary arterial hypertension (PAH) remains challenging to treat due to its complex pathobiology. The persistently high mortality observed in PAH, despite a recent evolution in available pulmonary vasodilator therapies, underscores a critical need to intervene upon fundamental disease biology. Our data show that abnormalities in long-chain fatty acid (LCFA) metabolism precede a clinical diagnosis of PAH in the at-risk scleroderma population. Despite increasing recognition of lipidomic aberrations in PAH, no studies have examined comprehensive high-resolution lipidomics in relation to measurements of right ventricular (RV) and pulmonary vascular (PV) function. Our preliminary single-center high-resolution lipidomic data show that lipid species with LCFA residues are associated with measures of RV-PV dysfunction. LCFAs are known to be biologically important mediators in the lung, and many are essential FAs obtained via dietary intake. The goal of the current proposal is to validate our single-center lipidomic observations in external cohorts with complementary data features and data structures. We hypothesize that the lipidomic signatures detected in our discovery cohort will reproducibly relate to specific RV-PV phenotypes and clinical outcomes, which will implicate biologically important aberrations in lipid metabolism that may be targetable via dietary or pharmacologic interventions. With Aim 1, we seek to validate lipidomic signatures in the larger, multi-center PVDOMICS cohort of patients with, or at risk for, pulmonary vascular disease, and to investigate lipid gradients across the pulmonary vasculature (e.g., differences in lipid abundance in blood samples collected from the mixed venous vs. wedged positions). Our second aim involves validating our preliminary lipidomic signatures in the ARIC cohort, a longitudinal study of initially healthy individuals followed forward in time. We will explore the relationships between dietary lipid intake, plasma lipid levels, and RV-PV function, hypothesizing that changes in LCFAs over time will predict RV-PV function. In Aim 3, we will prospectively follow patients newly diagnosed with PAH. We will investigate whether lipidomic aberrations, at baseline and in follow-up after initiation of standard PAH-specific therapy, can outperform traditional clinical measures of treatment response for predicting clinical worsening events. Completion of this project will yield a detailed understanding of lipid aberrations specific to phenotypes and outcomes in PH, which has the potential to identify novel biomarkers and therapeutic targets. Should our hypothesis be confirmed, the project stands to transform our approach to PH management via early identification of patients at high risk for experiencing poor outcomes, and potential early intervention based on lipidomic insights.

NSF Awards · FY 2025 · 2025-02

The broader impact of this I-Corps project is the development of a food safety testing system that handles large volumes of samples to detect dangerous bacterial contamination. Each year in the United States alone, hundreds of thousands of people become ill from consuming contaminated food products, resulting in billions of dollars in medical costs and lost wages. Current testing approaches rely on taking small samples from large production lots, which is both time-consuming and potentially unreliable. This new technology enables rapid screening of entire production batches, dramatically reducing both testing costs and time, while improving detection reliability. The system's affordability and simplicity make it particularly valuable for widespread deployment across the food supply chain - from farms to processing facilities to consumer-facing establishments. By enabling comprehensive testing at the source, this technology could reduce foodborne illness outbreaks while helping food producers operate more efficiently and maintain product quality. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on the development of a two-part food safety detection system that overcomes key limitations of current testing methods. The first component uses specially engineered polymer channels that can process large sample volumes and concentrate bacteria into small areas for analysis. The second component employs advanced optical techniques to rapidly identify bacterial species without requiring additional chemicals or labels. The system can process and analyze entire production lots in minutes rather than hours, while providing more reliable results than traditional sampling methods. Laboratory testing has demonstrated the ability to selectively capture and identify harmful bacteria from complex samples with high accuracy. The technology maintains sensitivity while eliminating complex sample preparation steps, making it practical for real-world deployment. 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 · 2025-02

Summary- Cell migration is a fundamental biological process underlying diverse (patho)physiological events, such as embryonic development, immune response, and disease progression. Cells in vivo travel through different tissues of varying extracellular fluid viscosities. Viscosity is thus a physiologically relevant physical cue, which has been largely overlooked. We were the first to establish that elevated, albeit physiological, levels of viscosity regulate tumor epithelial cell migration and invasion in vitro and in vivo. Cells not only sense and respond to fluid viscosity but also develop memory. Yet, our understanding of how memory is imprinted on epithelial cells and what changes viscosity imparts to the cell’s molecular machinery and chromatin architecture represent major unanswered questions of fundamental and potential translational value. Along these lines, how fluid viscosity affects the function of other cell types, such as immune cells, as well as their crosstalk with tumor epithelial cells, is currently unknown. In addition to fluid viscosity, cells in vivo are also exposed to other important physical cues, such as microenvironmental stiffness and confinement, which all trigger intracellular responses that allow cells to adapt to the diverse landscapes they encounter. We were the first to demonstrate that confinement alone regulates epithelial cell migration mechanisms. Intriguing preliminary data reveal that microchannel stiffness alters cell migration mechanisms in confinement. Yet, the interplay among fluid viscosity, confinement and stiffness on cell function represents an open and unaddressed question. To develop a comprehensive understanding of how physical cues modulate cell responses, we will examine the cell as whole using a holistic and integrated approach. Although prior work has established that the cell nucleus and plasma membrane molecules, such as mechanosensitive ion channels (MICs), sense and respond to mechanical cues, our understanding of the crosstalk between the nucleus and ion channel-mediated mechanosensation is at best limited. We are uniquely positioned to address all these key gaps in the literature by employing a holistic approach integrating cutting-edge in vitro models (hydrogel-based microfluidic channels of precisely tunable stiffness and degree of confinement) and sophisticated techniques (3-dimensional (3D) traction force microscopy, optogenetics, high-throughput sequencing etc) with the chick embryo model. Taken together, our proposed work over the next five years will generate new conceptual information on how key mechanical cues are sensed, interpreted and imprinted on cells via the crosstalk among the cell cytoskeleton, the nucleus and chromatin architecture, and MIC mechanosensing. Our work will unravel novel signaling mechanisms that may lead to the discovery of new therapeutic targets potentially applicable to various pathologies, like cancer, where the elevated viscosity of the local microenvironment has emerged as a key, but understudied, modulator.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Diabetic retinopathy (DR) is a common complication of diabetes that is traditionally associated with observable structural alterations in the retinal blood vessels, including microaneurysms, hemorrhages and exudates. Emerging research has shown that retinal neurodegeneration (DRN), or damage to the retinal neural tissue, precedes the manifestation of vascular abnormalities, and may be an early component of diabetic retinal disease. The use of optical coherence tomography (OCT) imaging allows precise and reproducible measurements of the retinal layers that can distinguish small alterations in thickness, that are associated with DRN in both type 1 (T1D) and type 2 diabetes (T2D). Several cross-sectional studies in adults with diabetes have shown reduced thickness of the retinal nerve fiber layer (RNFL) and ganglion cell- inner plexiform layer (GC-IPL) layers, as compared to healthy controls, but there is limited data available in the pediatric population. With prior NEI funding (R01EY033233) we conducted a rigorous, prospective trial from 2022-2024 resulting in a well-characterized cohort of 380 youth with type 1 and type 2 diabetes, 25 youth with prediabetes, and 21 age-matched healthy controls who underwent fundus photography for diabetic retinopathy screening using autonomous AI and point of care OCT imaging (NCT05463289). Utilizing this well described cohort with robust clinical data and quality fundus and OCT images, we hypothesize that thinning of the neural retina layers (RNFL and GC-IPL) will be more pronounced in youth with longer durations of diabetes, as well as worse glycemic control. Further, we hypothesize that DRN will be present in youth with prediabetes compared to healthy controls, but will be more severe in those with youth onset type 2 diabetes. In this proposal, we aim to describe retinal neurodegeneration in youth onset diabetes. In a cohort of youth with T1D, Aim 1 will determine if neuroretinal thickness is associated with duration of diabetes (Aim 1a), and assess the association of neuroretinal thickness with use of diabetes technologies and glycemic control (Aim 1b). In Aim 2, we will compare neuroretinal thickness between youth with T2D, prediabetes and youth without diabetes (Aim 2a), and assess the association of neuroretinal thickness with GLP1 use (Aim 2b). Earlier identification of diabetic retinal disease will further our understanding of alterations in the neuroretina and may optimize potential interventions to improve visual outcomes for the growing population of youth with diabetes.

NIH Research Projects · FY 2026 · 2025-01

Project Summary RNA chaperone proteins act as versatile matchmakers, delivering regulatory RNAs to their targets to rapidly modulate gene expression in response to environmental signals. In bacteria, the Hfq chaperone flexibly matches small non-coding RNAs (sRNAs) to complementary sites in target mRNAs to regulate translation and turnover of transcripts crucial for bacterial stress response, persistence, and virulence. Previous studies have offered insight into how Hfq mediates the sRNA-mRNA annealing process and the crucial roles of arginine residues on the lateral rim of the Hfq hexamer and intrinsically disordered C-terminal domains (CTD) that gate RNA binding and release from Hfq. These findings have provided a foundational understanding of Hfq’s chaperone activity, but do not address how this chaperone activity is achieved. The goal of this project is to develop a comprehensive, atomistic model describing RNA binding and diffusion on the Hfq chaperone. Aim 1: To use confocal single molecule Förester resonance energy transfer (smFRET) to describe how sRNAs diffuse on Hfq, and to decipher the role of the CTDs in sRNA diffusion. Aim 2: To use 19F nuclear magnetic resonance (NMR) spectroscopy to characterize how Hfq and sRNA dynamics are mutually affected during complex formation. Aim 3: To use all-atom molecular dynamics (MD) simulations to gain atomistic insight into changes in local Hfq and RNA dynamics that enable diffusion and annealing. Collectively, these results will offer a mechanistic understanding of fast dynamics that give rise to Hfq’s RNA chaperone activity. This mechanistic understanding will be applicable to many other RNA chaperones and RNA-binding proteins and will inform the development of next-generation antimicrobials that target bacterial virulence. Carrying out this research will deepen my knowledge of computational simulations while providing me with new skills in two biophysical experimental methods, confocal smFRET and NMR. My training will be conducted as part of the Ph.D. Program in Molecular Biophysics at Johns Hopkins University, which provides rigorous scientific development and monitoring of students. A mentoring committee with expertise in all of the research aims will meet with me regularly to provide scientific and professional advice, and to monitor my training and research progress. I will have access to world-class instrumentation and all necessary resources for completing each specific aim. Additionally, the collaborative and interactive Johns Hopkins biophysics community will offer abundant opportunities for scientific communication, networking and career development.

NIH Research Projects · FY 2026 · 2025-01

Modern guidelines recommend novel, effective therapies such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and non-steroidal mineralocorticoid antagonists (MRA) in people with diabetes. However, there are significant gaps in adherence to guideline-recommended care. Some groups face a disproportionate burden of diabetes and likely have larger gaps in care in diabetes. The high cost of newer medications may further exacerbate these differences. However, this variability in quality of diabetes care and outcomes across age, socioeconomic status, and race/ethnicity and their complex interplay have not been well characterized. Challenges to engaging in care are also understudied. Little is known about what prevents physicians from prescribing guideline-recommended monitoring and treatment. The overarching goal of this proposed study is to address the challenges that prevent provision of guideline-recommended diabetes care in the United States. This study will leverage rich real-world datasets on persons with diabetes from OptumLabs Data Warehouse (OLDW, n ≈ 8.1 M), Medicare (n ≈ 3.1 M), and Medicaid (n ≈ 6.2 M) and survey a national sample of physicians (n ≈ 1000) with three physician focus groups (n ≈ 24) to achieve the following specific aims: describing differences in care receipt by individual-level, neighborhood-level, and insurance-level characteristics (Aim 1), examining differences in outcomes and the extent to which they associate with care receipt with traditional mediation analyses as well as novel causal decomposition methods (Aim 2), and investigating physician perspectives on multilevel challenges to care (Aim 3). The proposed work will represent the largest number of people with diabetes in the United States with different socioeconomic backgrounds. This research endeavor, informed by national priorities, seeks to advance knowledge, inform policies, and improve diabetes care.

NSF Awards · FY 2025 · 2025-01

This project explores changes in work and educational relationships within the youth labor market in a context of where biomass-based electricity development is being initiated to meet rapidly increasingly energy needs. The establishment of technical education programs in energy development, alongside the launch of biomass-based electricity generation projects, signals a significant shift in energy extraction strategies, and the vocational labor training that is necessary to sustain the sector. This study offers insights into the broader implications of energy diversification efforts, highlighting their impact on rural youth. In addition to providing training for a graduate student in scientific methods of data collection and analysis, the project also includes pathways for disseminating the data and results to improve the public’s understanding of the scientific analysis of rural educational and development practices. To examine how youth engage with the energy diversification, this project employs behavioral observation within a vocational educational setting, engaging teachers, administrators, and students, as well as interviews with bureaucratic functionaries, school administrators, and students, and teachers at the three municipal high schools within which vocational training is conducted. The study explores three areas: how young people are integrated into new energy projects, the challenges they face in pursuing vocational education in these fields amidst socio-ecological transformations, and how they navigate labor opportunities within this emerging sector. This approach contributes to scholarly discussions in the anthropology of energy, education, and labor. It provides an opportunity to explore whether changing educational practices that focus on environmental science and bioenergy impact labor relations and socio-ecological relations. 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 · 2025-01

PROJECT SUMMARY The low chemical sensitivity of magnetic resonance imaging (MRI) has been a persistent obstacle for the development of molecular imaging agents that can be visualized using clinical scanners. These agents were often designed “one-to-one”, wherein one targeting molecule was attached to one signal-generating molecule, often with a linker. This monomeric design requires molecules that can generate strong MR signals; however, signal-generating molecules with these attributes are too toxic or immunogenic at detectable doses. To overcome this challenge, polymers recently have been incorporated into the design of molecular MRI agents. The repeated chemical groups of polymers can provide multiple attachment sites for the signal-generating molecule, enabling the number of less toxic and less immunogenic MRI signal-generating molecules to be increased to detectable levels. Previously, we demonstrated the proof-of-concept of polymeric molecular MRI agents with two formulations that could detect prostate-specific membrane antigen (PSMA) using the chemical exchange saturation transfer (CEST) MRI method. Still, the translation and widespread clinical use of polymeric molecular MRI agents will require improvements to their sensitivity and specificity. Physiochemical properties (i.e. charge, hydrophobicity) have been shown to influence the in vitro and in vivo specificity of molecular imaging agents. Research Plan: We propose to optimize polymeric CEST MRI agents by varying the charge and hydrophilicity of the signal-generating molecule. These molecular MRI agents will target CD154, an inflammatory marker that can detect benign prostate hyperplasia, a condition that that can mimic prostate cancer in PSMA images. Aim 1: We will synthesize and characterize CEST MRI agents of varying charge and hydrophilicity by adjusting the type and number of signal-generating molecules on the agent, as well as the length of its polymer. We will measure their uptake and internalization in CD154+ (BPH-1) and CD154-(LNCaP) cells. Aim 2: We will measure the uptake of two molecular MRI agent formulations in vivo in prostate models with varying levels of CD154 expression (BPH-1 > LNCaP). We will also measure the uptake of PSMA PET agent 18F-DCFPyL in these same mice (LNCaP > BPH-1). We will validate in vivo images using fluorescent microscopy.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY. Colorectal cancer (CRC) is the second leading cause of cancer–related mortality in the U.S. with a dismal 5– year overall survival rate at <15% for those with metastases. Immune checkpoint inhibitors (ICIs) lack therapeutic efficacy in the majority (~95%) of advanced CRC tumors that are microsatellite stable (MSS). Mutations in oncogenic KRAS (~40% of CRC) can further lead to immune evasion in the tumor microenvironment (TME) through the upregulation of immunosuppressive cytokines and impaired antigen presentation through downregulation of HLA I––together resulting in reduced T cell recruitment into the TME. There is thus a critical need for novel treatment strategies to improve ICI responses for patients with mutant KRAS (mKRAS) MSS CRC. We have developed a vaccine that pools six synthetic long peptides (SLPs) targeting the most common KRAS mutations (G12D, G12R, G12V, G12A, G12C, and G13D) –– termed ‘mKRASvax’. We are currently conducting a pilot study testing mKRASvax in combination with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) antibodies in PDAC and MSS CRC. Enrolled patients either have: resected pancreatic ductal adenocarcinoma (PDAC; Cohort A) or chemorefractory (two plus lines of chemotherapy) metastatic MSS CRC (Cohort B) [NCT04117087]. We have documented safety and a robust de novo induction of mKRAS–specific CD4 and CD8 T cells. Importantly, interim analysis for our PDAC cohort (Cohort A) shows that high–magnitude T cell responses correlate with greater recurrence–free survival (RFS). In our heavily pre–treated CRC cohort (currently enrolling), we have demonstrated the induction of de novo mKRAS–specific T cells in all the vaccinated patients, with tumor regressions in the first 3 of 9 enrolled patients, including those with liver metastases. Based on this data, we propose to conduct a Phase II clinical trial to study clinical responses (Aim 1) and immunogenicity (Aim 2) induced by mKRASvax in a novel combination with anti-PD-1, balstilimab, and more potent Fc– engineered anti-CTLA-4 antibody, botensilimab, in the first-line, maintenance setting after patients with mKRAS- harboring tumors have received 4 to 6 months of chemotherapy for metastatic CRC. Finally, we hypothesize that the immunomodulatory effects of small molecule inhibitors can be leveraged for more durable anti–tumor immunity when combined with mKRASvax and ICIs. In the true spirit of bidirectional translation, Aim 3 will focus on studying the potential for combining mKRASvax/ICIs and KRAS signaling inhibitors in mice. We will first utilize in vitro human and murine mKRAS CRC cell lines and organoids to assess HLA induction with the RAS(ON) inhibitor RMC-7977, KRASG12D inhibitors MRTX1133 or RM-044, and the MEK inhibitor avutometinib. We will use a KRASG12D–expressing CT26 murine cell hemispleen model to test the effects on tumor size and mouse survival of various combinations of, and therapeutic sequences for, mKRASvax, ICI and KRAS signaling inhibitors. We will also perform imaging mass cytometry (IMC) to study the immune architecture of the TME. Overall, these studies will lead to novel therapeutic mKRAS-based immunotherapies for metastatic CRC.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Citrullination is a physiologic post-translational modification found across multiple normal human tissues. Why this modification is the most important target of antibodies in rheumatoid arthritis (RA) is unknown. While the pathogenic role of anti-citrullinated protein antibodies (ACPAs) remains uncertain, the striking association between ACPAs and RA has raised the possibility that understanding the origin of these antibodies may shed light on the cause of RA. Interestingly, our preliminary studies provide evidence that ACPAs may originate from a distinct antibody targeting a different but structurally similar modification, known as carbamylation. Our overarching hypothesis is that ACPAs can arise during affinity maturation of germline encoded antibodies to carbamylated proteins. In this proposal, we will use RA-derived monoclonal ACPAs to support or discard this novel hypothesis. If the proposal is successful, this work may uncover a mechanism for why citrullinated proteins become immunogenic and potentially to support germline encoded antibodies to carbamylated proteins as initial players in the development of RA.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY This research focuses on a class of enzymes that are integral to human health, protein kinases. The most frequent post-translational modification of proteins is phosphorylation, and these modifications made by protein kinases. These additions are an integral component of the information flow controlled by numerous signaling pathways that control a myriad of cellular decisions ranging from cell growth to immune responses. Disruption of these pathways leads to diseases ranging from cancer to developmental defects. The goal of this research program is to determine the molecular mechanisms that regulate the activity of protein kinases. We will use the Hippo pathway, which controls decisions of cell fate and number, as a model system to investigate different mechanisms that modulate the activity of protein kinases. We will combine biophysical, biochemical, structural bioinformatics, and cellular approaches to examine how the activity of these enzymes is tuned. This work will address fundamental gaps in our understanding of protein kinase regulation, decipher the molecular mechanisms regulating the activity of the protein kinases in the Hippo pathway, and investigate novel routes of Hippo pathway modulation. The molecular insight gained from this research will accelerate the development of targeted therapies to block inappropriate kinase activity which will be broadly applicable to multiple diseases.

NSF Awards · FY 2025 · 2025-01

Prior research and applications of voice conversion models have raised challenging problems that are both theoretical and use-inspired. Notable challenges include processing emotional speech and speech in noisy environments and generating speech that represents the characteristics and expressiveness of specific speakers such as personality traits, mood, prosody, and emotional state. These challenges are exacerbated by a limited availability of data. Improving such capabilities will have a wide range of social impacts ranging from giving natural voice to patients who have lost it to rendering comprehensible and speaker faithful renderings of old poor quality recordings that have become hard to understand to generating seamless speech translations in real time communications while staying faithful to the voice characteristics of the speaker. To address these challenges, the project proposes to explore and expand theories about speaker identity, emotion, and expressiveness in challenging conditions. Practically, this means studying how factors like background noise, emotions such as stress, cultural differences or other idiosyncratic ways of speaking affect a system’s ability to recognize and render faithfully the speech of a specific individual. This work will enable a second aim of this project which is to create voice technology that can be used for safeguarding ethical and responsible use of voice generation. Sophisticated voice conversion techniques can be used to detect and prevent spoofing and other fraudulent activities and make it challenging for unauthorized users to mimic or imitate target speakers. Besides security and defense other areas that will benefit from this project include security and defense, accessibility and healthcare assistive technologies, medical voice preservation, speech therapy and rehabilitations as well as entertainment and gaming. This award aims to develop novel algorithms utilizing deep learning techniques to advance voice conversion models with the ability to represent faithfully the characteristics and emotional states of individual speech. The project includes the following key areas of research. The first research target is to explore learning speaker identity and emotion representations for robust voice conversion with self-supervision. By investigating joint representations, this project seeks to develop a deeper understanding of how speaker characteristics and emotions can be effectively transformed. The second research target is to investigate voice conversion solutions for challenging conditions such as noisy environment, emotional speakers, and limited training to enhance the expressiveness and naturalness of the converted speech. The third research target is to investigate novel deep learning techniques for the detection of synthetic voices and joint training strategies to further improve voice conversion performance and evaluation. By exploring the synergies between transformation and detection of synthetic voices, this project has the potential to significantly impact society with a) accurate and expressive voice-based applications and b) applying the same techniques to detect when speech is naturally occurring or synthetic for the prevention of spoofing. 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 2025 · 2025-01

Project Summary: The direction-selective (DS) circuits in the retina detect the direction of motion in the visual field. Starburst Amacrine Cells (SACs) are specialized interneurons in DS circuits that respond to increases (ON) or decreases (OFF) in light and asymmetrically synapse onto direction-selective ganglion cells (DSGCs). Very little is known about the development and specification of SACs and their downstream connections with DSGCs and other SACs in the human retina. In this project, I will explore mechanisms of SAC fate specification and characterize the development of SAC connectivity in human retinal organoids. The mechanisms controlling when and how SACs develop in the human retina are poorly understood. In my preliminary studies, I found that SACs arise early during retinal organoid development. In Aim 1, I will establish a timeline of SAC birth using IHC, live imaging, and EdU birthdating in organoids. The transcription factor ISL1 is required for SAC specification in rodents8. To assess the role of ISL1 in human SAC generation, I will differentiate organoids from an ISL1∆ null mutant stem cell line9 and assess the density and timing of SAC generation. SACs are classified as ON or OFF subtypes based on their responses to light intensity, soma positions, and gene expression. In Aim 2, I will establish a timeline of SAC subtype generation in human fetal retinas and organoids using IHC, RNA FISH and live imaging. The transcription factor FEZF1 regulates ON SAC cell fate in mice. Preliminary data shows that FEZF1 is expressed in a subset of SACs in the human fetal retina. I will test the role of FEZF1 in the specification of ON SACs by generating and analyzing a FEZF1∆ null mutant stem cell line. SACs synapse onto other SACs and DSGCs in DS circuits. While the identification of SAC synaptic partners has not been established in humans, my preliminary data show that SACs form close associations with retinal ganglion cells. In Aim 3, I will differentiate organoids carrying a VACHT-Cre/tdTomato reporter and infect with a virus harboring a WGA-GFP monosynaptic tracer. In this method, the presynaptic SAC will express tdTomato and GFP, and the postsynaptic cell will express GFP only. To examine homotypic SAC-SAC connections, I will use a chimeric organoid strategy. Successful completion of this project will identify mechanisms of SAC specification and DS circuitry in the human retina, providing insights will inform the development of therapies to treat vision disorders.

NIH Research Projects · FY 2026 · 2025-01

Our LONG-TERM GOAL is to test patterned micro-stimulation of intermediate and higher-level visual cortex as a prosthetic strategy for restoring 3D object vision. We think that compositional (parts-based) coding of shape in the ventral visual pathway can be hijacked as an unusually efficient way to generate unlimited shape percepts with a practical number of stimulation sites. Moreover, targeting intermediate/higher-level neurons that explicitly encode 3D shape fragments may be the only way to evoke 3D shape percepts, which normally depend on subtle shading, specularity, texture flow, and stereoscopic cues that would be difficult or impossible to duplicate with the phosphenes produced by micro-stimulation of retina or V1. We will combine array recording, stimulation, and behavior in macaque monkeys, to test the HYPOTHESIS that micro-stimulation-generated activity in recently demonstrated V4 clusters tuned for specific 3D geometric fragments causes perception of those fragments. The causal role of specific part signals in ventral pathway has never been tested. We will use linear probes to measure local V4 multiunit activity at 32 sites during passive fixation. We will analyze tuning for part geometry and spatial position at these V4 sites with our previously published methods. We will then start a 4-alternative 3D shape matching task, in which, for some trials, correct perception of the sample stimulus can partly depend on stimulation of a V4 site that adds signal strength for the geometric part and spatial location that the V4 site encodes. Visibility of the sample stimulus at this location will be variably obscured by dynamic pixel noise. Preliminary behavioral data with no stimulation show that match choice accuracy is a roughly sigmoidal function of signal to noise ratio of the obscured object part, near chance up to ~20% signal and at maximum above ~80% signal. Our EXPECTED RESULT is that stimulation of the V4 site during sample presentation will bias behavioral choices toward stimuli with the encoded geometry at the encoded spatial location. The sensitivity of this approach in dorsal pathway motion studies argues that we will be able to detect even weak causal V4 influences. We also expect to demonstrate that micro-stimulation adds specifically 3D perceptual evidence, by showing the same choice bias when 3D information is needed to choose between stimuli with identical 2D shape. If we do not observe micro-stimulation effects in V4, we will perform experiments in inferotemporal cortex, where multi-part 2D and 3D tuning have been observed, and where micro-stimulation is known to produce observable effects, though not yet for complex, specific shape information. The SIGNIFICANCE of the expected results would be (a) The first causal test of perception produced by compositional, 3D parts-based shape coding, which would have a major impact in resolving the nature of object representation in the brain, and (b) Justification for further exploration of 3D parts-based prosthetic strategies in intermediate/higher-level visual cortex, which could impact clinical approaches to blindness.

NIH Research Projects · FY 2024 · 2025-01

PROJECT SUMMARY Background: In the United States transgender and gender diverse (TGD) communities experience a higher burden of mental health disorders compared to their cis-gender counterparts. Stigma has been shown to be a key factor in mental health disparities in the TGD population, though comparatively little is known about how stigma on the structural level, including laws, policies, social attitudes, and norms, affect the mental health of TGD individuals, especially among those living in rural areas. Given the recent increase in laws and policies that restrict or ban access to gender-affirming care and the NIMH's Strategic Plan Goal 2 highlighting the need for greater understanding of social and environmental risk factors for poor mental health, it is a critical moment to further understand this topic. Study Goals and Aims: The proposed study explores the formation of structural stigma and its relationship with mental health of TGD individuals living in the rural Untied States. Study aims include: 1) Analyze the formative process of state-level policies and laws pertaining to transgender healthcare in a subset of US states; 2) Explore the experiences of structural stigma and its effects on mental health among TGD adults living in the rural US; and 3) Assess relationship between state-level structural stigma and individual-level depressive symptoms. Approach: An explanatory, sequential mixed-methods design will use a combination of publicly available data and survey data from the Rural Engagement and Approaches for LGBTQ+ Mental health (REALM) study, an ongoing NIMH-funded R01 cohort study of LGBTQ+ adults living in the rural US led by scholars at Johns Hopkins University and Emory University. Aim 1 will include a content analysis of legislation to understand the rhetoric and scientific evidence used to support recent state-level laws and policies focused on transgender health. Aim 2 will collect primary qualitative data through repeated in-depth interviews with 25-35 TGD individuals to understand experiences of structural stigma and its effects on mental health. Aim 3 will use structural equation modeling to explore the relationship between state-level structural stigma and individual-level depressive symptoms. Triangulating findings from Aims 1-3 will bring a holistic understanding of the research topic and can be used to inform future mental health policy specifically for TGD individuals. Fellowship Information: The proposed research will serve as doctoral dissertation of Kirsten F. Siebach, PhD student at Johns Hopkins Bloomberg School of Public Health. The training and research will be supported by a tailored mentorship team who, combined, offer expertise in mental health, policy, and relevant methodological techniques. The training plan will prepare Kirsten to become a leading independent researcher in the relationship between the structural environment and mental health of LGBTQ+ populations.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Endothelia and epithelia throughout the body rely on macromolecular complexes known as tight junctions to modulate tissue barrier selectivity, proliferation, and polarity. Tight junctions are intercellular adhesion complexes that form strands around the apical side of cell-cell junctions. Tight junctions act as barriers that protect organs from pathogens while simultaneously allowing for the selective passage of nutrients, which establishes the chemical microenvironments of all tissue compartments. Thus, tight junction dysregulation is a hallmark of many human diseases. According to prevailing models, tight junctions assemble around oligomeric strands of claudin integral membrane proteins. The properties and stoichiometry of these strands are then augmented by the integral membrane protein occludin and the peripheral membrane protein ZO-1. To date, no direct observation of the interaction of tight junction subunits has been observed to support these models. This is a major gap in our understanding of how the chemical microenvironments in all tissue systems are established, and a roadblock in therapeutic intervention. In this proposal, using an approach integrating structural biology, cell biology, and physiology, we will uncover the structural determinants of tight junction function through elucidating the mechanisms of claudin oligomerization, claudin barrier function, and how tight junction subunits assemble with claudins to tune tight junction function.