Johns Hopkins University

NIH Research Projects · FY 2026 · 2024-08

Project Summary/Abstract This Mentored Patient-Oriented Research Career Development Award application is for Dr. Lolita Nidadavolu, Assistant Professor of Medicine in the Division of Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine. Dr. Nidadavolu’s long term goal is to establish an independent research career in Alzheimer’s Disease (AD) focused on disease-associated changes in innate immune signaling and cell-free DNA (cf-DNA). To achieve this goal, the candidate has assembled an interdisciplinary team that includes experts in AD, clinical trials, gerontology, chronic inflammation, microglia biology, and biostatistics. The proposed research for this Career Development Award addresses the critical need to further understand chronic inflammation in AD, which may lead to development of novel treatment options targeting inflammation. Microglia, the resident immune cells of the central nervous system, are major contributors to chronic inflammation in AD. However, a knowledge gap remains in understanding factors that contribute to microglial activation and dysfunction in AD. One proposed contributor to AD-associated microglial activation is cell-free DNA, which is released following cell death processes and can be measured in serum. Prior studies demonstrate that individuals with elevated levels of cf-DNA in serum have lower cognitive test scores and a higher risk of developing AD. Additional preliminary evidence shows that patient-derived cf-DNA is sufficient to upregulate inflammatory cytokines in microglia in vitro. The hypothesis of this proposal is that cf-DNA are associated with microglia activation and can activate pro-inflammatory pathways known to be upregulated in AD. This proposal will use serum and autopsy samples from Rush Alzheimer’s Disease Center (RADC) Religious Orders Study and Memory and Aging Project (ROS-MAP) participants as well as Johns Hopkins Precision Medicine Center of Excellence in Alzheimer’s Disease (PMCoE-AD) and the Johns Hopkins Older American’s Independence Center (OAIC) to examine associations between cf-DNA and disease-associated microglial activation. First, associations will be examined between serum cf-DNA levels and microglia activation (Aim 1). Next, functional changes in microglia phagocytosis and pro-inflammatory pathway activation will be studied in human inducible pluripotent stem cell-derived microglia exposed to purified cf-DNA from individuals with AD and normal cognition controls (Aim 2 and 3). The successful completion of the proposed research will lead to a better understanding of associations between cf-DNA and microglia activation in AD. Additionally, the collaborations and training in this Career Development Award will provide the coursework, research experience, clinical trial skills, and mentorship to solidify the applicant’s expertise as an independent clinician scientist and leader in microglia function and dysregulation in AD.

NSF Awards · FY 2024 · 2024-08

When organisms are exposed to environmental differences, like changes in temperature conditions, they can grow into alternative forms that are more adapted to particular environments. This project investigates how a nematode roundworm makes the decision to become a long-lived and stress-resistant form instead of a proliferative form that is stress-sensitive. Currently there is little understanding how these types of decisions are made at the molecular level. High-throughput measurements, genome sequencing, and genetic methods will be used to examine this mystery and lay the groundwork for future projects examining how animal development changes in responses to divergent environmental cues. Undergraduate and high school student training is an important component of this grant. High school teachers will develop classroom activities for STEM students in cooperation with the principal investigator and high school students will visit the laboratory to carry out hands on experiments with the worms. Phenotypic plasticity, or the expression of different phenotypes by the same genotype, drives evolutionary adaptation to shifting environments. Despite numerous well-known examples, little is known about the genetic underpinnings and molecular mechanisms that generate phenotypic plasticity. The goal of this grant is to discover how microevolution of this plasticity occurs using the tractable metazoan system Caenorhabditis elegans. Depending on environmental conditions, these nematodes enter an alternative developmental fate, called dauer, or continue development to reproductive adults. Early larval-stage animals that sense high temperature, low food availability, and high population density initiate the development of the dauer stage. Once conditions improve, dauers re-enter development to become reproductive adults. Much of what is known about dauer comes from the study of a single laboratory strain. Although natural variation in dauer formation has been observed, the molecular mechanisms that lead to phenotypic differences remain unknown. An unbiased approach is needed to discover the genes that underlie natural variation in dauer formation in order to understand how phenotypic plasticity evolves. Species-wide association mapping will be performed using a novel high-throughput assay in order to identify loci that underlie differences in this developmental trait. These loci will be narrowed to candidate genes using well tested experimental and computational techniques and then variants will be validated using genome editing. These approaches will lead to discovery of the number and the sizes of genetic effects, the signatures of selection that occur at those loci, and then define the parts of the dauer network involved in the microevolution of phenotypic plasticity. 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 · 2024-08

Dementia is a leading cause of disability and death worldwide, with the most significant impact on those with young-onset dementia. Frontotemporal dementia (FTD) is the most common cause of dementia in patients under 60, and the behavioral variant (bvFTD) is the predominant presenting syndrome. Neuropsychiatric symptoms (NPS) are core features of bvFTD, and patients with bvFTD require family caregivers to dedicate significant time and resources to managing NPS. In contrast to Alzheimer’s disease (AD) in which the negative impact of NPS is well understood, prior research has not focused on the nature of NPS and its association with functional decline in bvFTD. The applicant has identified a discrete affective symptom (AS) cluster characterized by depression, anxiety, irritability, and agitation that occur in at least 50% of patients and accelerate functional decline in bvFTD. The treatments developed for the major psychiatric disorders are often ineffective in bvFTD. Given the high prevalence and disability resulting from AS in bvFTD, there is an urgent need for more effective and safe treatments to improve both AS and cognition. The long-term goals of this application for a Mentored Patient-Oriented Research Career Development Award (K23) from a geriatric psychiatrist are to enhance understanding of the neurobiology of NPS in bvFTD to inform the development of novel, precision-targeted therapies to slow functional decline, alleviate patient suffering, and ease caregiver burden. A Positron Emission Tomography (PET) study to measure glucose metabolism is proposed to measure changes in neural circuitry with multi-modal antidepressant (Vortioxetine) treatment that targets both serotonin receptors and serotonin transporters in bvFTD. PET measures of cerebral glucose metabolism to evaluate neural circuitry is a method that is sensitive to neurodegeneration and AS and cognitive impairment. The following aims are proposed: I. To identify the neural circuitry associated with AS and cognitive deficits in bvFTD and II. To identify the changes in neural circuitry following vortioxetine treatment in patients with bvFTD and AS. The overarching hypothesis is that Vortioxetine will improve AS and executive functioning in bvFTD and increase cerebral glucose metabolism in the salience network (SN) and default mode network (DMN), respectively. The research plan is complemented by a career development plan to advance skills in 1) clinical research methodology; 2) the design, application, image and statistical analysis, and interpretation of PET neuroimaging studies; 3) clinical and research applications of neuropsychological assessments and 4) grant writing and overall career development. The mentoring team, collaborators and consultants represent senior faculty with considerable expertise in these areas. Completion of the research and training objectives will advance the career of a junior investigator toward developing an independent research program focused on developing PET biomarkers of neuropsychiatric dysfunction in FTD and related dementias including AD to guide management and treatment selection as the focus of a future RO1 application.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with significant variation in disease manifestation, progression, and outcomes. There is increasing interest in precision medicine strategies in COPD to identify disease traits that, when targeted for treatment, result in improved outcomes. There has been increasing recognition of the prevalence of allergic disease and allergic sensitization in COPD, but the clinical significance of this overlapping trait has been unclear. Blood eosinophils have been recognized as a trait to help target treatment with inhaled corticosteroids among individuals with COPD but are imprecise as a biomarker of type 2 inflammation. We recently published compelling results showing that individuals with COPD having both allergic sensitization as well as concomitant exposure to common indoor aeroallergens, also having elevated total IgE, have a substantially higher risk of adverse outcomes. It is also well established that individuals with allergic asthma having sensitization with exposure to common indoor aeroallergens have significant benefit from treatment with omalizumab. Accordingly, we propose the Clinical trial of omalizumab for allergen sensitized and exposed individuals with COPD (COPD OMA) a masked, randomized, placebo- controlled multi-center phase 2 clinical trial of omalizumab versus placebo among individuals with COPD having sensitization with concomitant exposure to common indoor allergens. The trial will enroll 330 individuals with moderate to severe COPD in partnership with the American Lung Association-Airways Clinical Research Centers (ALA-ACRC) and will test whether omalizumab leads to treatment response, including improvement in exacerbation risk (primary outcome), disease status (measured by St. George's Respiratory Questionnaire and COPD Assessment Test Score), and lung function (secondary outcomes) over the course of 12 months. The study will be conducted at twenty centers throughout the US. In a mechanistic aim, we also propose to explore molecular signatures of IL-4 and IL-13 cytokines to understand drivers of disease morbidity as well as treatment response in this population. Accordingly, this is an ideal phase II clinical trial with the goals of detecting a signal for efficacy of omalizumab in improving relevant clinical outcomes among a high-risk subgroup of individuals; and understanding relevant biologic endotypes with increased responsiveness to treatment.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT The goal of this 5-year research infrastructure development grant (R61/R33) is to substantially strengthen a small but successful collaborative, international network – the SENSE Network – to accelerate and translate innovative research in sensory aging, Alzheimer’s Disease and Related Dementias (ADRD) and late-life wellbeing. MPIs of this proposal [Deal, Ehrlich] launched the SENSE Network in September 2020. Despite the Network’s successes, its growth and objectives have been limited by critical fiscal and organizational barriers. This proposal aims to address these barriers by growing the Network and undertaking key activities needed to develop and accelerate the pace of interdisciplinary sensory aging research, a field at the nexus of sensory health and gerontology. Objectives of the Network include: i) strengthening and expanding the SENSE Network’s coordination of resources, data, and expertise through an expanded Steering Committee and creation of Cores (Data Collection, Harmonization, and Integration Core; Research Development and Mentorship Core; and Dissemination and Translation Core); ii) creating novel integrated and harmonized data resources that include measures of sensory health and ADRD; iii) generating actionable scientific knowledge through pilot project awards; iv) supporting and guiding research of early-stage investigators; and v) disseminating and translating new scientific knowledge to inform clinical care, intervention design, and sensory health and ADRD-related policy. These objectives are directly aligned with R61/R33 key areas of interest of the NIA Divisions of Behavioral and Social Research (BSR) and Geriatrics and Clinical Gerontology (DGCG), including data infrastructure for longitudinal research; harmonization and data linkages across multiple data sets; demographic, social, economic, institutional, and geographic factors at the population level that influence health; and functional independence. The SENSE Network leadership team is comprised of investigators with an extensive track record of collaboration and experience creating research infrastructure, ensuring that the SENSE Network has the capacity to grow sensory aging research beyond what can be accomplished by individual experts and research groups. By accelerating and potentiating the impact of siloed researchers, data sets, and projects, the SENSE Network is poised to take a leading role in the field of sensory aging and ADRD research, advancing the science through in-depth interdisciplinary partnerships and collaborations to positively impact the health of older adults in the U.S. and globally.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Mitochondrial energy production in the heart is crucial for proper cardiac function due to its high energy demand. Cardiolipin is a phospholipid localized in the inner mitochondrial membrane that is necessary for mitochondrial energy production via oxidative phosphorylation. Consisting of two head-groups and four acyl-chains, there are tremendous numbers of molecular species of cardiolipin with varying acyl chain compositions. Among them, the heart enriches linoleic acid (LA)-cardiolipin. It has been suggested that the cardiac form of cardiolipin may be patho- and physiologically significant in cardiac function by facilitating energy production. Genetic disorders of enzymes in cardiolipin metabolism with the reduced LA-cardiolipin in the heart are accompanied by cardiomyopathy and mitochondrial dysfunction. Also, disturbed cardiolipin profiles are observed in several cardiac failures. However, the importance of correct cardiolipin acylation is not fully understood. The goal of this study is to determine the mechanisms underlying the specific regulation of cardiac cardiolipin by reconciling three hotly debated cardiolipin acylation theories: 1) LA-cardiolipin is dependent on an enzyme Tafazzin that remodels cardiolipin with acquired preference for LA; 2) IMM protein environment controls cardiolipin acylation, and; 3) tissue-specific lipid pools drive cardiolipin diversity. The contribution of each theory needs to be determined in the context of cardiac specific LA-cardiolipin. Cardiomyocytes may draw from all three to enrich LA-cardiolipin. I will test my central hypotheses that LA-cardiolipin optimizes cardiac bioenergetics and that cardiomyocytes have an integrated system to generate and dominantly maintain LA-cardiolipin. I will determine the significance/preference of LA-cardiolipin in cardiac energy production (Aim 1), characterize the contributions of the cardiac IMM protein environment in LA-cardiolipin control (Aim 2), and identify the cardiac LA-pool and pathway that concentrates LA in cardiolipin (Aim 3). This study will provide a fundamental understanding of a cardiac-specific mitochondrial lipid. Also, characterizing this heart-specific system will expand our knowledge of basic cardiac biology and energy metabolism. Performing this study in conjunction with the proposed career development plan, including solid mentorship and training, as well as institutional support, will develop my research-related and professional skills. This will enable my transition toward the achievement of my career goal to become an independent investigator who conducts phospholipid studies with multi-directional skill sets and expertise.

NIH Research Projects · FY 2025 · 2024-08

Every year, 50,000 preterm infants are diagnosed with chronic lung disease (CLD). CLD is associated with reduced lung function and morbidity that persists into adulthood, with glaring health disparities. Black preterm infants with CLD have higher rates of respiratory symptoms, medication use, emergency department visits, and readmissions in the first year of life, although White preterm infants are more likely to be diagnosed with CLD at birth. Few studies with Black preterm infants have focused on this critical period of the lifecourse after hospital discharge. Patient and family engagement interventions can promote equity and improve health outcomes by centering on patients’ lived experiences. This may be especially true for Black preterm infants with CLD whose engagement in care is impacted by complex medical needs, social determinants, and parental mental health and wellbeing. Guided by an inclusive and multidisciplinary advisory board co-led by Black parents, this proposal will provide novel insights into the hospital to home transition for Black preterm infants with CLD. It will also address a critical need for health equity interventions in pediatrics. Aim 1 is to characterize profiles of preterm infants with CLD by medical needs and social determinants and identify profiles associated with the highest risk of respiratory morbidity. Aim 2 is to describe the lived experience of parents of Black preterm infants with CLD in the first year of life. Aim 3 is to develop and evaluate the feasibility and acceptability of a pediatric-adapted collaborative goal setting (P-CGS) tool piloted with parents of Black preterm infants with CLD during a primary care visit and explore preliminary child and parent outcomes. This K23 proposal addresses two critically important NHLBI priority areas: 1) pediatric lung health disparities, and 2) the transition from hospital to home for preterm infants with CLD. It will also provide the applicant, Dr. Brandon Smith, MD, MPH, the opportunity to become an independent clinician investigator with expertise in parent engagement interventions in primary care to advance health equity. The proposed research and career development plan will support Dr. Smith’s four training objectives: 1) acquire skills in advanced statistical methods; 2) gain expertise in designing and leading qualitative research; 3) attain skills in the development and testing of interventions in pediatric primary care; and 4) obtain in-depth understanding of patient engagement theory and practice to promote health equity with emphasis on local expertise. Dr. Smith will take advantage of a committed and multidisciplinary mentorship team and strong training environment at the Johns Hopkins Medical Institutions to launch his independent career. The results of this study will provide preliminary data for a future R01 application to test the efficacy of the P-CGS tool in reducing lung health disparities for Black preterm infants with CLD using a randomized, clinical trial.

NIH Research Projects · FY 2025 · 2024-08

Project Summary α-Synucleinopathies includes Dementia with Lewy Body (DLB), Parkinson's Disease with Dementia (PDD), and Alzheimer's Disease with Lewy Body Dementia (AD-LBD), that are highly associated with Alzheimer's Disease and Related Dementia (ADRD). The "Prion-like α-Syn Propagation" theory, suggesting the GI tract as the origin of α-syn pathology and its subsequent spread to the brain, is a focal point of discussion. This cascade is implicated in neuroinflammation and cognitive decline, particularly in ADRD cases featuring α-syn pathology. Utilizing the established Gut-Brain α- synucleinopathy (GBAS) model, we aim to investigate the progression of these pathologies from the gut to the brain, emphasizing the gut-brain axis's role in ADRD. Additionally, we shed light on the often- overlooked area of adaptive immunity, specifically T cell-mediated responses, noted for their diverse functions and immune potency, which may play a role in governing α-syn pathology, based on recent research findings. Looking ahead, we explore the emerging potential of T-cell immunity in α-synuclein propagation within α-synucleinopathies. An interdisciplinary research team is poised to examine the impact of T-cell responses on α-syn pathology progression and explore potential applications of immunotherapy. This collaborative effort aims to enrich our understanding of the complex mechanisms underlying neurodegenerative diseases and offer innovative therapeutic strategies for the future.

NSF Awards · FY 2024 · 2024-08

Surprisingly, when tissues like the skin or cornea are wounded, our bodies immediately respond by creating a natural electric field pointing toward the wound center. These fields have nothing to do with the brain or nervous system. Instead, cells can actually use the electric field to navigate, leading them to the wound site (“electrotaxis” or “galvanotaxis”). Controlling this electrical signal is thought to be able to improve our own ability to heal. However, developing next-generation ‘electroceutical’ tools requires us to better understand what cells are doing when following this signal – how do they detect an electric field, and what limits their ability to sense it? Understanding this requires a focus on the interaction between biological cell motility and the physical forces applied to molecules on the cell’s surface. Currently, most of the data in this field suggest that cells follow electric fields because charged sensor molecules are redistributed on the cell’s surface. However, these molecules are so small that the electrical signal will be competing with fluctuating thermal forces (Brownian motion). This competition could affect how accurately cell can respond to the electrical signals and understanding it could lead to better ways to deliver electrical signals to improve cell responses. This project will study how these physical factors limit the accuracy of how both individual cells and groups of cells follow fields. The research is a collaboration between the Camley group, who model how groups of cells respond to chemical cues and have recently developed a biophysical model for single-cell galvanotaxis, and the Cohen group, who are experts in engineering and controlling electrotaxis at the tissue scale. This project will support the development of computational models that include the motion of sensor molecules on the cell’s surface in response to electric fields, the crawling of the cell, and the ways in which cells can influence the electric fields around them. The project will then involve testing these models using experiments with single cells, small numbers of cells, and tissues, and use this data to refine the models. The Broader Impacts of this work include a better understanding of these processes essential to wound healing, as well as developing tools to help guide individual cells or cell sheets—all of which brings us closer to new bioelectric technologies for healing. In addition, this project will support training of scientists in broad communication, outreach, and storytelling through an expansion of Cohen’s ‘Lab Tales’ storytelling training workshop where trainees learn science history and storytelling through a week of hands-on instruction. In more detail, this award will aim to answer three broad questions. First: how does a cell’s shape affect its ability to sense a field? Many single eukaryotic cells stretch perpendicular to an applied electric field. Why? Does it benefit them? To answer, the project will study how the ‘front’ and ‘back’ of a cell reorients when exposed to an electric field, and how this depends on cell shape and orientation. The project will control cell shape by using adhesive micropatterns, allowing for quantitative comparison with theory. Second: Do cells interact while galvanotaxing? Cells, by their presence on the substrate, will alter the local electric field. Can pairs of cells interact through the electric field, with one cell causing the other to reorient? Third: Can groups of cells improve their accuracy by aligning? Many cell types develop so-called “nematic” alignment, where cells’ long axes align with each other – this also includes keratinocytes following electrical fields. How does this affect the group’s ability to respond to signals? 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 2024 · 2024-08

PROJECT SUMMARY Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea, that continues to be associated with significant morbidity, mortality and stunting, among children <5 years of age living in low and middle income countries (LMIC). Although many ETEC vaccines are in clinical trials, none are currently licensed. To avoid further morbidity and mortality due to ETEC, an efficacious vaccine given effectively is urgently required. While the logical target group for ETEC vaccine would be infants, children in LMICs have been difficult to effectively immunize with other oral vaccines. To address this critical problem of low oral vaccine immune responses among infants in LMICs, an alternative strategy for protecting infants against ETEC needs to be explored. We hypothesize that maternal immunity may contribute to protecting infants from ETEC. However, the protective benefits and the components of maternal immunity associated with protection in infants from enteric infections like ETEC has not been widely studied. Therefore, if this route of passive immunity is feasible for ETEC is uncertain. Our aim is to study natural infections of ETEC in the mothers and babies to determine if the maternal antibodies to ETEC could prevent ETEC infections in children. We will also identify the ETEC antigens that are immunogenic and whose humoral immunity is transferable and protective to the neonates. Our specific hypothesis is that the antibodies to ETEC heat labile toxins, colonization factors and specific novel antigens transferred through breast milk would protect the infants from ETEC diarrhea and asymptomatic infections. ETEC-antibodies in the cord blood may also contribute to this protection. This passive protection may be enhanced by the bioactive factors like cytokines in the breastmilk and cord blood. To address our aims, we will enroll pregnant mothers and newborn dyads and follow them for two years of the child's age in Lima, Peru. This study will uncover the possibility of a more effective immunization approach for protecting infants from ETEC infections in the first year of life and beyond.

NIH Research Projects · FY 2025 · 2024-08

The goal of this application, submitted in response to RFA-MH-23-275, “Using Secondary Data Analysis to Determine Whether Preventive Interventions Implemented Earlier in Life Reduce Suicide Risk,” is to conduct research that will integrate and harmonize existing large prevention trial datasets. The included randomized clinical trials (RCT) were delivered before adulthood (prior to age 18) and did not explicitly target suicidal thoughts and behaviors (STB). Each RCT consists of well-characterized participant-level prospective data with consent that allows for the harmonized data to be submitted to the NIMH Data Archive and allows for National Death Index searches. This study will examine ‘cross-over effects’ (e.g., unanticipated beneficial effects) of the RCTs in reducing risk for later fatal and nonfatal STB, and related outcomes such as overdose, Substance Use Disorders (SUD), Opioid Use Disorders (OUD), accidents, and all-cause mortality. This U01 proposal has obtained 29 existing prevention trial data sets with collaboration of the principal investigators and data custodians who have rights to the original data. We will de-identify, aggregate, and harmonize the prevention trial datasets and utilize advanced computational/analytic strategies to examine whether intervening early reduces the risk for STB and related outcomes. We will identify the most potent aspects by examining the various components of each intervention as well as the proximal and distal targets, format, setting, dose/duration, developmental timing, and quality of implementation. Potential mediators and mechanisms of action (e.g., aspects of parenting, social factors, emotional and behavioral regulation) will also be studied and identified. This effort will examine moderators of the effects of preventive interventions, including specific subpopulations of individuals facing documented health disparities. Data will be utilized from 29 trials involving 14 programs and 42,509 individuals. With over 40,000 participants across all studies, harmonizing data will allow for more complex, multifactorial, multi-level analyses to explore intervention impacts on fatal and nonfatal STB and related outcomes as well as potential mediators, mechanisms, and moderators of impact. The U01 team will oversee the preparation of a final harmonized prevention trial dataset to be deposited to the NIMH Data Archive (NDA) with data dictionaries and associated documentation from the original studies. This project has the potential to inform the refinement and development of future preventive intervention strategies delivered early and scaled to address suicide and overdose in the US.

NIH Research Projects · FY 2025 · 2024-08

This project addresses a pressing American health priority: developing effective strategies to help people living with HIV stay engaged in treatment when they also face stigma related to HIV and drug use. Stigma — the shame and discrimination people experience because of their HIV status or substance use — is one of the most significant barriers to HIV care in the United States today. Americans living with HIV, particularly women and people with substance use disorders, face these overlapping stigmas daily, contributing to missed medications, dropped care, and ultimately worse health outcomes. Yet few interventions have been designed and rigorously tested to address both stigmas at once. This project will develop and pilot-test such an intervention, then generate findings directly applicable to U.S. HIV care programs and clinical practice. The research is conducted in Ukraine because Ukraine offers a scientifically unique and efficient setting for this work that is not available in the United States: it has one of Europe’s most concentrated HIV epidemics, a high burden of injection drug use, and a population of women living with HIV who use drugs that is substantially larger than comparable U.S. populations. This makes it possible to recruit, enroll, and study a sufficient number of participants to rigorously test the intervention in a way that would take far longer and cost far more in a U.S. setting. Ukraine also has a highly experienced research team and established research infrastructure with a strong track record working with this population, ensuring high-quality data and efficient use of NIH resources. Moreover, the Ukrainian Institute of Public Health Policy (UIPHP) has extensive experience testing interventions (e.g., MARTAS/Modified ARTAS and HPTN 074), with evidence from these efforts informing effective practices later used in the United States, thereby enhancing the feasibility, rigor, and translational potential of the proposed study. The scientific insights gained — about which intervention components reduce stigma, improve medication adherence, and increase retention in care — are directly transferable to American communities where HIV and substance use intersect. We will adapt the evidence-informed “Workshop” intervention, a small-group, multi-session program designed to reduce internalized and anticipated stigma, strengthen coping and communication skills, increase social support, and address structural barriers to HIV treatment and substance use services. This pilot study will increase understanding of the intervention and contextual factors that will facilitate a larger RCT to determine the effectiveness of the intervention for HIV+ WWUD. Importantly, the study will generate evidence directly relevant to U.S. efforts to improve HIV retention in care, reduce disparities through a solution-oriented approach, strengthen integration of HIV and addiction services, and identify factors that improve the uptake of and access to existing medical and behavioral interventions that can significantly limit and eventually eradicate HIV infection from the United States.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Spinal muscular atrophy is a monogenic motor neuron disease and is historically a leading inherited cause of death in infancy and childhood. While development of SMN-dependent therapies has significantly improved patient outcomes, continued neurological deficits in most patients highlights the need for SMN- independent therapeutics to improve motor neuron (MN) function and survival. This effort is hindered by the lack of understanding of how SMN deficiency impacts MN development and degeneration. Our laboratory recently demonstrated that severely impaired proximal motor axon radial growth beginning at mid-late embryogenesis and rapid degeneration of the entire MN postnatally are prominent features of type I SMA patients, but the molecular mechanisms driving these cellular events and the importance of these pathologies to milder forms of SMA are unknown. Historically, it has been difficult to obtain transcriptomic data from MNs in vivo due to their sparseness within the spinal cord, and while in vitro models can provide detailed transcriptomic data, these models forgo MN heterogeneity and the complexity of the spinal cord environment. To circumvent these difficulties, we have collaborated with Dr. Le Pichon at the NIH to produce two SMA mouse models that express GFP-tagged Sun1, a nuclear envelope protein, in choline acetyltransferase (ChAT) positive neurons of the spinal cord for FACS sorting and subsequent single nucleus RNA sequencing (snRNAseq). Using snRNAseq, we aim to elucidate the aberrant developmental pathways that drive early stages of SMA pathogenesis, and further compare the magnitude and temporality of the identified mechanisms in severe and mild models of SMA. We aim to do this by characterizing and performing snRNAseq on two SMA mouse models, the severe model (Smn-/- SMN2+/+) and a mild model (Smn2B/-). Each model will be behaviorally and histologically characterized in Aim 1 to identify appropriate time points for snRNAseq in Aim 2. In Aim 3, genes and pathways of interest will be validated using qRT-PCR, in situ hybridization, and protein quantification in both mouse models and in human autopsy tissues. Together, these studies aim to identify shared and divergent developmental and degenerative mechanisms across the spectrum of disease severity to inform future therapeutic development.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Despite excellent short-term outcomes after transplantation, the long-term survival of transplanted organs has stagnated for several decades. Recent clinical studies have demonstrated that acute cellular rejection, which is mediated by alloreactive T cells, is a risk factor for later graft failure. In order to effectively prevent acute rejection, deeper understanding of how T cells response to allogeneic antigen are needed. The CD28 pathway blocker belatacept (a CTLA-4 Ig derivative) offers significant long-term benefits versus calcineurin inhibitors for kidney transplant patients, but has limited efficacy in restraining CD8+ T cells and acute cellular rejection. Despite a great body of work investigating the programming of effector CD8+ T cells (TEFF) that respond to infections, relatively little is known about CD8+ TEFF that respond to allogeneic antigen in the context of an allograft. We found that after grafting, a subset of CD8+ TEFF expressing the activated CD43 isoform (defined by the 1B11 epitope) are formed during acute effector timepoints from day 7-21 post-graft. CD43 is a cellular receptor that influences T cell receptor signaling cascades and cellular trafficking, but its role in transplantation is undefined. Relative to other TEFF subsets, CD43+ TEFF appeared highly activated, displayed vigorous effector functions, and drove accelerated graft rejection. In human renal transplant patients, CD43+ CD8+ T cells infiltrate the kidney allografts of patients treated with belatacept, and CD43+ CD8+ T cells are functionally resistant to CTLA-4 Ig in vitro. Together, these data form the premise for our hypothesis that CD43+ TEFF are a potent effector population that can be targeted to limit acute rejection following transplantation. In this proposal, we will use an innovative MHC Class I tetramer to characterize the role of CD43 on graft-specific CD8+ T cells. Specific Aims: First, we will define the effector mechanisms that distinguish CD43+ TEFF function as a population from CD43- TEFF. Using adoptive transfer approaches, we will investigate the differentiation pathways that lead from naïve CD8+ T cells to CD43+ TEFF, the mechanisms by which CD43+ TEFF traffic from the draining lymph nodes into graft tissue, and the role of the Inducible T Cell Costimulator (ICOS) receptor signaling in the fate of CD43+ TEFF. Second, we will investigate the role of CD43 receptor signaling on CD8+ T cells. Using a CD43 knockout mouse model, we will interrogate the requirement of CD43 signaling for graft rejection, how CD43 controls T cell at the clonal level, and the role of CD43 in determining the quality of secondary memory responses. Third, we will explore the potential of CD43 as a therapeutic target to limit alloimmunity in humans and mice. We will evaluate whether targeted deletion of CD43+ TEFF in vivo with an antibody-drug conjugate can elicit tolerance in combination with CD28 blockade. We will explore whether human CD43+ CD8+ T cells are a significant contributor to alloreactivity and resistance to CD28 blockade. This proposal will generate deeper understanding of allogeneic TEFF that will lead to new strategies to restrain CD8+ T cells that mediate acute rejection.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT … Extracorporeal Membrane Oxygenation (ECMO) is a life-saving therapy for people with severe heart and lung failure, and its use as therapeutic support continues to increase in the United States. However, acute brain injury (ABI) commonly occurs during this intervention, often leading to considerable disability or even death. Currently, we lack a solid understanding of why ABI occurs during ECMO, although previous research has implicated the potential impacts of carbon dioxide (CO2) regulation on cerebral physiology. For example, we do not have a good understanding of the sequelae resulting from the rapid physiologic changes that accompany ECMO support in the first 24 hours of treatment, when refractory cardiopulmonary failure in these patients is being rapidly reversed. These patients frequently experience severe acidosis and hypercapnia prior to cannulation, which is rapidly reversed upon ECMO initiation by adjusting sweep gas flow across the oxygenator membrane. The proposed research aims to address this evidence gap, by improving our understanding of the early physiologic changes that impact outcomes after ECMO initiation. We hypothesize that the acute △PaCO2, which often accompanies the initiation of ECMO with its rapid correction of PaCO2, causes cerebral vasoconstriction resulting in a substantial decrease in cerebral oxygen delivery and ABI. The rationale for our hypothesis is that CO2 is a potent cerebral vasodilator and prolonged hypercapnia can impair cerebral autoregulation. Our preliminary data provide convincing evidence that △PaCO2 represents a major mechanism for ABI in ECMO patients, leading to poor long-term neurological and psychiatric outcomes. Our data also show that bedside detection of ABI is feasible using readily available low-field portable brain MRI and brain injury plasma biomarkers. Our proposed research, the DELTA ECMO ABI study (Assessing Acute Brain Injury after Rapid Reduction of PaCO2 upon ECMO Cannulation using Portable MRI and Biomarkers) uses an innovative neuroimaging system and plasma biomarkers to test our central hypothesis that higher peri-cannulation △PaCO2 is associated with ABI, leading to poor long-term neuropsychiatric outcomes. We will prospectively enroll ECMO patients and collect multiple arterial blood gas samples (every 4 hours) 24 hours pre- and post-cannulation. ABI will be diagnosed by early low-field portable brain MRI at 24 and 72 hours along with the assessment of elevated plasma biomarker levels and cerebral autoregulation. We will investigate whether the magnitude of peri-cannulation ΔPaCO2 is associated with cerebral perfusion autoregulatory dysfunction and ABI (Aim 1); and whether the presence of ABI is associated with worse 6-month neuropsychiatric outcomes (Aim 2). Our proposed research is a high-reward project that holds significant potential to change clinical practice, by investigating an innovative hypothesis utilizing a unique approach. Our research can significantly advance the understanding of ECMO- associated ABI, setting the stage for the development of future approaches aimed at mitigating ABI as a complication of ECMO therapy.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY/ABSTRACT Rates of homelessness among youth and young adults living in the United States have more than doubled in the last decade, and transition-age youth face elevated levels of housing insecurity and an increased risk of homelessness. Developmental and systemic challenges during this critical life stage—such as aging out of foster care, limited access to stable employment, and gaps in social support—contribute to the heightened vulnerability to homelessness in this group. Housing instability among transition-age youth can exacerbate existing risk factors for poor health outcomes and create new environments that pose additional risks, including survival sex, physical and/or sexual abuse, and injection drug use. To add to this, unstable housing may challenge already suboptimal access to and engagement with healthcare services, including HIV prevention and treatment. Existing guidelines and strategic plans in the United States emphasize the importance of safe and affordable housing to HIV service utilization and outcomes, but innovative strategies that operate within the existing program environment and effectively cater to the distinctive needs of young people are largely unavailable and understudied. While housing support programs and rental assistance are not novel among the array of existing social safety net interventions, their effective implementation has faced obstacles such as administrative complexities, conditions linked to work or behavior change, and a lack of adaptability to evolving needs. To address these complexities, we will first document the existing program environment that influences housing and HIV, and second partner with Point Source Youth (PSY), an advocacy leader in the youth homelessness space, to refine and measure the implementation of a housing support program intervention for youth at or about to enter the homelessness system in Baltimore City. 60 young people will be provided with rental support over two years to sustainably exit homelessness, find housing in alignment with apartment share arrangements, and more easily access HIV services. To guide this research, we will use two implementation science frameworks in conjunction: the Consolidated Framework for Implementation Research (CFIR) 2.0 and Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM). The proposed strategy is grounded in insights from community-identified needs and barriers, consideration of implementation challenges at the individual and organizational levels, and an understanding of the ongoing evolution of the program context. The specific aims of this study are: Specific Aim 1 – Map existing municipal and state programs that impact housing and HIV among young people and generate a program index to quantify their breadth and depth, 2020-2025 Specific Aim 2 – Inform and tailor the implementation of a housing support program intervention for youth based on stakeholder perspectives in Baltimore City Specific Aim 3 - Measure the implementation of a housing support program intervention to address homelessness and improve HIV service engagement among youth in Baltimore City

NIH Research Projects · FY 2026 · 2024-08

SUMMARY The long-term goal of my laboratory is to elucidate the mechanisms that regulate the development and function of hair bundles of cochlear hair cells, and how defect in hair bundles cause disease. We propose here to study the function of two genes, clarin1 (CLRN1) and clarin2 (CLRN2) that have been linked to hearing loss. Mutations in the murine Clrn1 and Clrn2 genes cause defects in hair bundle development and MET. We hypothesize that CLRN1 and CLRN2 form protein complexes with proteins that have previously been linked to hair bundle development and MET to affect the development and function of hair cells. To test our hypothesis, we will use genetically modified combined with immunohistochemistry, electron microscopy as well as biochemical, cell biological and electrophysiological methods to study CLRN1 and CLRN2 function in hair cells. Our preliminary data show the feasibility of our approach. We have identified CLRN1 and CLRN2 binding partners that are encoded by genes linked to deafness and our findings suggest that these bindings partners act in concert with CLRN1 and CLRN2 to regulate hair cell development and function.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Weight gain with Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), has been observed in People living with HIV (PLHIV) including postpartum women. How DTG-based ART regimens affect postpartum weight is not known. Understanding the impact of maternal DTG-regimens on the physiology of postpartum body weight regulation has clinical significance as postpartum weight retention is known to increase future maternal risk of overweight, obesity and non-communicable diseases (NCD). DTG-based ART is being rolled as the first line regimen in Sub-Saharan Africa for HIV management. Therefore, it is imperative to better understand how DTG regimens affect the physiology of postpartum body weight regulation and appetite, to identify potential interventions to reduce future overweight and NCD risk in this population. To address this research gap, we propose to leverage our R01 study (MI-DART), focused on energy intake and energy expenditure in a cohort of mother-infant dyads with and without HIV, to further study the impact of DTG on appetite regulation in these postpartum women (Aim 1). This maternal–infant cohort will also allow us to define the impact of maternal DTG-ART regimen on appetite in their HIV exposed uninfected (HEU) infant compared to HIV unexposed uninfected infants (Aim 2), and how they relate to infant growth and body composition. In addition to the comparison by maternal ART regimen, our study will help us understand the mechanisms behind one of the most clinically significant observations in HEU infants: infant growth deficits in HEU infants with mothers on non-DTG regimen compared to HUU infant; and whether maternal DTG containing ART regimens have a similar impact. We will use targeted approaches to assess appetite regulation, including subjective appetite questionnaires and pre- and post-prandial levels of objective panels of appetite-stimulating and appetite-reducing peptides and hormones, along with short-chain fatty acids that regulate levels of these hormones. Unbiased approaches include assessment of the microbiome as it regulates these hormones and short-chain fatty acids involved in appetite. We will pair these measures with secondary objective assessments of physical activity along with energy intake and total energy expenditure data obtained from the parent study to better understand the impact of appetite, energy intake and energy expenditure. Through these two aims, we address an urgent need to understand how maternal DTG impacts the physiology of body weight regulation and appetite in postpartum women and their HEU infants. These maternal- infant populations have a unique physiological profile with increased energy demands on the lactating mother and breastfeeding infant to sustain growth. Our detailed metabolic assessments will further help identify potential therapeutics (e.g. related to intake/appetite, expenditure, or metabolic pathways) for management of postpartum weight and infant growth in maternal-infant populations with HIV.

NIH Research Projects · FY 2025 · 2024-08

Genetic counseling is increasingly recommended as a key component of genomic medicine across specialties. Genetic counselors are clinically effective with acumen identifying and interpreting genetic tests, facilitating cascade genetic testing, and promoting patient empowerment. Many have extensive disease-specific subject matter expertise and deep clinical insights that are valued by patients and colleagues alike. Despite these strengths, genetic counselors’ research engagement has been limited due to: 1) insufficient practical research experience, 2) limited didactic research design and methods training, and 3) narrow professional research networks all leading to lack of research confidence, particularly in younger genetic counselors. The consequences are that research questions vital to advancing genomic medicine and ELSI research in which genetic counselors hold key expertise have been underfunded and under-researched. PROMOTE-GC is a tailored 18-24 month part-time (12 person-month) research training program for early-mid career genetic counselors who wish to develop skills to conduct independent genomic medicine or ELSI research that is designed to overcome these barriers. PROMOTE-GC leverages the breadth of genomics expertise across Johns Hopkins University (JHU) to achieve three aims. 1) We will guide participants in mentored intensive practical research experiences. These include longitudinal engagement with a research mentoring team, embedding in a funded genomics medicine or ELSI research team to complete a small research project, and drafting a grant. 2) We will engage the many resources at JHU to provide tailored didactic training in research methodology. We plan a Fundamentals of Genetic Counseling Research course developed specifically for PROMOTE-GC participants and also will guide participants to enroll in highly-rated research methods courses to meet their interests and professional goals. We also provide opportunities to attend in-depth offsite research training courses. 3) Finally, we will facilitate participants in creating a durable, multidisciplinary professional research community to support their future careers through supporting genetics professional society engagement, assisting in outreach to methods experts and mentors, and providing carefully planned opportunities to engage a multidisciplinary community of experts in evaluating new research and its future implications. The long-term over-arching goal of PROMOTE-GC is to benefit not only the individual genetic counselors who participate, but also the genetic counseling and genomic medicine enterprise by enhancing the research capacity of these vital members of the genomic medicine workforce.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT/SUMMARY Effective HIV treatment during pregnancy is critically important, both for the health of women living with HIV (PWHIV) and for prevention of perinatal HIV transmission. In the United States, Nigeria, and globally, Dolutegravir (DTG)- based antiretroviral therapy (ART) is being expanded as part of the preferred 1st-line ART regimen, but emerging data show that DTG-based regimens are associated with excessive weight gain, treatment-emergent obesity, and metabolic dysfunction in PWHIV. Excessive weight gain and metabolic syndrome are critical during pregnancy because they increase the risk for pregnancy-related complications, such as preterm birth, pre-eclampsia, gestational diabetes, fetal obesity, macrosomia, low birth weight, Cesarean delivery, and neonatal intensive care unit admissions. Yet, the mechanisms by which DTG-based ART-cause weight gain and metabolic syndrome in PWHIV are poorly understood, limiting our ability to fully deploy DTG- based ART in this special population. To address this goal, we will leverage NIH infrastructure to conduct a prospective cohort study at 4 sites in two countries (US and Nigeria). Within this cohort, we will first identify cases of metabolic syndrome by examining the association between DTG-based ART regimens and metabolic syndrome risk using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for pregnant and postpartum women living with HIV, and cohort-specific percentiles for waist circumference, systolic blood pressure, and serum glucose for their offspring. Subsequently, among PWHIV diagnosed with metabolic syndrome (compared to controls), we will apply advanced integrated proteomic and metabolomic targeted profiling techniques to measure maternal proteins and metabolites (during pregnancy and postpartum) and umbilical cord blood proteins and metabolites to understand whether signature clusters of proteins and metabolites differ between PWHIV diagnosed with metabolic syndrome (compared to selected controls), and if any signature clusters are associated with adverse maternal and child metabolic health. Biomarkers identified through integrated profiling would enhance the synergistic power of these ‘omics’ approaches to enable early detection of metabolic syndrome (even before clinical symptoms manifest), provide insights into treatment efficacy and potential adverse effects, and contribute to the development of personalized medicine strategies for PWHIV to guide the selection of interventions and therapies tailored to specific metabolite profiles in clinical practice.

NIH Research Projects · FY 2025 · 2024-08

Summary Synapses, the connections between neurons, play a crucial role in determining circuit connectivity and function. Visualizing their structure and dynamics is challenging due to the vast number of synapses and the complex interactions between them. Prior studies have explored some aspects of synaptic plasticity, primarily focusing on postsynaptic neurons and utilizing imaging techniques to observe dendritic spines, which are widely recognized as key synaptic structures. Nevertheless, there remains a significant gap in our understanding of how these changes are linked to their specific input sources, leaving the identity of these synapses largely uncharted. To overcome this limitation, researchers have developed dual-component synapse detectors, like the neurexin-neuroligin complex and split fluorescent proteins. However, split fluorescent proteins have limitations, such as slow maturation and irreversible associations, hindering real-time synaptic observation. To address these challenges, we developed a reversible fluorescent sensor technology using dimerization-dependent fluorescent proteins (ddFPs) named SynapShot. These ddFPs emit fluorescence only when they heterodimerize, which happens quickly and reversibly. With this technique, we successfully monitored synaptic dynamics in real time, including synaptic formation and elimination, as indicated by changes in dendritic spine size. We also distinguished connections from one postsynaptic neuron to multiple presynaptic neurons. In this proposal, we will further explore the uncharted territory of synaptic dynamics in both local and long-range circuits in in vivo setups. In the first aim, we will investigate the functional implications of synaptic labeling detected by the SynapShot. Synaptic plasticity will be tested in single dendritic spines to demonstrate the ability of tracking structural changes in real-time. In the second aim, we will explore inhibitory synaptic connections, especially those involving genetically-defined interneuron cell types, using the SynapShot method. In the third aim, we will employ synapShot to observe synaptic changes during the acquisition of a new learning task, study dendritic integration dynamics, and examine the rules governing connections among engram neurons. In summary, SynapShot provides a means to observe bidirectional changes in synaptic contacts both in vitro and in vivo and can differentiate distinct populations of synapses when used in dual-colored configurations. This platform contributes to understanding the relationship between time-dependent synaptic structure changes and various brain functions and diseases. The successful completion of this project promises to be a valuable asset in advancing the field of neural circuit research.

NIH Research Projects · FY 2026 · 2024-08

This K23 career development award proposal addresses the underutilization of pain psychology, an effective frontline treatment, among individuals from low SES backgrounds suffering from chronic low back pain (cLBP). The primary investigator (PI) seeks to bridge this healthcare disparity through a three-fold research strategy. Aim 1 proposes to investigate the impact of socioeconomic status on pain psychology utilization via a retrospective cohort analysis. The PI will leverage data from a large, PCORI-funded trial across healthcare systems in Baltimore, MD, and Salt Lake City, UT. Aim 2 aims to identify the challenges and facilitators to pain psychology utilization through qualitative interviews with psychologists and patients from a low socioeconomic stratum. This step will guide the development of the Empowering Pain Psychology Access and Collaboration (EPPAC) intervention, a patient-centered approach using shared decision-making and motivational interviewing. Aim 3 pilots the EPPAC intervention among patients from low SES backgrounds with cLBP, evaluating its acceptability, feasibility, and preliminary efficacy compared to a usual care control group. This K23 career development award proposal is spearheaded by Dr. Fenan Rassu, an Assistant Professor in the Department of Physical Medicine and Rehabilitation and a clinical researcher at The Johns Hopkins University School of Medicine who is determined to address underutilization of evidence-based pain psychology treatments among individuals from low SES backgrounds with cLBP. The proposed career development plan includes didactic and research training activities that will substantially build his skills and expertise. These will include training in health services research, stakeholder engaged research and qualitative research methods, and implementation science . This training will occur in the rich training environment of the Johns Hopkins Medical Institutions, including the Bloomberg School of Public Health. He will receive guidance from his outstanding team of mentors and advisors with expertise in the methodologies needed for conducting the planned research, and a track record of mentoring and funding. The award and protected time will allow Dr. Rassu to build an independent NIH-funded research career and become a leader in improving access and engagement in evidence-based treatments for populations from low SES backgrounds living with pain.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Violence is a widespread public health problem, yet sexual and gender diverse (SGD) populations are disproportionately impacted by multiple forms of violence, affecting feelings of safety and contributing to physical, mental, and behavioral health disparities. SGD populations also experience disparities in poverty rates and financial security as a result of structural vulnerability in employment, education, and wages. Strengthening financial security is a promising violence prevention strategy that has not been examined for SGD populations. This study will improve insights into financial security as a determinant of violence and safety and evaluate the role of policy in shaping SGD violence disparities, informing the utility of violence prevention strategies promoting financial security for SGD populations. To accomplish this, specific aims are to: 1) Examine the association between household income and violence victimization rates and assess moderating effects of sexual and gender identity; 2) Explore the role of financial security in feelings of safety; and 3) Evaluate state Earned Income Tax Credit (EITC) expansions for their impact on SGD violence rates. Aim 1 will utilize linear mixed effects models to assess the relationship between household income and violent victimization rates by sexual and gender identity in a secondary analysis of National Crime Victimization Survey (NCVS) data from 2017-2023. Aim 2 will leverage the data and infrastructure of an existing study conducting lifeline interviews with 60 transgender, nonbinary, and gender diverse people in Baltimore City to qualitatively explore the relationship between financial security and feelings of safety. Aim 3 will apply innovative policy evaluation methods, including comparative interrupted time series designs and synthetic control modeling, to examine the impact of state EITC expansions and state-level violent victimization rates among SGD populations in 22 states using NCVS data. This multi-method study uniquely combines an in-depth exploration of financial security as a mechanism by which societal factors lead to violence disparities with the investigation of an actionable policy approach to advance health disparities science. This research will contribute to the evidence base for upstream prevention strategies concerned with redistributing social and structural determinants of health to alleviate disparities and promote SGD safety and well-being. The proposed research will fulfill the dissertation and degree requirements for Ms. Kennedy, PhD student at the Johns Hopkins Bloomberg School of Public Health. The training will be mentored by experts in SGD health equity, policy evaluation, social science methods, and translational science with one Sponsor, one Co-sponsor, and two Collaborators. The training plan outlines didactic coursework, trainings, and workshops, experiential learning via research assistantships, mentored dissertation study, and other advanced training opportunities to prepare Ms. Kennedy to meet her career goal of becoming a leading health equity researcher and advocate in violence prevention for SGD populations.

NSF Awards · FY 2024 · 2024-08

Various plasma waves are excited in near-Earth space during geomagnetic storms, and the waves affect the behavior of particles carrying the ring current and the strength of the flux of energetic electrons in the radiation belts. Ultra-low-frequency (ULF) waves with frequencies below 100 mHz play an essential role in this regard, and understanding the spatial and temporal occurrence patterns and the excitation mechanism of the waves is a crucial element in magnetospheric research. The investigation focuses on a recently reported new type of compressional ULF waves in the inner magnetosphere with a symmetric (fundamental) mode structure about the magnetic equator. Antisymmetric (second harmonic) waves are commonly detected and well-documented in the literature. The team aims to determine the relevance of drift compressional instability (DCI) to stormtime magnetospheric ULF waves. The investigation has broader impacts regarding wave-particle interactions occurring on other planets and in laboratory plasmas. In addition, the investigation will contribute to building improved space weather models that are valuable beyond the context of basic research. The goal of the investigation is to observationally determine whether the physical properties of symmetric ULF waves and the particle environment associated with the symmetric waves are consistent with DCI. To this end, we will use data from the Van Allen Probes (RBSP), which include electric and magnetic fields, plasma, and energetic particles. With the RBSP mission providing measurements in the inner magnetosphere ( < 6) over a 7-year period (2012–2019), the data are ideal for determining the mode structure of ULF waves, their spatial and temporal distributions, and the properties of the background particles. We will determine the mode structure by paying attention to the relation between the spacecraft latitude and the location of the equatorial node/antinode of ULF waves. The relevance of DCI to observed symmetric waves will be discussed by evaluating the theoretical instability condition using observationally determined energy and radial distance dependence of the phase space density of ions in the ring current energy range (1-300 keV). We will discuss the statistically determined spatial occurrence pattern of the waves in relation to the drift of ions injected from a nightside source region. 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 · 2024-08

Project Summary/Abstract Alzheimer's disease (AD) is a global issue that must be solved urgently because of its significant impact on public health and economics, as well as the quality of life of individuals in the United States and other aging societies. Once cognitive impairment occurs in the AD continuum, there are great difficulties in modifying the devastating disease process. Pathological changes inside the brain begin silently many years before the onset of cognitive impairment. This long “preclinical” stage provides us with an opportunity for timely therapeutic and preventive interventions. Therefore, the development of tools that can predict future cognitive decline during the preclinical stage of AD is crucial. There is a consensus that neurodegeneration has a stronger correlation with cognition in the disease progression along the AD continuum, compared to the diagnostic AD biomarkers such as amyloid and tau proteins. In contrast, neuroimaging modalities currently used to detect biomarkers for neurodegeneration are not sensitive enough to detect minute changes during the preclinical stage of AD. Here, Dr. Yuto Uchida hypothesized that myeloarchitectonic features observed in the entorhinal-hippocampus pathway could serve as sensitive neurodegenerative biomarkers given that AD pathogenesis occurs in the entorhinal cortices. In this project, he will conduct a proof-of-concept study to examine microstructural neurodegeneration of the entorhinal- hippocampus pathway in a combined framework: ex vivo ultra-high-field quantitative MRI followed by histological verification in Aim 1, and in vivo ultra-high-field quantitative MRI in clinical settings for healthy controls in Aim 2 and for preclinical and prodromal AD individuals in Aim 3. In Aim 1, postmortem hemibrains will be scanned on a human 7T MRI scanner and compared with the corresponding histology in the entorhinal-hippocampus pathway to fill the gap between the MRI findings and microscopic observations. In Aim 2 and Aim 3, cutting-edge, deep learning-based susceptibility tensor imaging (DeepSTI) and DeepSTI-based tractography will be applied to an ongoing cohort study (RF1AG071515), which comprises healthy, preclinical, and prodromal AD individuals. In Aim 2, reference ranges for quantitative MRI measures in the entorhinal layer II and the perforant path fibers will be established. In Aim 3, comparative analyses of these quantitative MRI measures among the groups will be done cross-sectionally, which will be followed by a longitudinal study to examine these associations with cognitive decline along the AD continuum. In summary, the long-term objective of this K99/R00 application is to support Dr. Yuto Uchida’s ability to conduct studies aimed at developing biomarkers for neurodegeneration that can visualize and quantify microstructural brain alterations during the preclinical stage of AD using ultra-high- field quantitative MRI. Dr. Uchida will be co-mentored by Drs. Kenichi Oishi, Xu Li, Jeremias Sulam, Hanzhang Lu, and Juan C. Troncoso, who are experts in neuroanatomy, MRI physics, deep learning-based algorithms, neurofunction, and histopathology, respectively. Having multiple mentors with different areas of expertise can broaden Dr. Uchida’s technical and scientific skills and further his goal of becoming an independent investigator.