Johns Hopkins University

NIH Research Projects · FY 2026 · 2024-01

Measles remains one of the most important causes of child mortality with recent increases in cases exacerbated by lapses in immunization during the COVID-19 pandemic. Measles virus (MeV) is a highly infectious non-segmented negative-strand RNA virus. Studies of measles in children and a well-characterized rhesus macaque model have shown that wild type (WT) MeV infection is initiated in the respiratory tract and spreads to lymphoid tissue with profound short and long-term effects on the immune system. Measles induces intense immune activation, increases susceptibility to other infections, decreases Ab to other pathogens, can trigger autoimmune encephalomyelitis, and induces life-long immunity to MeV. Although infectious virus is cleared during the rash-associated adaptive immune response, viral RNA persists in peripheral blood mononuclear cells (PBMCs) and lymphoid tissues for months with ongoing immune stimulation and continued production of MeV-specific antibody-secreting cells, antibody maturation and multiple waves of functionally distinct T cells. The live attenuated measles vaccine (LAMV) was developed by passage of WT MeV in chicken cells, licensed in 1963 and has been remarkably successful in controlling measles. Safety and availability of reverse genetics has led to development as a vaccine vector and oncolytic agent. However, there is little knowledge of where LAMV replicates, mechanism(s) of attenuation or how the immune responses induced differ from WT MeV for protective immunity or immunosuppression except to note that Ab titers are lower and protection less durable. We have shown that a central difference between infection with LAMV and WT MeV is replication in immune cells, that antiviral treatment accelerates RNA clearance and impairs antibody production. We hypothesize that persistent viral RNA is required for stimulation of durable immunity to MeV and that immune activation in response to infection affects pre-existing immunity. We will address these gaps in knowledge of LAMV biology through the following specific aims: (1) Identify the viral determinants of inefficient LAMV replication in immune cells through construction of recombinant LAMVs with WT sequences; (2) Identify the in vivo sites of LAMV replication and dynamics of RNA clearance compared to WT MeV through study of MeV replication in rhesus macaques; (3) Define the immune responses to infection with LAMV and WT MeV and effects of antiviral therapy in rhesus macaques; and (4) Determine the mechanism(s) by which WT MeV infection decreases Ab diversity in rhesus macaques and whether this occurs after infection with LAMV.

NIH Research Projects · FY 2025 · 2024-01

ABSTRACT Autophagy is an evolutionarily conserved cellular housekeeping system that mediates the removal of damaged or excess organelles and harmful protein aggregates. Selective autophagy targets specific substrates and is mediated mainly by autophagy receptors, which contain an LC3-interacting region and can therefore bind directly to the mammalian ATG8 (ATG8) family of proteins, including MAP1LC3A (LC3A), LC3B, LC3C, GABARAP, GABARAPL1, and GABARAPL2. Viral xenophagy (virophagy) is a form of selective autophagy targeting finally assembled virions or components thereof and is believed to be the first line of host defense against virus infection. While several different mechanisms of virophagy to some viruses have recently been proposed, it is largely unknown how antiviral selective autophagy is activated by infection by human gammaherpesviruses, including human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). HHV-8 is the etiological agent of at least three human malignancies, Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease in immunodeficient individuals with HIV-1 infection or those taking immunosuppressant drugs. Two infection stages of HHV-8 in the host, latency and lytic replication, are causally associated with HHV-8 pathogenesis. To comprehensively assess the functional involvement of selective autophagy in HHV-8 infection, we generated the cell lines of BCBL-1, an HHV-8-infected PEL cell, that are knocked out for each gene of ATG8 proteins. While any of the single gene knockout (KO) of the ATG8 family did not affect the growth of latently infected cells, a loss of LC3B, but not the other members, promoted productive virus replication, potentially through selective upregulation of the late lytic gene expression and suppression of type III interferon (IFN) expression. In addition, we found that intracellular viral DNA (vDNA) content and nuclear size significantly increased in lytic LC3B KO cells. LC3B overexpression significantly reduced the nuclear size of lytic cells, but this effect was reversed by autophagy inhibition. Moreover, the formation of nuclear blebs, indicative of nucleophagy, was reduced in lytic LC3B KO cells. Therefore, we hypothesize that LC3B may play a crucial role in the host antiviral response to lytic replication by mediating the nuclear export of nascent vDNA for autophagic degradation and type III IFN expression. To test this hypothesis, we will first custom-develop methods to detect nuclear exported (cytoplasmic and virion-free) vDNAs and identify the molecular mechanisms of LC3B-mediated nuclear export of vDNAs by performing mutagenesis and structure-activity relationship studies and examining the interaction between LC3B and Ku70. Secondly, we will assess the functional effects of the LC3B/Ku70-mediated vDNA export in reactivation-induced innate immune response and lytic replication. The proposed study should broaden our knowledge of autophagy-mediated antiviral mechanisms and provide a molecular basis for future studies of viral evasion from these mechanisms and their therapeutic targeting in HHV- 8 diseases.

NIH Research Projects · FY 2026 · 2024-01

Posttraumatic stress disorder (PTSD) is a common psychiatric condition that affects millions of people worldwide. Individuals with PTSD experience persistent fear and distressing memories of traumatic events that are often resistant to cognitive-behavioral treatments like exposure therapy. This loss in inhibitory control poses a major challenge to clinical interventions and may be driven in-part by hyperexcitability of the amygdala, a brain region known to store fear memories. Despite the known associations between activity in this brain region and fear regulation, there is a fundamental gap in our understanding of how dysfunction in amygdala circuits generates pathological fear, and an even larger gap in understanding how circuit-based findings in rodents translate to human disease. My long-term goal is to better understand how cellular and molecular function in neural circuits underlying fear regulation is affected by acute trauma, and to use this information to develop novel therapeutics targeting analogous circuits in humans. The overall objective of this proposal is three-fold: 1) establish, in mice, a causal role of amygdala inhibitory neurons that express the neuropeptide cortistatin (CST+) in fear extinction, 2) determine how this cell type is impacted by acute trauma, and 3) identify analogous cell types in the human amygdala. Based on our previous findings implicating CST+ neurons in PTSD, my central hypothesis is that traumatic events impair the cellular and molecular function of inhibitory CST+ neurons in the basolateral complex of the amygdala (BLA), which are critically involved in extinction learning (the psychological basis of exposure therapy), and that this ultimately results in unregulated, pathological fear in individuals with PTSD. The rationale for the proposed research is that, once causal links between CST+ neuron function and trauma-induced deficits are established in mice, identifying human analogs of CST+ neurons can facilitate development of novel therapeutics that specifically target these cells. The central hypothesis of this proposal will be tested by pursuing three specific aims: 1) determine if BLA CST+ neurons play a causal role in fear extinction in mice by suppressing the activity of fear-encoding BLA neurons, 2) investigate how trauma that impairs extinction learning also impacts the molecular and cellular function of BLA neurons, including CST+ neurons, and 3) map trauma-impacted BLA cell types from the mouse to the human brain using next-generation sequencing coupled with advanced computational approaches. This approach is innovative because it proposes to causally link trauma-induced deficits in fear suppression to a novel, disease-associated cell type while also identifying and mapping trauma-susceptible cell types in the human brain with high resolution, which has not been done before. The proposed research is significant because the results are expected to advance our understanding of the neural circuitry underlying fear suppression, as well as provide potential avenues for cell type-specific therapeutic targeting for treatment of fear- and anxiety-based disorders. It is likely that selective targeting of neuronal cell types will prove efficacious in reducing symptomology and improving the quality of life for individuals living with these disorders.

NIH Research Projects · FY 2026 · 2024-01

Project Summary It is well-established that premenopausal females have blood pressure that is ~10mmHg lower than that of males. We previously reported that an evolutionarily conserved olfactory receptor, OLFR558, is expressed in the kidney; we have now uncovered that OLFR558 is required for sex differences in blood pressure. OLFR558 localizes to renin-containing juxtaglomerular cells in the kidney, and to vascular smooth muscle cells. KO females exhibit increased blood pressure (and increased pulse wave velocity), whereas KO males exhibit decreased blood pressure (and decreased renal expression of renin, and, decreased plasma renin activity). As a result, blood pressure is similar in KO males and females. Our understanding of OLFR558’s role is currently hindered by our poor understanding of OLFR558 ligands. The central Aim of this proposal is to advance our understanding of OLFR558 ligands in order to better develop our understanding of OLFR558 physiology. In Aim 1, we will work to better understand putative endogenous ligands of OLFR558. To date, we have identified 18 ligands which activate OLFR558 in vitro; however, it is unclear how many of these ligands circulate at levels that activate OLFR558 in vivo (Aim 1a). Of note, several of these ligands modulate additional pathways; thus, we will measure blood pressure responses to each ligand in both OLFR558 WT and KO mice to define the OLFR558-mediated response (Aim 1b). Several of the best ligands for OLFR558 are produced by microbiota; in Aim 2 we will determine if the commensal microbiome influences OLFR558 signaling. Finally, in Aim 3, we will leverage our recent success in discovering novel synthetic OLFR558 agonists with high potency and selectivity, as well as a novel OLFR558 antagonist. These novel probes will be used as research tools to selectively manipulate OLFR558 activity in vivo; at the same time, this Aim will explore the therapeutic potential of these novel ligands.

NIH Research Projects · FY 2026 · 2024-01

Hepatocellular carcinoma (HCC) is the most common primary liver cancer that represents the second most common cause of cancer-related death worldwide. In addition, the liver the most common site for metastatic cancer. Transarterial chemo- or radio-embolization (TACE/TARE) for unresectable HCC exploits the hepatic tumors’ blood supply via the hepatic artery to selectively deliver the embolic agents and therapeutics into targeted region of the liver. However, these treatments are largely palliative and direct visualization of the delivery after contrast washout is not possible. Thus, new theranostic modalities are urgently needed. Alpha- emitting radiopharmaceutical therapy (αRPT) is emerging as a highly potent treatment that effectively targets single cells, minimal residual disease, and micrometastatic lesions to eradicate cancer cells that exhibit resistance to conventional treatment. To address diffusion-limited penetration depths of αRPT that may result in partial tumor irradiation, we propose to develop a dual modality imaging-visible, exosome-mediated radiotheranostic platform for an alpha emitter delivery. In Specific Aim 1, we will evaluate the imaging visibility and targeting ability of radiolabeled exosomes in cell monolayers and 3D vascularized spheroids. A selected αRPT formulation will be tested in ectopic and orthotopic HCC mouse models (Aim 2), allowing us to evaluate its biodistribution, efficacy and safety via intratumoral and intraarterial delivery. The proposed study brings a unique combination of expertise in radiosynthesis, dosimetry, medical imaging, and animal model of cancers, to address the critical challenges for effective HCC treatment. Successful completion of the proposed activities will have vast ramifications for advancing the development of exosome-mediated αRPT for treating HCC or other cancers.

NIH Research Projects · FY 2026 · 2024-01

Michael Fang, PhD, MHS is an Assistant Professor in the Department of Epidemiology at Johns Hopkins Bloomberg School of Public Health. He seeks a K01 Mentored Research Scientist Development Award in order to obtain essential skills and mentored research experience for an independent career as a scientist in the field of diabetes epidemiology. The research proposal details a five-year plan to characterize the epidemiology of type 1 diabetes in children and adults in the US. Using a large administrative claims database, the specific aims of the research agenda are to: 1) Describe trends and sociodemographic disparities in the use of diabetes technologies; 2) Quantify changes in the attainment of glycemic control and rates of morbidity and mortality, overall and across subgroups; and 3) Develop a new simulation model of type 1 diabetes progression to characterize disparities in life expectancy and lifetime risk of complications. Findings from the proposed research will identify the most pressing health problems affecting persons with type 1 diabetes, identify critical gaps in care, and inform efforts to reduce health disparities in the population. As part of his mentored career development, Dr. Fang will receive in-depth training in risk prediction, simulation methods, and translational research under the mentorship of Dr. Elizabeth Selvin, PhD, MPH, and Dr. Jung-Im Shin, MD, PhD. Dr. Fang’s immediate career goals include developing expertise in analyzing “big” electronic health records data using a broad range of analytic approaches, including risk prediction, simulation modeling, and health informatics methods; generating rigorous evidence that can inform type 1 diabetes management and health policy; and fostering local, national, and international collaborations with researchers in similar and complementary areas of research/expertise. Long-term, Dr. Fang aims to establish a research program to characterize the global epidemiology of type 1 diabetes, with the goal of informing clinical recommendations and health policies for type 1 diabetes management worldwide.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY (30 lines max) Incarceration, which disproportionately impacts minoritized and socioeconomically disadvantaged groups, is a salient form of structural inequality that impedes individuals’ sexual and reproductive health (SRH) and autonomy. Most research in this area, which focuses almost entirely on females, finds that women involved in the criminal justice system have minimal access to SRH services, experience high rates of unplanned and undesired pregnancies, and are more likely to underutilize contraception to help meet their reproductive goals. However, we know almost nothing about the SRH needs and care of young men (aged 15-29) involved in the criminal justice system, despite this group being identified as a “high-priority target population” among SRH experts for at least the past two decades. Instead, the few studies related to justice-impacted men’s SRH have taken a harm reduction approach (e.g., an exclusive focus on sexual risk reduction) that overlooks other facets of men’s reproductive lives. This proposed R21 breaks new ground by focusing on young males’ reproductive attitudes, behaviors, and SRH needs prior to the birth of children, in order to identify upstream social determinants for intervention that contribute to the cycle of disadvantage faced by justice-impacted individuals, their partners, and their families. Informed by the socio-ecological framework of young men’s SRH care, the proposed study will examine formerly incarcerated young men’s SRH attitudes and behaviors, as well as their experiences with, and barriers and facilitators to, accessing SRH education and care. In Aim 1, we will employ secondary, population-based data from the National Survey of Family Growth (NSFG) for the years 2011-2019 to compare SRH outcomes between eligible participants with and without incarceration histories. We will focus on outcomes including risk for unintended pregnancy, need for family planning, and SRH education exposure and care use. In Aim 2, we will conduct semi-structured interviews with recently incarcerated young men (ages 15-29, incarcerated in the past 12 months) who have yet to father children. We will recruit a diverse sample across three regions: the Mid-Atlantic [Maryland], the Midwest [Minnesota], and the Southwest [Texas]. In Aim 3, we will conduct key informant interviews with national and regional justice, medical, and public health experts to elicit their perspectives and experiences pertaining to formerly incarcerated young men’s SRH education and care. We will identify potential intervention approaches using a consensus building methodology. Critically, we will organize a Justice-Impacted Youth Advisory Board for this study to integrate the input of youths with lived experience into all stages of the research. Study findings will inform the development of regionally focused interventions to support the SRH goals, education, and care of formerly incarcerated young men, and will provide critical preliminary data to develop a national agenda for further research centering this neglected and understudied group.

NIH Research Projects · FY 2026 · 2024-01

Project Summary Cardiovascular disease (CVD) remains the leading cause of mortality in women, with approximately one woman dying per minute in the US. Women living with HIV (WLHIV) are a particularly high-risk group of women with high CVD prevalence who have long been understudied in clinical research. As compared with uninfected women, WLHIV have a 2 to 4-fold increased CVD risk that persists later life and which is on par with men living with HIV. Additional research on sex-specific mechanisms of HIV-associated CVD will better inform the development of CVD prevention and treatment approaches clinically relevant to over 16 million women with HIV globally. Current CVD treatment approaches for PWH are lacking and have focused on applying cardiology guidelines from the general non-HIV population to PWH, however traditional risk assessments tend to underestimate CVD risk, possibly due to higher levels of chronic inflammation recognized in PWH, and pronounced in WLHIV. Initial work performed in the Hays lab demonstrated that nitric-oxide mediated coronary endothelial dysfunction, which contributes to atherosclerosis and predicts adverse cardiovascular events, is present at early ages in women and men with HIV compared to age-matched control participants without HIV. During the course of our initial work, we identified emerging risk markers in women and men with HIV such as abnormal fat distribution and associated inflammation, lipoprotein metabolism, and early menopause (in women) which may contribute to early impaired CEF. However, these early studies were cross-sectional in nature, and it is unclear how these important risk markers influence vascular health over time in women compared to men with HIV. The goal of the Hays lab over the next few years will be to: 1) better understand contributors and sex- specific pathways that underlie progression of heart disease in PWH with a focus on the role of ectopic fat deposition on long term vascular endothelial health 2) to evaluate and test novel risk markers (both targeted and untargeted markers using proteomics) for sex-specific CVD risk in PWH and 3) identify potential treatment targets that may be rapidly translated and tested in clinical trials in PWH. For the first two goals, we propose a longitudinal study with equal numbers of men and women with HIV across the lifespan to test the hypothesis that a hyperinflammatory milieu characterized by abnormal fat distribution, increased systemic inflammation and abnormal lipoprotein levels result in worsening CEF over time in PWH. The identification of important biologic drivers of increased CV risk in PWH is critical to define new therapeutic approaches. We will also study glucagon-like peptide-1 receptor agonists (GLP-1RA) that may reduce ectopic fat and slow the progression of CVD in PWH. My research program will address significant knowledge gaps regarding sex-specific factors that affect vascular health in PWH and provide data to design future interventional studies to improve health outcomes in PWH and cardiometabolic disorders.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT This mentored career development award proposal will facilitate my career goal to become an independent translational researcher using advances in experimental genomics and bioinformatics to develop improved precision medicine therapies for children with difficult-to-cure cancers. During the 5-year training period I plan to acquire critical skills in computational biology and pursue additional didactic training in transcriptional regulation, death pathways, single cell analyses, and early-phase clinical trial design. The proposed studies and training will be completed under the co-mentorship of Dr. Kai Tan and Dr. Sarah Tasian, both internationally recognized leaders with complementary expertise in systems and single cell biology and in translational leukemia research, respectively. My multi-disciplinary Advisory Committee is composed of world-renowned scientists who have extensive mentoring experience and diverse expertise, including Drs. Chi Dang, Nancy Speck, John Maris, and Xiaolu Yang. The scientific proposal is aimed at elucidating critical dependencies that synergize with kinase pathway oncogene addiction in Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL), a kinase-driven leukemia with dismal outcomes. Ph-like ALL comprises 15-40% of childhood and adult ALL cases and is associated with extremely high relapse rates and very poor overall survival. We observed in preclinical Ph-like ALL models that treatment with the JAK inhibitor ruxolitinib has incomplete efficacy and also resulted in global gene expression changes. Thus, combination therapy approaches that effectively target key therapeutic escape mechanisms are needed. Additionally, single-cell variability in Ph-like ALL that may drive targeted therapy resistance is unknown. I hypothesize that ruxolitinib treatment in JAK/STAT pathway-altered Ph-like ALL cells leads to rewiring of the gene regulatory network at transcriptional and epigenetic levels (likely mediated by c-MYC), resulting in cell cycle arrest and apoptotic priming amenable to co-targeting. I propose in Aim 1 to model patient leukemia reponse to kinase inhibition in vivo and to identify transcriptional regulatory network changes during chronic ruxolitinib treatment with subsequent functional validation. This represents an unbiased approach to identifying unknown oncogenic dependencies. In Aim 2, I will use single-cell techniques to examine genetic and non-genetic sub-populational changes during targeted drug perturbation over time, then to characterize and target resistant cell states. These studies will form the basis for developing rational combinations of molecularly targeted therapies to improve cure rates for patients with Ph-like ALL. In summary, I will benefit from the exceptional interdisciplinary expertise and track-record of my mentors and Advisory Committee, as well as the rich intellectual environment and scientific resources available at CHOP and Penn, which provide an ideal setting in which to conduct cutting-edge omics analyses for eventual clinical translation. These research and training efforts will help me realize my ultimate goal to translate “big data” into clinically relevant cures for children with cancer.

NIH Research Projects · FY 2025 · 2024-01

Project Summary/Abstract Cancer is the second leading cause of death in the United States where delays in diagnosis and treatment lead to increased mortality and advanced-stage disease. Developing artificial intelligence (AI) and deep learning (DL) approaches for the automatic characterization of malignant disease can facilitate the early detection, diagnosis, prognosis, and treatment of cancer. Radiomics and DL approaches extract quantitative information and visual features from radiological data to glean insights into a patient’s disease. Traditional radiomics approaches suffer from reproducibility issues due to small dataset sizes and differences in imaging scanners, reconstruction methods, and operator variability in regions of interest segmentation. DL methods require training on large datasets with annotated ground truth, which is difficult to obtain due to the limited availability of physician-defined annotations and histopathological ground truth. Radiomics and DL methods are often trained on datasets that encompass a specific malignancy, which additionally limits their generalizability and overall utility. Nuclear medicine imaging modalities provide important functional information regarding radiotracer uptake in benign and malignant pathologies that can help inform diagnosis and treatment. There is a significant unmet need to develop research and clinical tools that address the challenges of enabling large-scale AI-based pipelines in nuclear medicine. Aim 1 will build a large database of clinical positron emission tomography (PET)/computed tomography (CT) images with physician-annotated ground truth. Aim 2 will develop a physics-guided deep generative modeling approach to generate realistic simulated PET/CT data with known ground truth. Aim 3 will quantify the robustness of radiomic features using both simulated and clinical PET/CT data. Aim 4 will develop and validate a simulation-based transfer learning approach on automated lesion detection, segmentation, and classification tasks. Aim 5 will develop and validate a multipronged approach that combines robust radiomics, DL, and ensemble meta-learning to predict clinical outcomes from PET/CT images of patients with cancer. In the K99 training phase of this grant, Dr. Kevin H. Leung will conduct the proposed research under the guidance of Dr. Martin G. Pomper with the support of outstanding advisory committee members with extensive expertise in radiology, oncology, PET, CT, and medical imaging physics. The major objective of the mentored research phase is to create a large clinical PET/CT database encompassing a wide range of cancers and to develop a physics- guided approach to generate realistic simulated PET/CT data that reflect clinical population-level characteristics. The technology developed from the K99 phase will be expanded in the independent R00 phase into a generalized platform that will enable large-scale AI in nuclear medicine for a wide range of medical image analysis tasks. The rich resources and strong collaborations available at Johns Hopkins provide an ideal training environment that is completely supportive of the proposed research and the academic advancement of Dr. Leung.

NIH Research Projects · FY 2025 · 2024-01

NIH Research Projects · FY 2026 · 2024-01

The order Rickettsiales includes arthropod-associated, obligate intracellular bacteria that cause diseases in humans ranging from relatively mild to potentially fatal. A mechanistic understanding of growth and pathogenesis of rickettsial pathogens would potentiate therapeutic strategies to control rickettsial disease. However, because of their obligate intracellular lifestyle and consequent challenges in culturing and genetically manipulating these species, our understanding of fundamental aspects of rickettsial biology is limited. Within the Rickettsia genus, the Spotted Fever Group (SFG) includes tick-borne human pathogens that cause diseases ranging from mild to life-threatening. Among the SFG bacteria, R. parkeri causes a relatively mild disease and presents a tractable model for probing the biology of this group. In the past, research leveraging a relatively small collection of transposon mutants of R. parkeri has yielded important insights into Rickettsia pathogenesis and host interactions. Here, we propose to expand the genetic toolkit available to study R. parkeri, generating a large-scale transposon mutant library of R. parkeri in the R61 phase of this project and using it to gain mechanistic insights into rickettsial growth and division in the R33 phase. In Aim 1, we will develop and validate plasmid constructs for (1) generating transposon mutants of R. parkeri with desired characteristics and (2) expressing genes of interest with and without tags in R. parkeri. In Aim 2, we will generate, map, and organize a library of ~2000 transposon mutants of R. parkeri. In the R33 phase, we will perform global analysis of growth kinetics and cell morphology of all mutants in the transposon library in Aim 3. In Aim 4, we will leverage insights from morphology screening to identify and characterize candidate factors that are important for peptidoglycan cell wall hydrolysis during R. parkeri cell division. Completion of this project will generate important genetic resources for the study of all aspects of R. parkeri biology and will provide foundational knowledge about growth and cell division in an important tick-borne, obligate intracellular pathogen that may aid in the design of new antibacterial therapeutic approaches.

NIH Research Projects · FY 2025 · 2024-01

Johns Hopkins University proposes to create PERLHS: Promoting Embedded Research in a Learning Health System. We aim to prepare embedded investigators to apply rigorous methods to generate and disseminate actionable knowledge. In this proposal, we describe our plans to train investigators in comparative effectiveness research and patient-centered outcomes research (CER/PCOR) in service to a learning health system (LHS). We will expressly engage three distinct populations of embedded researchers for training: clinical investigators embedded within the precision-medicine initiatives of Johns Hopkins, investigators embedded within the operational functions of the Johns Hopkins Health System, and investigators embedded in entities working to advance population health across Maryland. Training these diverse investigators gives us the opportunity to extend the impact of PERLHS outside of the academic institution to other settings that will beneϐit from having trained embedded researchers. Our training model will focus on building these researchers’ CER/PCOR skills by engaging them in a longitudinal training program modeled after the Leadership Academy of the Armstrong Institute for Patient Safety and Quality at Johns Hopkins. Our training program will be an 11-month experience for the scholars during which time they will engage in asynchronous didactic learning, participate in monthly small-group workshops as a cohort of scholars, and complete a project to fulϐill a need of their sponsoring entity closely supervised by a PERLHS mentor who will assist with design, analysis, and access to resources. We will develop an Administrative Core, a Research Education Core, and a Research Data and Analysis Core to meet the learning needs of the 10 scholars plus one post-doctoral fellow that we will enroll annually. We will evaluate the individual scholars and conduct a formative program evaluation annually with the help of our diverse advisory board. We will work towards a sustainable program by the end of the award where the teaching and mentoring is supported by tuition remission dollars for our faculty and staff, and scholarship funds for our external learners.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY Cisgender Black women in the United States (US) shoulder a significant burden of HIV and sexually transmitted infections (STIs), with persistent disparities driven by stigma, implicit bias, and structural barriers. The disproportionate impact of HIV/STIs among Black women in the US underscores a stark race disparity that requires urgent action to address social and structural determinants of health (SSDHs). Maryland, a priority state for the Ending the HIV Epidemic (EHE) initiative, has struggled to mitigate these disparities despite significant prevention efforts. HIV prevention efforts in the United States have often been siloed and focused on individual behavior modification, leaving significant gaps in addressing the complex interplay between individual, structural, and social determinants of health that contribute to the disproportionate burden of HIV and STIs among Black women. This R36 dissertation proposal seeks to bridge this gap by conducting a convergent mixed-methods study to gain a comprehensive understanding of how existing SRH services can be adapted or expanded to better address the prevention needs of Black women at risk for HIV in Maryland. By examining the current availability, accessibility, and acceptability of SRH services for this population, this study aims to identify gaps in service provision and explore the personal experiences and perspectives of Black women who have accessed or attempted to access SRH services. The findings from this research will inform the development of evidence- based recommendations for adapting or expanding existing SRH services to integrate HIV testing and prevention strategies into broader SRH services, for an improved prevention approach that appeals to vulnerable populations and accounts for social, structural, interpersonal, and individual factors. This study aligns with EHE efforts and the National Institute of Mental Health (NIMH) Division of AIDS Research (DAR) priorities, as it aims to inform the development targeted interventions for Black women at risk for HIV in Maryland. By employing a scientifically rigorous, theory-based approach, the findings will contribute to the development of interventions that contribute to both proximal and long-term distal outcomes for HIV prevention.

NIH Research Projects · FY 2026 · 2024-01

Retinopathy of prematurity (ROP) is the leading cause of blindness in the U.S. and other developed countries in the pediatric population. A pivotal aspect of early ROP is retinal avascularity, which leads to advanced stages of ROP and pathologic retinal NV. Deficiency in vascularization of ischemic tissue is a major challenge in this disease condition. Current treatments for ROP are largely focused on later stages of disease characterized by pathologic pre-retinal neovascularization. These treatments are associated with significant side effects and do not address the retinal avascularity, which has an impact on the patient’s ultimate visual function. There is great need for early treatment, directed toward the promotion of “physiologic” retinal vascularization (i.e., vascularization of the avascular/ischemic retina), which would relieve retinal hypoxia, leading to resolution of pathologic neovascularization and optimizing visual function. Although revascularization of ischemic retina (reparative angiogenesis) is a highly desirable objective in ROP, accomplishing this objective has posed a significant challenge. In this respect, there is a great need for better understanding of the cellular mechanisms regulating reparative angiogenesis, as well as for treatment strategies. It has been especially elusive why endothelial cells fail to vascularize the ischemic retina and instead grows into the preretinal space. In order to fully realize the goal of promoting reparative angiogenesis, it is critical to better understand how to promote endothelial cells toward revascularizing the ischemic retina, especially in identifying important angiogenic regulators. We have identified a novel molecular mechanism regulating the angiogenic phenotype of retinal endothelial cells. This project will examine the functional role of this angiogenic regulator in endothelial cell activity and dissect mechanisms of its angiogenic regulation. This project could thereby lead to insights into a new target for treatment and develop therapeutic strategies for revascularization that could be beneficial for ROP and other ischemic retinal diseases.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT Candidate’s Long-Term Career Goal: By pursuing the training plan in this F32 proposal, Dr. James W. Womer will learn key skills in clinical epidemiology and health services research, while writing a K23 award and ultimately becoming an independent physician-scientist designing predictive tools and interventions to help identify and assist patients at risk for impaired recovery from respiratory illness. Clinical Problem to be Addressed: Financial toxicity affects patients suffering from a variety of acute and chronic conditions, and is associated with worse clinical outcomes. The prevalence and risks associated with financial toxicity in pneumonia are not known but are likely significant. Candidate Background: Dr. Womer is a fellow in Pulmonary and Critical Care Medicine at Johns Hopkins. He received his MD from Temple University. To date he has published 8 original peer-reviewed manuscripts, one as first author. He will be presenting his current work at the American Thoracic Society 2023 meeting. His department has a strong commitment to his academic career, including placing him on a T32 grant and funding a year-long training program in clinical investigation. Career Development Plan: In order to achieve these goals, he proposes to develop expertise in statistics through a combination of mentored learning, investigative research work, and formal coursework to obtain a Master of Health Science (MHS) degree from the Johns Hopkins Bloomberg School of Public Health. Mentors: His primary mentor is Dr. Theodore J. Iwashyna at the Johns Hopkins School of Medicine, who has served as the primary mentor on 8 K-awards (5 of whom have transitioned to R01), including 5 individual K awards, and as co-mentor on another 5. His co-mentor is Dr. Michelle Eakin, who has several NIH grants and won awards for her mentorship of many fellows and junior faculty. Aims: Using data from the Medical Expenditure Panel Survey, 1: to test whether new onset financial toxicity due to pneumonia is associated with increased subsequent need for acute care; 2: to test whether new onset financial toxicity due to pneumonia increases the risk of later disability. Deliverables from Aims: His proposed Aims will lead to 3-4 publications with semiannual presentations at institutional conferences and yearly presentations at national conferences. This proposal will constitute the foundational work for a future K23 application to build a predictive model of which patients will suffer financial toxicity and test the efficacy of possible interventions.

NIH Research Projects · FY 2025 · 2023-12

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease caused by mutations in the PKD1 or PKD2 genes. Many patients often lose kidney function due to limited therapies to delay disease progression. The kidney is a highly metabolically active organ that relies on specialized tubular epithelial cells to reabsorb most of the filtered water and solutes in the body. Normal kidney tubules are highly enriched in mitochondria and preferentially use fatty acid oxidation (FAO), which generates more adenosine triphosphate (ATP) than glucose metabolism. However, one hallmark of metabolic derangement in ADPKD is decreased fatty acid oxidation (FAO) and increased aerobic glycolysis (Warburg effect). This metabolic derangement supports the growth of cysts that eventually lead to renal failure. We propose to study: 1) the role of enhancing FAO in delaying progression of ADPKD, 2) the role of ketogenic diet, FGF21 signaling and ketone body oxidation in ADPKD. Although dietary restrictions, such as time-restricted feeding or the condition of ketosis have been shown to ameliorate renal cyst progression in animal models of PKD1 mutation, the detail molecular mechanisms are not fully elucidated. The clinical application of long-term dietary intervention is challenging because of non-compliance and high dropout rates. There is, therefore, a critical need to determine the roles of metabolic reprogramming and the molecular mechanisms underlying beneficial effects of dietary intervention, such as a ketogenic diet. We propose to investigate the effect of 5 genetic mouse models of enhanced FAO, decreased FGF21 signaling or impaired ketone body oxidation in the kidney-tubule specific PKD1 deletion mouse model of ADPKD. The metabolic status will be elucidated using metabolic flux analysis, metabolomics and targeted proteomics of metabolic proteins. In addition to mouse experiments, mechanistic studies will be performed using human cell line with PKD1 mutation. Finally, human induced pluripotent stem cell derived kidney organoids from ADPKD patients will be applied to confirm the results observed in mouse models and PKD1 cell line. Upon completion of the proposed research, the expected outcomes are an understanding of the role of metabolic reprogramming and FGF21 and the mechanisms underlying the beneficial effects of ketosis in ADPKD progression. These findings are expected to have an important impact by contributing to a conceptual framework that will subsequently drive development of novel dietary interventions or supplements for ADPKD patients, facilitated by the use of iPS- derived kidney organoids generated from ADPKD patients.

NIH Research Projects · FY 2026 · 2023-12

Project Summary / Abstract Alzheimer’s Disease (AD) and related dementias (ADRDs) are the leading causes of dementia and afflict millions of people every year, and projected cases are expected to rise exponentially due to the aging population. Clarification of disease mechanisms and target identification are critical unmet needs in the field. While the canonical amyloid-beta (Aß) and tau pathologies are implicated in AD cases, recent evidence revealed that non- canonical pathologies, including TDP-43 pathology, occur in the majority of cases. TDP-43 pathology is observed in up to 40% of all AD cases and about 50% of frontotemporal dementia (FTD) cases. Importantly, AD cases with TDP-43 pathology, compared to those without, exhibit steeper cognitive decline and more extensive brain atrophy. The underlying molecular mechanism of TDP-43 that drives neurodegeneration and cognitive impairments, however, remains elusive. Previous work in our lab, as well as other human studies, showed that loss of TDP-43 nuclear function, as opposed to its cytoplasmic aggregation, as a splicing repressor of cryptic exons underlies its pathology. To elucidate the molecular mechanisms by which loss of TDP-43 contributes to neuron loss, it is necessary to develop models of mixed etiology dementias (MEDs), which exhibit Aß and tau pathologies in combination with TDP-43 pathology, to mimic the human pathological context. Our lab previously showed that, in the presence of Aß plaque, expression of a human tau four-repeat fragment (Tau4R) can seed pathological conversion of endogenous tau, but additional risk factors are required to drive tauopathy. Due to the requirement of additional factors to promote tauopathy and our finding that loss of TDP-43 leads to worsened neurodegeneration, we hypothesize that loss of TDP-43 exacerbates tauopathy-driven neuron loss. Aim 1 will focus on characterizing an FTD and corticobasal degeneration (CBD)-like mouse model involving intraparenchymal injection of AAV.PhP.eB encoding Tau4R or Tau4R with an aggregation prone mutation in the hippocampus of mice conditionally lacking TDP-43 in forebrain neurons. I will use this same AAV-mediated approach in Aim 2 to characterize a model of AD with TDP-43 pathology, which involves Aß, tau, and TDP-43 pathologies. Both of these aims will involve evaluating the extent of tauopathy and neuron loss, examining microglia signatures, and correlating my findings in human tissue. Successful completion of the proposed research will help elucidate causal mechanisms of neurodegeneration and identify novel therapeutic targets for AD/ADRDs. Additionally, this project has immense training potential as I will gain new expertise across multiple techniques including biochemical tau protein extraction, Gallyus silver staining, single-cell RNA-Sequencing, bioinformatics and analysis of post-mortem human tissue. This research will be performed in a highly collaborative environment, where I will have numerous opportunities to receive quality mentorship and training, to develop my written and presentation skills, and to grow as a mentor to junior scientists.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Host status plays a major role in tuberculosis (TB) disease outcomes, with many efforts to develop host-directed therapies to boost immune response. It is unknown how these strategies will perform in people living with HIV/AIDS (PLWHA) who are at increased risk of adverse TB treatment outcomes. Persistent Mycobacterium tuberculosis (Mtb), which obligates prolonged TB treatment, highly expresses the stringent response protein RelMtb. One attractive host-directed therapeutic strategy is boosting RelMtb-specific cellular responses. We developed a novel therapeutic DNA TB vaccine that promotes immune responses to RelMtb, which are further enhanced by fusion with a chemokine gene, Macrophage Inflammatory Protein-3 alpha (MIP-3α), that targets relMtb to immature dendritic cells (DCs). Our data show that an intranasal (IN) or intramuscular (IM) DNA vaccine expressing MIP-3α/relMtb (“fusion” vaccine) demonstrated greater adjunctive therapeutic efficacy when combined with the first-line TB treatment in Mtb-infected mice as compared to IM vaccination with relMtb alone (“non-fusion” vaccine). This proposal will dissect the mechanisms of this novel therapeutic strategy, specifically with IN administration which had the highest efficacy. We will also test whether this strategy is likely to perform in PLWHA, analyzing whether RelMtb-specific immune responses in PLWHA can predict therapeutic TB outcomes. Aim 1 will investigate the molecular mechanism by which the IN administration potentiates anti-TB drugs, while Aim 2 will focus on the role of DCs in the adjunctive therapeutic efficacy of the fusion vaccination strategy. Aim 3 will test the translational potential of the RelMtb-specific T-cell immunity in PLWHA. In Aim 1, we test if IN vaccine administration enhances the host response to Mtb infection through increased IL-17A secretion. We will perform single-cell transcriptomics on cells from murine lungs to confirm the upregulation of IL-17A response pathways in the IN arm, followed by Mtb-infected IL-17A knockout murine experiments. In Aim 2, we hypothesize that the IN fusion vaccine leads to more efficient systemic and local T-cell maturation, activation, and differentiation through enhanced DC activation compared to the IN non-fusion vaccine. Aim 2a will assess differences in DC activation by flow cytometry, DC and T-cell co-localization in murine tissues, and differences in T-cell activation/differentiation using co-culture experiments with DCs derived from each vaccination group. In Aim 2b, we will adoptively transfer DCs from mice immunized with either vaccine into Mtb-infected mice concurrently with TB treatment to compare the adjunctive therapeutic efficacy. In Aim 3, we hypothesize that RelMtb-specific Th1/Th17 cell responses in peripheral blood mononuclear cells derived from HIV-infected and uninfected patients receiving treatment for pulmonary TB, correlate inversely with sputum culture conversion and TB recurrence rates, independently of HIV status. The proposed studies will uncover critical details of the mechanism of a novel therapeutic vaccination approach against TB with important implications in PLWHA and help the PI to gain significant expertise in TB/HIV immunology.

NIH Research Projects · FY 2026 · 2023-12

Project Summary Understanding how the brain stores and accesses information is one of the fundamental goals of neuroscience. This question has been addressed across many scales, spanning detailed genetic analyses of expression patterns of key molecules supporting neuronal communication to functional recordings of intact brains in behaving animals. Over the past 50 years, synaptic plasticity has emerged as a leading cellular pathway underlying learning and memory. During synaptic plasticity, dynamic regulation of AMPA-type glutamate receptors (AMPARs) bidirectionally tunes synaptic strength, leading to long-lasting changes in the efficacy of chemical communication between neurons. Synaptic plasticity is active in nearly every region of the brain and plays a role in diverse processes, from innate fear behaviors to high-level cognition and memory. Despite the prevalence and importance of synaptic plasticity, we still lack basic knowledge regarding how information is distributed in synapses across the brain during learning and behavior, and even less regarding which specific synaptic changes are necessary for long-term memory, mainly due to technical difficulties arising from the immensely complex nature of synaptic networks. Here, we present a suite of novel methodologies that breaks through these barriers. Our approach leverages transgenic labeling of endogenous synaptic proteins and in vivo two-photon microscopy to enable visualization of synaptic plasticity in real time in behaving mice. Using deep network learning, we will develop algorithms to automatically detect and track how the strength of millions of individual synapses changes during learning. This will enable exploration of circuit-specific learning mechanisms within discrete cell types and specific presynaptic inputs. Ultimately, this pioneering approach has the potential to provide an unprecedented view of synapses in behaving animals, enabling new discoveries regarding how dynamic regulation of synaptic strength encodes learning and memory.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract: Small-vessel-related vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of cognitive dysfunction in older individuals. However, quantitative measures indexing key vascular processes related to VCID that are suitable for use as diagnostic biomarkers or endpoints in clinical trials are still lacking. In particular, biomarkers are playing an increasingly important role in biological/etiological classification of patients with Alzheimer’s Disease and Related Dementias (ADRD), following the development of the “A/T/N” classification system. However, the current “A/T/N” scheme is only applicable to dementia of AD type. Therefore, the development of a biomarker to extend the “A/T/N” classification scheme to “A/T/N/V” is of potentially high impact. Cerebral physiological parameters can report key process leading to the pathological cascade in the brain and usually occur early in disease. Drugs that can alter physiological process such as perfusion are also readily available. Therefore, a physiology-based biomarker in VCID will have a major impact on the diagnosis and treatment selection/monitoring of patients with vascular cognitive impairment, vascular dementia, or mixed dementia which are common in ADRD. The PI’s lab recently pioneered a non-invasive MRI technique to measure the oxygen extraction fraction (OEF) of the brain, a parameter indexing the balance between oxygen supply and consumption, with a scan time of merely one and a half minutes. Our preliminary studies provided strong evidence that elevated OEF is a physiological hallmark of VCID and tracks the progression of vascular risks and the growth in white-matter-hyperintensity (WMH) volume. Therefore, the central hypothesis of this project is that OEF is a sensitive and practical marker in classifying “V” in the A/T/N/V system. This project has three Aims. Aim 1 will examine the cross-sectional relationship of OEF with vascular abnormalities on MRI, cognitive function, and clinical diagnosis in a VCID-enriched cohort. Our novel cohort will consist of impaired patients (subjective cognitive decline, MCI, and mild dementia) with MRI-confirmed small vessel abnormalities such as WMH, microbleeds, or lacunar infarcts. Aim 2 will be a longitudinal study (30-month follow-up) of these participants. Changes in OEF will be studied along with their relationship with changes in cognitive function and vascular abnormalities. Baseline OEF will also be investigated to examine if it can predict changes in clinical and cognitive scores. Aim 3 will operationalize the OEF marker to make it ready for use in clinical/research studies. We will also consider the relationship of OEF with other markers being tested in the field such as the MarkVCID Study. The PI has assembled an outstanding team of multi- disciplinary investigators for this project and all of them have worked together previously.

NIH Research Projects · FY 2026 · 2023-12

Summary Recent studies show that whole genome duplication (WGD) is a frequent event in cancer evolution that promotes chromosomal instability and aneuploidy. WGD tumors have worse prognosis, elevated drug resistance, and increased metastatic potential when compared with near-diploid counterparts. However, the mechanisms driving WGD during cancer evolution remain unclear. This is because the events that lead to WGD occur asynchronously and at low frequency, making them difficult to capture using traditional approaches such as fixed endpoint approaches. My lab has pioneered genetically encoded biosensors and image analysis techniques to biochemically characterize thousands of individual cells for multiple days as they go through normal or aberrant cell cycles. Using these approaches, we have found that WGD occurs in response to common stress conditions such as osmotic stress, DNA damage, and ribosome collisions. This process involves two steps: first cells go from G2 to G0 without entering into mitosis (i.e. mitotic bypass). Second, some cells escape cell cycle arrest and enter S- phase, thereby re-duplicating their genome. Furthermore, our data show that DNA damage caused by commonly used chemotherapeutics promotes WGD in cancer cells raising questions about the role of chemotherapy- induced WGD in acquired drug resistance. This is particularly important in metastatic Triple Negative Breast Cancer (mTNBC), for which DNA damaging agents are still a mainstream treatment, and the development of resistance continues to be a devastating health care problem (median survival rate <18 months). Here I propose to use our live single-cell approaches to characterize the causes and consequences of WGD in cancer progression and acquired drug resistance. In Aim 1, we will combine live cell imaging and single-cell sequencing to uncover how physiological stresses trigger mitotic bypass and WGD in non-transformed cells. In Aim2, we will study the mechanisms of chemotherapy-induced WGD in cancer cells. In Aim 3, we will use human breast cancer organoids and patient derived xenografts to define the role of chemotherapy-induced WGD in acquired drug resistance. Overall, our work will pave the way toward characterizing cell-cycle dynamics in cancer cells to identify unique vulnerabilities that target the aberrant cell cycles that drive tumorigenesis.

NIH Research Projects · FY 2026 · 2023-12

Project Summary Nearly three million people worldwide are currently living with multiple sclerosis (MS), a complex neurological disease that primarily affects individuals between 20-45 years of age. MS is characterized by peripheral immune cell infiltration into the central nervous system (CNS) with associated reactive gliosis, oligodendrocyte (OL) death, demyelination, and neuroaxonal degeneration. Some of the infiltrates that migrate to the CNS are lymphocytes that target the myelin sheaths of axons. Existing therapies predominately inhibit adaptive immune cells in circulation; however, these medications are often not effective in halting the pathophysiology that underlies progressive CNS degeneration in MS, where immune cell infiltration and activation are minimal. No therapies currently exist to treat this pathology because the molecular mechanisms by which CNS lesions occur in patients with MS is not fully understood. Since disability in progressive MS is driven by the chronic loss of OLs and neurons, this study will investigate the distinct degenerative process of both cell types utilizing relevant models. The ultimate objective of this proposed research is to identify how neurons and OLs die in the context of MS. Understanding this will help identify therapeutic targets to stop these degenerative processes from occurring in patients with MS. For the past decade, our lab has studied a novel, non-apoptotic cell death pathway, parthanatos, that plays an active role in various neurological conditions. Parthanatos-inducing conditions that lead to DNA damage, such as high ROS concentrations, are pathologically prevalent across many neurological diseases including MS. Herein, our lab has created a mouse line with a point mutation that selectively ablates the enzymatic activity of the downstream executioner of parthanatos cell death, macrophage migration inhibitory factor (MIF) nuclease, and synthesized a compound that specifically inhibits MIF nuclease. Both genetic and pharmacologic developments have been shown to mediate protection of dopaminergic neurons in the alpha-synuclein plaque-forming fibril model of Parkinson’s Disease. These experimental tools will be used here to assess the therapeutic efficacy of targeting MIF nuclease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and neonatal-derived mouse OLs following exposure to MS-relevant insults. My preliminary data suggest that genetic ablation of MIF nuclease in EAE mice led to decreased neurologic impairment over time. Importantly, genetic ablation of MIF nuclease in EAE mice did not affect peak EAE disease severity or peripheral immune cell infiltration into the spinal cord. I also determined that genetic ablation and pharmacologic inhibition of MIF nuclease in EAE mice protected against retinal ganglion cell and lumbar spinal cord neuron loss. I further revealed that OL precursor cells underwent parthanatos following DNA damage, and that this cell death process was limited by inhibiting upstream parthanatos enzymes in vitro. Therefore, I hypothesize that neurons and OLs die by parthanatos in MS, and that inhibition of MIF nuclease will protect against neuron and OL degeneration in MS-relevant models. Collectively, if neurons and OLs degenerate by parthanatos in MS as indicated by my preliminary data, this proposed research could establish a pharmacological target that can be inhibited to directly mitigate the ongoing loss of grey and white matter in the CNS of patients with this disease.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Sensory experience facilitates structural and functional maturation of the developing nervous system, and sensory deprivation severely impairs them. Although the time course for experience-driven sensory development is specific for each modality, the developing brain acts as a whole. Therefore, sensory perturbation in one modality results in adaptive reorganization of neural pathways within the unaffected, spared modalities, a phenomenon known as “crossmodal plasticity.” Although a large body of literature has demonstrated adaptive crossmodal changes in the auditory cortex (ACtx) during the `classic critical period' (brief developmental period of enhanced sensory plasticity) after visual deprivation, it is, however, still not known how early in development crossmodal changes emerge. Based on recent findings that peripheral perturbations can alter ACtx circuits and function during the first two postnatal weeks of newborn mice (precritical period) and that crossmodal corticocortical connections are observed between the ACtx and visual cortex (VCtx), we hypothesized that complete retinal deprivation at birth results in crossmodal functional changes and circuit rearrangement in the ACtx and VCtx, during the precritical period. We will perform in vivo calcium imaging in unanesthetized mouse pups during the first two postnatal weeks before and soon after their ears and eyes are open (onset of the critical period) to assess crossmodal functional changes in the ACtx and VCtx following bilateral enucleation (complete retinal deprivation) at birth. We will also perform a combination of laser scanning photostimulation and in vitro whole cell patch clamp recording in slices as well as in vivo extracellular electrophysiology in unanesthetized pups to assess intra- and inter-cortical circuit changes following bilateral enucleation at birth. Results from the proposed experiments will provide, for the first time, functional evidence and a thorough assessment of crossmodal changes in the ACtx and VCtx during the precritical period as a result of complete retinal deprivation since birth and will provide a clear template to guide investigation of early crossmodal changes in other sensory pathways (e.g., somatosensory) and in other species during development. Moreover, the results will accentuate the impact of well-balanced ambient sensory environment in sensory development and will shed light on novel therapeutic interventions for the recovery of function of deprived senses in infants with sensory disorders, e.g., congenital hearing impairment.

NIH Research Projects · FY 2026 · 2023-12

Hearing loss is highly prevalent among older adults, yet hearing aid uptake remains low and gaps in hearing care delivery persist. Asian Americans have among the lowest rates of hearing aid use and represent one of the fastest-growing segments of the aging population in the United States. Older Korean American adults, many of whom are monolingual and first-generation residents, represent a population that may experience challenges in accessing hearing care related to limited English proficiency, health knowledge, navigation of healthcare systems, and financial constraints. National attention has increasingly focused on the need for affordable hearing care models that can be implemented across a wider range of settings, and community health worker–supported models of care have been recognized for their role in extending service delivery beyond traditional clinical environments. The HEARS intervention (Hearing Health through Accessible Research and Solutions) is a theory-driven, evidence-based hearing care program designed for delivery through a peer educator model using over-the-counter hearing technology. HEARS was developed in part by the multiple-PI investigative team and has since been adapted for delivery to older Korean American adults through faith-based organizations (K-HEARS). An NIH Stage IB pilot study demonstrated feasibility, acceptability, and preliminary efficacy of a community health worker–delivered hearing care intervention designed for dyads, consisting of an older adult with hearing loss and a communication partner, delivered through faith-based organizations. Building on these findings, we propose an NIH Stage III efficacy trial using a two-arm cluster randomized design, enrolling 440 dyads of older Korean American adults with hearing loss and their communication partners. The proposed study has the following aims: Aim 1: To test the effect of K-HEARS on communication function and health-related quality of life among older Korean American adults with hearing loss compared with a six-month delayed treatment group. The trial is powered to detect a 0.32 effect size or greater difference on the Hearing Handicap Inventory for the Elderly–Screening between groups at six months. Aim 2: To evaluate the effect of K-HEARS on third-party disability and health-related quality of life among communication partners compared with a six-month delayed treatment group. Exploratory Aim 1: To examine the effect of K-HEARS on dyadic relationship outcomes, measured by mutuality, six months post-intervention. Exploratory Aim 2: To identify factors that influence implementation of a faith-based, community health worker–supported model of hearing care to inform future dissemination efforts. This project leverages a multidisciplinary bilingual investigative team and long-standing partnerships with local organizations. Delivering hearing care through faith-based organizations has not been previously studied at scale, and no prior research has systematically designed and tested a dyadic hearing care intervention using community health workers and over-the-counter hearing technology. Findings from this study will inform strategies for strengthening locally delivered hearing care models for older adults and their families across a variety of service settings.