Johns Hopkins University

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.

NIH Research Projects · FY 2025 · 2023-12

Project Summary Malaria remains an important public health issue. The oocyst stage is the most under-studied stage of the malaria parasite due to technical difficulties in isolating and staining these parasites and the lack of robust in vitro cultures. This is the expansion phase of the parasite in the mosquito host yet we have only a rudimentary understanding of the magnitude of this expansion: To date, only two studies have attempted to quantify the number of sporozoites in single oocysts, likely due to the time-consuming nature of manual counting. To overcome this and perform more robust quantification, we will develop methods to accurately quantify sporozoites in single oocysts using super-resolution imaging and deep-learning based image processing pipelines. The methodology will be validated by manual quantification. Furthermore, we will use the method to investigate mosquito species-specific differences in the magnitude of oocyst maturation using different parasite isolates in Asian and African mosquito vectors. This method can be further developed to classify oocyst microstructures and enable in-depth studies of stage specific gene and protein expression over the entire developmental cycle of the oocyst in combination with in situ -omics methodologies. It is also anticipated that an accurate assessment of the magnitude of oocyst maturation will improve our understanding of the quantitative dynamics of parasite transmission from mosquito to mammalian host.

NIH Research Projects · FY 2026 · 2023-12

The rising prevalence with advancing age and the adverse impact of debilitating diseases like Alzheimer’s disease and related dementias (ADRD) has led to a need for clinical and research methods for measurement of effects of these diseases. Cognitive tests, biomarkers, informant reports, imaging data, and a wealth of other measures play major roles in detecting, diagnosing and monitoring disease status and progression. Greater demographic diversity creates special challenges for accurate measurement of cognition. Most cognitive tests that are in clinical and research use were developed using psychometric methods from the first half of the 20th century. There have been substantial advances in measurement theory and methodology, notably item response theory (IRT) and associated latent variable modeling methods, that could have an important impact on the measurement of cognition. There have been parallel advances in statistical methodology for modeling longitudinal cognitive trajectories and identifying characteristics that impact these important outcomes. This conference series is designed to promote the application of modern psychometric and statistical methods in research on cognitive aging and ADRD. Specific goals are: 1) to expose developing and established researchers in cognitive aging and ADRD research to modern psychometric and statistical modeling techniques, 2) to expose experts in psychometric theory and statistics to the practical and theoretical concerns of cognitive aging and Alzheimer’s disease research, and 3) encourage collaborations of researchers, psychometricians, and statisticians during these conferences. We have conducted 14 successful annual conferences since initial funding of this grant in 2008, which has generated 84 collaborative publications to date. This experience has helped to shape our plans for the next generation of conferences. The format of the conferences includes didactic presentations by experts in cognitive aging and applied psychometric theory, demonstrations of methods, and most importantly, hands-on experience using real data. This content and format is not only appropriate for encouraging education and collaboration of seasoned researchers but has also been an extremely effective learning environment for graduate students, postdoctoral fellows, and junior faculty. Conference themes for the proposed five-year renewal period are: 1) Cross-national comparisons of cognitive aging outcomes and correlates, 2) synthetic data sets, 3) Advances in algorithms for diagnosing cognitive impairment and dementia, 4) Advanced Methods for Understanding Racial and Ethnic Inequalities in Cognitive Aging and Dementia, and 5) Global pandemic and Cognitive Aging. All conferences address methods and substantive science issues that are relevant for research to understand, diagnose, monitor, and treat ADRD and related causes of cognitive decline. There will be a heavy emphasis on workgroups organized around scientific analyses of real data, and we plan to disseminate the information resulting from these workshops through publications in peer reviewed scientific journals and through conference presentations.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract: The pathologic accumulation of misfolded α-synuclein (α-syn) in neurons leads to neurodegeneration and cognitive dysfunction and dementia in a family of disorders designated α-synucleinopathies, which includes Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) dementia (PDD). DLB and PDD are clinically similar and share characteristic neuropathologic changes. Recent studies indicate that activation of poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) contributes to the neurodegeneration induced by pathologic α-syn through the Parthanatos associated AIF (apoptosis-inducing factor) Nuclease (PAAN) also known as MIF, where PAAN/MIF is the executioner of parthanatic cell death via its nuclease activity. This form of cell death has been designated parthanatos to distinguish it from other types of cell death such as apoptosis, necroptosis or autophagic death. Interference with each step of the parthanatic cascade has been shown to be neuroprotective in a variety of disease models. Recently, MIF nuclease activity was shown to be required for neurodegeneration of dopamine neurons in three orthogonal models of PD. Importantly, the role of PAAN/MIF nuclease activity in the cognitive dysfunction in α-synucleinopathies is not known. Moreover, the effect of PAAN/MIF nuclease-specific inhibitors in α-synucleinopathies cognitive dysfunction has not been investigated. MIF has also been suggested to be required for inflammasome activation. MIF possesses both nuclease and tautomerase activity that act independently of one another. It is not known whether PAAN/MIF’s nuclease activity plays a role in activation of the double strand DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) and subsequent STING (stimulator of interferon genes) pathway and inflammasome activation. What role MIF’s tautomerase activity plays in inflammasome activation is also not known. Determining whether MIF nuclease activity or tautomerase activity is required for cGas-STING pathway activation is important since it could direct the development and use of specific MIF inhibitors to prevent cGas-STING pathway and inflammasome activation. Accordingly, in this project we will examine the neurobehavior and neuropathology of pathologic α-syn in the gut-brain model in MIF wild type and MIF E22Q (nuclease-deficient) and MIF P2G KI (tautomerase-deficient) mice and test whether the brain penetrant MIF nuclease inhibitor, PAANIB-1, can prevent the spread of pathologic α-syn and cognitive behavioral abnormalities in the gut-brain model in behaviorally presymptomatic and symptomatic mice. In addition, we will determine whether MIF nuclease activity is required for cGas-STING pathway and inflammasome activation in pathologic α-syn induced neurodegeneration and explore the role of neuronal versus microglial MIF nuclease activity in pathologic α- syn induced cognitive dysfunction and neurodegeneration.

NIH Research Projects · FY 2026 · 2023-12

The E4 allele of apolipoprotein E (APOE4) is the most common genetic risk for Alzheimer's Disease (AD). Given the function of apolipoproteins in the transport of lipids and cholesterol, it is believed that individuals with APOE4 have impaired lipid metabolism leading to atherosclerosis and dementia. However, the role of APOE4 on Alzheimer's Disease and dementia remains unclear, and there are likely to be additional roles for APOE4 beyond its putative role in lipid transport. There is emerging evidence that the hypothalamic pituitary adrenal (HPA) axis, which is necessary for mounting the fight-or flight stress response, may be dysregulated in individuals with the APOE4 allele. Specifically, APOE4-carrying individuals and mice with APOE deficiency both exhibit elevated levels of baseline stress hormones as well as pronounced stress response following exposure to stress. There is already substantial evidence linking chronic exposure to stress and subsequent repetitive HPA axis activation to AD. Aging, the primary risk factor for AD, can be defined as the body's lifelong effort to maintain allostasis, which refers to the mechanism engaged by the body to maintain homeostasis during cumulative “wear and tear” from various forms of environmental stressors. As such, the failure to achieve allostasis results in increased “allostatic load” in the form of elevated levels of the catabolic stress hormone cortisol. Chronically elevated levels of cortisol have long been linked to cognitive impairment and reduced brain volumes, which are the hallmark symptoms of AD. Taken together, these studies raise the possibility that APOE deficiency may precipitate AD- related symptoms by overstimulating the HPA axis and causing excess “wear and tear” across age. We will explore this potential interaction between the APOE gene and the HPA axis by using mice harboring the humanized APOE3 protective allele or the APOE4 risk allele and subjecting them to chronic stressors. We will document their stress hormone and lipid levels and correlate them to scores on tests of learning and memory. This will help us determine whether cortisol or lipid levels mediate the effect of APOE deficiency on cognition. To find further evidence of HPA axis dysregulation, we will examine stable epigenetic changes in the function of genes that are associated with the HPA axis. We will examine an epigenetic modification known as DNA methylation that has been linked to allostatic load in mice exposed to stress hormones. Identification of these changes in stress exposed APOE3/APOE4 mice will provide strong evidence for HPA axis dysregulation in APOE4 mice. Finally, we will pharmacologically and genetically alter the ability of APOE4 mice to mount a stress response. We will measure the effect of using inhibitors and modulators of two primary proteins that regulate stress hormone signaling on learning and memory. Genes that encode these two proteins will be epigenetically manipulated using a modified gene-editing tool to further corroborate our hypothesis. Proving our hypothesis will not only lead to a paradigm shift in our view of the role that APOE plays in AD, but also provide novel therapeutic strategies that are much needed for the prevention and treatment of AD.

NIH Research Projects · FY 2025 · 2023-11

Project Summary Extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) bloodstream infections (BSI) are associated with mortality upwards of 30%. It is unknown whether optimal antibiotic treatment differs based on the type of ESBL enzyme produced. Most microbiology laboratories do not test bacteria for ESBL production, opting instead to use non-susceptibility to third-generation cephalosporin antibiotics “3GCephNS” (e.g., ceftriaxone MIC ≥2 µg/mL) as a proxy for ESBL production. While this approach is pragmatic, it has hampered progress in understanding the molecular epidemiology and targeted treatment strategies for ESBL families. Our preliminary data suggest that 3 ESBL families account for ~99% of ESBLs: CTX-M (~60%), SHV-variants (~25%), and TEM-variants (~15%). However, our understanding of optimal treatment of ESBL-E is limited to CTX-M-producing infections. A resistance mechanism-based approach has been used to optimize antibiotic treatment against carbapenemase genes (e.g., blaKPC, blaNDM), contributing to a ~200% reduction in mortality. We believe a similar “precision medicine” approach should be investigated for treating ESBL-E BSI. The need to characterize the type of ESBL produced is demonstrated by a clinical trial comparing outcomes of patients with 3GCephNS BSIs receiving either piperacillin-tazobactam (PTZ) or meropenem. Mortality was significantly lower for patients receiving meropenem. Meropenem was henceforth adopted as first-line therapy for 3GCephNS BSIs (and by extension ESBL-E BSI). However, 87% of patients (no US patients included) were infected with CTX-M-producing isolates. While CTX-M are the most common ESBL enzymes, they are not the only ESBLs. It is unknown if meropenem is the preferred therapy for SHV and TEM ESBL variants. There are differences in preferred substrates, inhibitors, and hydrolyzing abilities across ESBL enzymes. PTZ may be effective treatment for BSI caused by specific ESBL families, as supported by our preliminary data. If indeed, PTZ is a reasonable treatment option for certain ESBL-E families, then prescribing meropenem for all ESBL-E infections without discrimination based on the type of ESBL family will only serve to fuel the crisis of carbapenem-resistant Enterobacterales, without leading to improvements in patient outcomes. Using a cohort of 2,000 consecutive 3GCephNS Enterobacterales BSI (diverse species) from 5 US hospitals, we will characterize the epidemiology of β-lactamases. We hypothesize that blaCTX-M genes comprise ~60% of β-lactamase genes. For ~40% of isolates, non-CTX-M ESBL genes (± ampC or narrow-spectrum β-lactamase genes will be identified). Then, we will conduct an observational study to determine if patients infected with BSI isolates producing non-CTX-M ESBL enzymes (i.e., SHV or TEM) have improved outcomes if receiving meropenem vs. PTZ using a sophisticated inverse probability of treatment weighting approach incorporating propensity scores. We hypothesize that PTZ will be effective treatment for ESBL-E caused by SHV and TEM families given their reduced β-lactam hydrolyzing potential.

NIH Research Projects · FY 2025 · 2023-11

PROPOSAL SUMMARY The incidence of HIV in Baltimore, MD is among the highest in the US, with men who have sex with men (MSM) bearing a disproportionate burden of the disease. As we enter the “95-95-95” era of the Joint UN Program on HIV/AIDS (UNAIDS) Fast Track targets, research into innovative approaches that extend the prevention toolbox is needed. Long-acting (LA) cabotegravir (CAB) for HIV pre-exposure prophylaxis (PrEP) was recently approved by the FDA based on data that demonstrated superiority to tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). LA PrEP may help overcome key challenges of oral PrEP by increasing PrEP use/uptake, particularly among key populations, such as MSM. Furthermore, much research has shown that social and structural determinants of health (SSDoH), such as poverty, racism, access, homonegativity and discrimination and individual and community-level factors, such as stigma, knowledge, and perception towards PrEP shape access and uptake of PrEP among MSM individuals. Studies to date have explored the acceptability of LA PrEP as a hypothetical option among MSM; however, since the FDA approval of LA CAB in December 2021, little is known about perceptions and acceptability of LA PrEP in high-risk MSM communities and its relation to sexual network structures (e.g., how do the perceptions and behaviors of one’s contacts influence one’s own perception of LA PrEP). Further, even among those on oral PrEP, little is known about the knowledge, acceptability, and preference of daily tenofovir alafenamide (TAF) vs. TDF-based regimens and further still, daily oral PrEP vs. TDF/FTC 2-1-1 (on-demand) PrEP, which was not included in CDC guidelines until 2021. The applicants proposed study, Extending the Prevention Toolbox: Exploring the Acceptability and Impact of Long-acting Injectable PrEP among MSM in Baltimore: A Pilot Study will address this gap. This study will gather data on community preferences for PrEP choices among MSM in Baltimore and use this information to inform messaging and support mechanisms, as well as generate data on behaviors and networks to inform epidemiological models and policies to reduce barriers to PrEP. This will be accomplished through the following aims: Aim 1: To use thematic analysis from the parent study focus group interviews, to refine a cross-sectional survey including a DCE module for PrEP preferences with random allocation of attributes (i.e., cost, side-effects, effectiveness, insurance coverage etc.) within each PrEP choice set. Aim 2: To characterize MSM sexual networks in Baltimore (N=500) to determine the impact of predisposing, enabling, and perceived need factors on PrEP use/uptake. Aim3: To evaluate how sexual network characteristics impacts PrEP use/uptake and preferences among MSM; H1: The use/uptake of PrEP is positively associated with PrEP use within sexual networks and H2: PrEP preferences, as determined in the DCE are positively associated with sexual network partner preferences. This innovative study builds on over many months of preliminary work of conducting focus groups and qual data analysis for the parent study. It establishes a foundation for future studies to evaluate the role of LA PrEP in MSM communities to implement an informed PrEP strategy.

NSF Awards · FY 2023 · 2023-10

Abstract The tightening of regulation in the U.S. banking sector following the Financial Crisis of 2008 contributed to a surge of alternative nonbank lenders and, in particular, business development companies (BDCs). This sector has expanded rapidly over the last two decades. This project will construct an extensive database and conduct the first systematic analysis of the BDC sector. The project will focus on these new lenders and provide insights into an important yet understudied segment of the U.S. economy - the middle market, which accounts for a third of private-sector employment. Specifically, the project will investigate the impact of nonbank lending on middle-market firms and economic growth. Overall, the project will have important policy implications for the role of financial intermediation in the economy. By constructing a novel database, this project will advance the body of knowledge on nonbank lending. First, the project will investigate the causes of the BDC sector growth and analyze their role in financing middle-market firms. The granularity of the dataset will additionally allow to characterize the borrowers targeted and lending solutions offered. Second, the project will use the location information of BDC portfolio companies to estimate the real effects of these direct lenders on middle-market firms and, more broadly, on local economic growth. Third, the project will investigate how access to capital markets affects investment activities of direct lenders. Finally, since BDCs provide funding to firms without relying on deposit insurance, they put forward a new lending model that may offer an improvement to the current deposit-based banking system. To understand the effects of this alternative lending mechanism, the project will develop a quantitative framework to conduct a welfare analysis of transitioning to a new lending environment. 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 · 2023-10

PROPOSAL SUMMARY Migration is a social determinant of health which has profound and long-lasting health consequences, and contributes to the significant disparities in mental health outcomes experienced by Latina immigrants. Shifts in migration patterns from Latin America over the last decades – driven in part by sociopolitical conflict, organized violence, and evolving gender norms – have contributed to unprecedented growth in the population of Latinas in the US. Latina immigrants face cumulative exposure to an array of traumatic experiences before, during, and after migration – including sexual assault, natural disasters, kidnapping, separation from/and death of family members, and deprivation of basic needs. These are deeply traumatic experiences which are associated with poor mental health outcomes (posttraumatic stress disorder, depression and anxiety). Presently, suicide is a leading cause of death among Latinas in the U.S., but there is limited research seeking to identify the distinct factors that heighten the risk of suicide and that promote resilience among Latina immigrants. Furthermore, there is a significant gap in knowledge regarding Latina immigrant’s lived experiences with suicide and migration- related trauma and understanding how these women utilize communal and cultural resources – such as communal coping, collective rituals, and traditional gatherings – to cope with the collective impact of migration- related trauma and chronic stress. This exploratory sequential mixed-methods study aims to generate a rich understanding of the experiences of Latina immigrants with migration-related trauma, suicide and suicidal ideation, and social stressors, and to identify salient cultural and communal factors that shape these experiences. This will be accomplished through the following aims: 1a) explore how exposure to migration-related trauma, communal coping, and social stressors influence the risk of suicidal ideation and mental health symptoms among adult Latina immigrants (n=20) using individual interviews and focus groups; 1b) understand community providers’ and team members’ (promotoras, nurses, and clinicians) (n=16-20) perspectives of how migration- related trauma, communal coping, and social stressors impact the mental health outcomes of Latina immigrants using focus groups; 2) examine how migration-related trauma, social stressors, communal coping and other salient cultural, migratory, and communal factors impact suicidal ideation and mental health symptoms among Latina immigrants using a cross-sectional survey; and 3) collaborate with community partners and the community advisory board to interpret and integrate findings and identify risk and resilience factors that shape experiences with suicide and the mental health outcomes of Latina immigrants. This innovative study builds on over a year of preliminary work, including community engagement efforts, a systematic review of the literature and concept analysis, and conceptual framework development. We center the cultivation of collaborations between the PI, mentorship team, our community partners at Centro SOL, and the Latino(a) immigrant community in the Baltimore Metropolitan Area. To our knowledge, this innovative proposal will be the first to explore the impact of migration-related trauma (across the stages of migration), social stressors, communal coping, and other salient cultural and communal factors on the mental health outcomes of Latina immigrants.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Neutral sphingomyelinase 2 (nSMase2 encoded by SMPD3 gene) is a membrane associated enzyme that catalyzes the hydrolysis of sphingomyelin (SM) into phosphorylcholine and ceramide. Formation of ceramide- enriched areas by the action of nSMase2 is known to facilitate generation of extracellular vesicles, which participate in intercellular communication in both physiological and pathological processes through encapsulation and transfer of diverse types of substances including tau protein. Interestingly, post-mortem brains from AD patients exhibit abnormal increases in ceramide. Inhibition of nSMase2 has therefore become an attractive therapeutic strategy to treat AD by inhibiting EV biogenesis to slow the spread of pathogenic cargo. The main objective of this project is to conduct structural optimization using (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6- dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC), a prototype nSMase2 inhibitor, as a molecular template with the ultimate goal of identifying development candidates with balanced overall pharmacological profiles required for clinical translation. By assembling a multidisciplinary team of investigators with complementary expertise, we are poised to seize this opportunity by executing the following specific aims; (Aim 1) Conduct structure-activity relationship (SAR) studies on nSMase2 inhibitors containing a core scaffold different from that of PDDC; (Aim 2) Characterize the ADME (absorption, distribution, metabolism and excretion) and in vitro selectivity/toxicity profile of potent nSMase2 inhibitors from Aim 1. Identify optimal dosing for efficacy studies in Aim 3; (Aim 3) Evaluate selected nSMase2 inhibitors from Aim 2 for efficacy and tolerability in an AAV tau propagation model and a PS19 transgenic model of AD.

NIH Research Projects · FY 2023 · 2023-09

PROJECT ABSTRACT Of the nearly one million people who reside in assisted living (AL), up to 70% have some form of cognitive impairment and 40% have a diagnosis of Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD). AL staff provide services including help with dressing and meals, and nearly 25% of ALs provide specialized care for people living with AD/ADRD (also known as “memory care”). Very little is known about the quality of memory care. To improve AD/ADRD care, consumers must understand whether the quality provided in memory care settings, at a surcharge of almost 36% compared to a room in general AL, is worth the cost. The objective of this application is to examine variation in the quality of care for AL residents with AD/ADRD. It is hypothesized that residents with AD/ADRD in ALs that provide memory care receive higher quality care than their counterparts in ALs that do not provide memory care (“between” AL effects). Also, it is hypothesized that residents with AD/ADRD in ALs without memory care experience poorer quality of care than residents without AD/ADRD (“within” AL effects). Conversely, residents with AD/ADRD in ALs with memory care experience similar quality of care compared to residents without AD/ADRD. To test these hypotheses, the research team will leverage the data and methods that they have developed to 1) identify Medicare beneficiaries residing in ALs; 2) connect policy data to specific AL communities; and 3) combine more than 2,000 AL communities’ employee and resident/family satisfaction surveys with national, administrative data. In response to NOT-AG-21-046, the project has the following specific aims: 1. Compare quality outcomes (i.e., worker satisfaction, resident/family satisfaction, healthcare utilization) between ALs that do and do not provide memory care. Working hypothesis: ALs that provide memory care will have better quality outcomes than ALs that do not provide memory care. This aim looks at how quality varies between ALs. 2. Compare the difference in quality outcomes of residents with and without AD/ADRD within ALs that do and do not provide memory care. Working hypotheses: 2a) within general ALs, residents with AD/ADRD will have poorer outcomes than residents without AD/ADRD; 2b) within memory care ALs, there will not be a significant difference in quality outcomes between residents with and without AD/ADRD. This aim looks at how quality varies within ALs. 3. Understand the processes of care that contribute to quality outcomes for residents with AD/ADRD among ALs that do and do not provide memory care. Semi-structured interviews and on- site observations in ALs that do and do not provide memory care will identify the processes of care that are associated with satisfaction and experience of care for residents with AD/ADRD. The project is significant because it will provide national data about AL care for people living with AD/ADRD.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Cigarette smoke (CS) is a complex mixture of toxins (e.g., nicotine, carbon monoxide) that affects multiple tissues of the eye including the cornea, the outermost tissue of the eye. The cornea is at high risk due to its proximity to the burning end of the cigarette and flying ash. Corneal endothelium (CE) is the innermost layer of the cornea responsible for corneal hydration. CS results in progressive corneal endothelial cell (CEC) loss leading to corneal edema and vision loss if remains untreated. The severity of CS-induced corneal edema is further compounded with preexisting morbidities such as corneal endothelial dystrophies and diabetes. Our preliminary studies of proteome profiling have demonstrated that CS triggers CEC loss and disruption of critical structural proteins in Descemet’s membrane (DM). We further identified elevated levels of oxidative stress-associated indicators and decreased levels of CE-associated markers in response to cigarette smoke extract (CSE) treatment in human induced pluripotent stem cell (iPSC)-derived CEC monolayer cultures. In parallel, we have shown that human embryonic stem cell (hESC)-derived CECs can form a functional CE on denuded DM (DM without CE) in rabbits and monkeys. Moreover, we have also shown that injected hESC-derived CECs can form a functional CE on denuded stroma (stroma without CE and DM). In this application, we will build on these datasets through large-scale screening of cellular pathway modulators to establish a non-invasive topical eye drop approach. In parallel, we will demonstrate the efficacy of the iPSC-derived CECs injection technique as a minimally invasive, donor tissue-independent, treatment modality. Taken together, the combined knowledge gained from identifying modulators and cell therapy will make a paradigm by offering an unlimited source for the treatment of oxidative stress-induced CE disorders.

NIH Research Projects · FY 2025 · 2023-09

Opioid use disorder (OUD) is a rapidly escalating public health crisis with recent evidence suggesting that close to 70% of drug overdoses involved opioids in the last year. Although many individuals seek treatment for OUD over half return to use despite being maintained on a medication for opioid use disorder (MOUD), underscoring the critical need to identify factors that are associated with OUD reoccurrence. Chronic opioid use has been linked to disturbances in sleep continuity and architecture, increased risk of sleep disordered breathing (SDB), and abnormalities in proxy measures of circadian rhythms. However, less is known about the longitudinal association of sleep/circadian phenotypes with non-medical opioid use among individuals in OUD treatment, and malleable pathways that may account for these associations. Such knowledge is critical to informing translational research and the development of novel interventions aimed at improving sleep, circadian rhythms, and OUD outcomes. The proposed observational, longitudinal study will capitalize on existing collaborations with community-based providers to determine the association of sleep duration, sleep architecture, SDB, and proxy measures of circadian rhythms with illicit opioid use during treatment, and potential pathways (e.g., positive and negative affect) that may influence these relationships. Participants (N = 130) will be enrolled in buprenorphine or methadone treatment and complete a 6-month longitudinal study wherein they will complete overnight, in-lab polysomnography (PSG) sessions three times to assess changes over time in sleep metrics (e.g., total sleep time, sleep architecture, SDB). Before and after PSG sessions, we will collect saliva samples from participants to determine diurnal cortisol patterns. Participants will also be fitted with a wrist-worn actigraphy device to further quantify sleep and circadian rest activity rhythms. At baseline and during the final week of each month of treatment, participants will complete a week-long “data burst” that includes ecological momentary assessments of affect, craving, and stress. Participants will complete urine toxicology screens and self-report on their drug use at the end of each data burst. Specific aims of the study are to (Aim 1) determine the bi-directional association of circadian RARs and diurnal cortisol patterns with non-medical opioid use, (Aim 2) investigate whether sleep duration and architecture over the course of treatment are associated with non-medical opioid use, and (Aim 3) examine (a) associations of MOUD use with SDB, and (b) whether SDB is associated with low positive affect and high negative affect. We will also explore whether clinically significant sleep and circadian rhythm phenotypes are associated with low positive affect, high negative affect, and non-medical opioid use, and whether affective processes mediate the association of sleep/circadian rhythm phenotypes and opioid use. Findings from this project will enhance our understanding of specific sleep and circadian rhythms parameters implicated in OUD, and the relationships among sleep phenotypes, affective processes, and non-medical opioid use. This highly rigorous study will shed light on clinically relevant endpoints for future intervention trials.

NIH Research Projects · FY 2024 · 2023-09

Project Summary- Prehospital Emergency Medical Services (EMS) are an indispensable component of the US health care system, occupying a crucial role at the intersection of medical care, public health, and public safety. EMS professionals' work is unique, extraordinarily demanding at cognitive and physical levels, and requires highly adaptive, unwaveringly resilient performances. The unpredictable nature of each dispatch, scene setting and patient presentation brings together a myriad of performance shaping factors that often very dynamic and highly variable. Study of `real time' pre-hospital cognitive work, at the individual (EMS professionals) and distributed/ team-based levels (EMS interactions with patients/caregivers, 911 dispatch) is limited despite being fundamental for navigating fluctuating degrees of risk inherent in prehospital emergency care. In response to the need for targeted research in support of overlooked areas of EMS cognitive work, we propose to establish the Resilient_EMS Patient Safety Learning Lab (PSLL), focused on enhancing and supporting safety, quality, and equity within pre-hospital emergency care. This project will focus particularly on prehospital care of older adults (≥ 65 yrs). The Resilient_EMS PSLL is tailored to use systems and human factors engineering approaches to innovate in support of EMS professionals' cognitive work as individuals (e.g., decision making) and in a distributed manner (e.g., sharing mental models). As such, we will conduct a 4- year, multi-site, multi-method field study of geriatric pre-hospital emergency care to achieve 3 specific aims: Aim 1. To identify and define individual and distributed cognitive work system characteristics that impact safety, quality, and equity along the continuum of prehospital resuscitative care (dispatch call transition of care) for older adults presenting with a `potentially critical' chief medical (non- trauma related) complaint (e.g., respiratory distress, acute onset of altered mental status etc.). Aim 2. To co-design with key stakeholders (EMS professionals, patients (older adults)/ caregivers, other professionals) potential solutions to support cognitive work of EMS professionals (individual and team/based levels) required for dynamic resilient performances using `human-centered/ inclusive design' principles and methodologies. Aim 3. To implement and evaluate proposed design/redesign solutions using a multi-pronged approach for improving safety/ quality/ equity along the continuum of resuscitative care for older adults through support and enhancement of EMS professionals' individual and distributed cognitive team-based work. Resilient_EMS PSLL's long term impact will be new insights into the very challenging domain of prehospital care that will aid in creation of innovative and inclusive/ human-centered solutions. Our research team is composed of experts in patient safety, human factors, systems engineering, communication, prehospital care, emergency medicine, geriatrics, nursing, health disparities, and patient/family partners. The study will address several AHRQ priority populations (older adults, low income, racial/ ethnic minorities, rural/inner-city residents, women).

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY ABSTRACT Electronic cigarettes (e-cigarettes) are among the most important issues in public health today. Although e- cigarettes have shown promise as a cessation aid for traditional cigarettes, the public health benefits of these products may be undermined by the soaring rates of initiation among previously nicotine-naïve youth and the propensity for these products to foster nicotine dependence. There are a growing number of people who report wanting to quit using e-cigarettes and not being able to do so successfully, underscoring the need for research to determine factors that impede e-cigarette cessation. When smokers abstain abruptly from combustible cigarette use, a withdrawal syndrome emerges that includes core symptoms of negative affect and craving, impaired cognitive functioning, and disturbed sleep, all of which ultimately hinder cessation attempts. However, there is very limited controlled research on e-cigarette withdrawal, and it is unknown the extent to which nicotine contributes to any emergent e-cigarette withdrawal syndrome. This project will use a rigorous residential laboratory design to evaluate e-cigarette withdrawal expression and experimentally determine the role of nicotine in this syndrome. Healthy adults who exclusively use e-cigarettes (N=120) will undergo monitored e-cigarette abstinence over seven days (1 week) in a residential unit. We will evaluate the contribution of nicotine to withdrawal expression by assigning participants to one of three conditions: active nicotine patch, placebo patch control, or no patch to control for expectancies. Standardized behavioral and biological measures associated with withdrawal including patient report, cognitive task performance, and biometrics will be collected throughout to establish a rigorous timecourse of withdrawal and evaluate the contribution of nicotine to these symptoms. Three Specific Aims are designed to test core features of nicotine withdrawal mirroring three core areas of nicotine/tobacco withdrawal described in the DSM-5. Specific Aims will evaluate the timecourse and contribution of nicotine to withdrawal-induced changes in subjective mood (Specific Aim 1), cognitive performance (Specific Aim 2), and sleep disturbance (Specific Aim 3). An Exploratory Aim will evaluate the impact of withdrawal on motivation and return to use. We hypothesize negative affect and craving will increase, cognitive performance will decrease, and sleep will be impaired during the residential abstinence period. We also hypothesize that withdrawal symptoms will be attenuated with nicotine patch relative to both control conditions. This research will use a rigorously-controlled residential study to provide vital information about the clinical significance of behavioral and biological e-cigarette withdrawal symptoms and demonstrate the role of nicotine in the expression of withdrawal to inform the viability of translating established and readily accessible nicotine replacement interventions to e-cigarette cessation.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Universal firearm injury and violence prevention counseling of parents and patients has been recommended by multiple national organizations for over a decade, yet clinicians rarely deliver this counseling. Barriers to its implementation must be addressed in order to effectively deliver firearm related injury prevention efforts. The research team has demonstrated success in the implementation and sustainability of alcohol screening, brief intervention and referral to treatment protocols in two federally funded multi-site trials at pediatric trauma centers. The team also has expertise in clinically-based strategies for firearm injury prevention and educational program development. We will apply our implementation science and subject matter expertise to implement a universal firearm injury prevention initiative within a national cohort of three pediatric trauma centers with which we have previously collaborated on multisite research. Our long-term goal is to demonstrate best practices for pediatric trauma center-based firearm injury prevention strategies that promote safe storage practices and reduce firearm related injury and death. This proposal, submitted in response to RFA-CE-23-006 funding option B, will test the effectiveness of a comprehensive training strategy for improving the implementation of a universal firearm injury prevention effort, ACTFAST (Adopting Comprehensive Training for FireArm Safety in Trauma centers), through the following primary aims: 1) increase the adoption, implementation and sustainability of a universal firearm injury prevention initiative within participating pediatric level 1 trauma centers; 2) increase firearm safety knowledge, attitudes and safe firearm storage practices among parents of pediatric trauma patients treated within participating pediatric level 1 trauma centers, and through the following secondary aims: 1) increase trauma center clinicians’ firearm safety knowledge and confidence in delivering a firearm safety intervention; 2) increase firearm safety knowledge, attitudes and firearm safety practices of adolescent trauma patients (11-17 years) within participating pediatric level 1 trauma centers. Using the RE- AIM methodology, we will evaluate our comprehensive strategy across the domains of adoption, implementation, and maintenance at the institutional level. We will measure clinician firearm safety knowledge and confidence in delivering firearm prevention counseling after participation in the clinician training program as measured by pre and post training surveys. In addition, we will collect and analyze parent (n=560) and adolescent patient (n=280) data before and after ACTFAST implementation for changes in knowledge, attitudes and, most importantly, practices at baseline and at 2 weeks and 3 months after hospital discharge.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Accurate shape perception is crucial to identifying and manipulating objects in our environment. Among our senses, vision and touch are unique in that they both convey geometric shape. Although haptic and visual sensory inputs are initially processed along distinct sensory pathways, we experience an object’s shape as a unified, modality-independent percept. How the brain generates modality-independent representations of shape remains unknown. Human fMRI studies have identified the lateral occipital complex (LOC) as a key area for visuo-haptic integration, yet the low spatial resolution of fMRI has failed to reveal the neural code used for representing object shape. To address this knowledge gap, I propose to study the representations of haptic and visual shapes in macaque inferotemporal cortex (IT), the homologue of human LOC. Specifically, I will test the hypothesis that macaque IT creates modality-independent representations of haptic and visual shapes. To this end, I will record the simultaneous activity of multiple neurons in IT while macaques are exposed to objects presented as visual images or as 3D-printed haptic objects. First, I will identify if and how IT neurons represent haptic shapes. Second, I will explore the neural basis of visuo-haptic shape representations in IT. By elucidating the neural mechanisms by which IT generates modality-independent shape representations, this research will shed light on how the brain is able to recognize shapes across sensory modalities. Furthermore, the findings of this project will support the development of next-generation neuroprosthetic implants that can leverage both haptic and visual sensory input.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Project Summary: Methadone is the oldest approved medication for treating opioid use disorder (OUD) and, for many patients, it is the optimal treatment for managing symptoms and reducing overdose risk. Since its approval in 1972, methadone has been dispensed nearly exclusively through highly regulated opioid treatment programs (OTPs), operating in fixed locations. In June 2021, however, the US Drug Enforcement Administration released a rule expanding methadone access by allowing OTPs to create mobile treatment units (motor vehicles equipped with secure dispensing) under their existing registration. To encourage mobile methadone implementation, the New York Office of Addiction Services and Supports launched a statewide pilot grant program to support the creation of mobile methadone and selected an initial thirteen grantees. Mobile methadone has the potential to expand methadone access and other services (e.g., counseling) to people who otherwise would need to travel long distances or experience challenges reaching traditional programs. This project will examine implementation of the New York pilot program with the goal of informing the feasibility and scope of implementing similar programs in other states during an ongoing national overdose crisis. This is consistent with the NIDA goals of increasing the public health impact of research and developing novel approaches to treatment. Aim 1 proposes to study barriers and facilitators to launching mobile programs among pilot OTPs and their community partners. Semi-structured interviews (N=40) will be conducted with staff members from pilot OTPs partner organizations that serve people with OUD in the local pilot site communities, such as social service agencies and harm reduction organizations. Interviews will explore opportunities and constraints that shape the early implementation of units in pilot site communities. Aim 2 explores the need and preferences for receiving mobile services among current and potential patients. A survey will be fielded with people with OUD (N=160): 80 current mobile methadone patients and 80 people with OUD not currently using any mobile services. Questions will examine preferences for care, individual service needs, and prior experiences receiving care. Aim 3 develops a location simulation tool to inform the selection of treatment stops for mobile units. Using claims data from the state the locations of current and potential mobile methadone clients (people with diagnosed OUD) will be mapped in relation to the brick-and-mortar OTPs. Using geospatial clustering methods, we will identify areas in the state with unmet need for services and develop a simulation approach for selecting areas within driving distance of the OTP to be served by mobile units, and predict the likely number of patients who would receive care at the units. The project will include regular briefings with stakeholders in New York, including OASAS staff and pilot grantees. Research will inform a future R01 to evaluate the longer-term impact of the New York program on access and overdose.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Choroidal neovascularization (CNV) is the leading cause of vision loss due to AMD. Although anti-vascular endothelial growth factor (VEGF) therapy has shown a great breakthrough in CNV treatment, persistent disease activity (PDA) is common. PDA has been demonstrated in 53% and 71% of patients treated monthly with ranibizumab and bevacizumab, respectively. 20% of patients become legally blind and another 30% suffer from some degree of vision loss after 5 years of anti-VEGF therapy. While AMD is a serious problem, one critical barrier limiting the ability to test novel therapies in preclinical settings is the lack of CNV animal models with PDA and the lack of methods for longitudinal monitoring of disease biomarkers and response to therapy. The goal of this project is to develop state-of-the-art multimodal molecular imaging for non-invasive and longitudinal assessment of the imaging biomarkers in a new CNV rabbit model with PDA to offer a platform technology for the development of novel therapeutics. We have developed a high resolution, multimodal ophthalmic imaging system incorporating photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence microscopy (FM). Novel chain-like gold nanoparticle clusters have been developed and used to enhance molecular imaging and target integrins present in CNV. We have also developed a robust animal model of PDA using older rabbits that demonstrate minimal response to anti-VEGF therapy. Encouraged by these exciting preliminary results, we propose to further develop this platform molecular imaging technology for AMD with a central hypothesis that a multimodal molecular imaging system that can evaluate the CNV animal model could contribute to understanding the fundamental biology of AMD and the development of new pharmaceutical therapies to treat CNV. We will test our hypothesis with the following Specific Aims: Aim 1: Upgrade the multimodal PAM, OCT, and FM system for real-time imaging in rabbit eyes. Aim 2: Test the prediction that young rabbits with robust response to anti-VEGF demonstrate capillary CNV while older rabbits demonstrate arteriolar CNV that can be visualized with multimodal imaging. Aim 3: Test the prediction that the rabbit models of CNV in response to anti- VEGF can be visualized at a molecular level with multimodal imaging powered by ultraminiature chain-like gold nanoparticles. The results of this work will include concepts, tools, and strategies for future research across several disciplines: a) Fundamental biology of AMD to visualize and quantify, with high spatial and temporal resolution, functional and molecular changes in living animals. b) Strategies for testing and developing novel drugs and non-pharmaceutical therapies in large eye models, particularly for CNV with PDA. c) Improved prognostication research to enable real-time molecular biomarkers of treatment response.

NIH Research Projects · FY 2025 · 2023-09

Defects of the anterior segment (AS) tissue lead to a group of highly debilitating eye disorders referred to as Anterior Segment Dysgenesis (ASD). ASD represents one of the leading causes of congenital corneal opacity and leads to glaucoma in ~50% of the cases and are often associated with myopia. Although few causative genes have been identified, little is known about the molecular and cellular mechanisms underlying tissue malformation in this class of diseases. Several ciliopathies including Meckel, Bardet Biedl, and Joubert syndromes display conditions affecting tissues of the AS including severe myopia. We have recently reported that conditional ablation of the primary cilium in neural crest cells (NCC) leads to ASD in the mouse model with conditions similar to those observed in humans. We have shown that primary cilia of the neural crest derived POM mediate the Hedgehog (Hh) pathway. However, our preliminary results suggest that the cilium could play distinct roles in a tissue specific manner important for AS morphogenesis and repair. The objective of the proposed study is to elucidate the signaling pathways and cellular mechanisms orchestrated by ciliary proteins during morphogenesis of the cornea and other AS structures. Specifically, we will test our central working hypothesis that primary cilia enable neural crest-derived cells of the POM to interpret local morphogenetic cues and elicit distinct cellular behaviors during morphogenesis and repair of different structures of the AS. To test this hypothesis, we have generated specific genetic and computational tools and developed an in vivo imaging approach that will allow us to a) elucidate overlapping and distinct roles of primary cilia and the Hh pathway during the development and repair of AS tissues; b) To identify signaling networks downstream of the primary cilium relevant for AS morphogenesis, and c) conduct a functional characterization of a novel cilia-dependent cell population of the pNC lineage with chondrogenic capabilities. Collectively, the outcome of this work will reveal the integrative role of primary cilia signaling necessary to achieve normal AS morphogenesis. Importantly, delineation of the cilia-related signaling cascades will enable the identification of new therapeutic strategies to treat ASD and trauma.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Chronic low back pain (LBP) imposes tremendous burden on affected individuals, healthcare systems, and society. LBP has been identified as the most common cause of disability globally and in the United States (US). LBP is also the largest driver of US healthcare spending ($135 billion in 2016) and the most common diagnoses associated with opioid prescription and consumption. For patients with chronic LBP, physical therapy has been shown to be a cost-effective method for improving pain and disability. In addition, physical therapy has been shown to decrease the risk of advanced imaging, injections, surgery, and opioid use in patients with chronic LBP. Despite available evidence in support, only 7-13% of patients with LBP, including those with chronic LBP, go on to receive physical therapy services, with patients reporting barriers accessing physical therapy, such as transportation, provider availability and missed work time. Access is especially limited in rural communities where there are approximately 40% fewer physical therapists available per capita compared to metropolitan regions. In addition, patients living in rural communities likely need to travel longer distances to receive physical therapy, requiring additional missed work time and transportation costs. This lack of access to physical therapy in rural communities likely contributes to the greater rates of LBP-related disability and opioid consumption that have been observed in rural communities compared to metropolitan areas. Innovative methods for improving access to physical therapy are urgently needed to address disparities in outcomes for patients with chronic LBP living in rural communities in the US. Telehealth has rapidly expanded during the COVID-19 pandemic. This includes policy changes that have allowed physical therapists to begin providing care remotely, also referred to as telerehabilitation. Telerehabilitation stands to improve access to physical therapy for patients with chronic LBP living in rural communities and may serve as a means of improving outcomes of these patients. We will conduct a single-blind prospective randomized clinical trial addressing key questions to understanding the effectiveness of a risk-stratified telerehabilitation to reduce opioid use and LBP-related disability and to improve physical function and health-related quality of life (HRQoL) in patients with chronic LBP. Additionally, we will explore implementation outcomes using a mixed methods approach consisting of electronic surveys and semi-structured interviews with patients, physical therapists, practice managers, and outpatient services administration focusing on perceived quality and impact on barriers to care. We will enroll 434 patients with LBP presenting to primary care clinics serving rural communities (TidalHealth, Salisbury, MD). Eligible patients will provide informed consent and be randomized to either an educational control or risk-stratified telerehabilitation (low-risk, remote therapeutic monitoring; medium-risk, physical therapy telehealth visits; or high-risk, psychologically informed physical therapy telehealth visits). Primary effectiveness outcome is difference in change in LBP-related disability (Oswestry Disability Index) and in opioid use after 8 weeks of treatment.

NIH Research Projects · FY 2026 · 2023-09

Lifetime cumulative exposures to interpersonal violence can have a significant negative impact on health. Individuals with such exposures often face substantial mental and physical health challenges, including conditions such as PTSD and HIV/STIs, alongside ongoing safety risks. Despite these needs, many do not seek formal support services because of barriers such as isolation, mistrust, or limited awareness of available resources. Thus, there is a critical need for accessible, evidence-based digital interventions that can reach people outside traditional service settings. Being Safe, Healthy, and Positively Empowered (BSHAPE) is a trauma-informed digital intervention designed to improve physical health, mental health, and safety outcomes for women with cumulative exposures to interpersonal violence. Results from a pilot trial indicated the intervention is feasible and acceptable, with participants reporting reduced stress, increased self-efficacy, improved mental health, and enhanced safety-related empowerment. This project employs a sequential, mixed-methods longitudinal design to refine and evaluate BSHAPE in a large randomized controlled trial. In Phase 1, we will optimize usability, engagement, and accessibility by incorporating structured feedback from the pilot and qualitative input from participants to inform adaptations to content, interface, and delivery. In Phase 2, we will conduct a randomized controlled trial enrolling 676 participants who meet the study eligibility criteria. Participants will be randomized 1:1 to the BSHAPE (n = 338) or a control arm (n = 338). Primary and secondary health- and safety-related outcomes will be assessed at 3-, 6-, and 12-month follow-ups. We hypothesize that BSHAPE participants will demonstrate improved mental health, reduced stress, enhanced self-care, and increased safety. The study will also examine potential mediators and moderators to clarify how and for whom the intervention affects key outcomes. The resulting evidence-based digital BSHAPE intervention is intended to provide flexible, remote support for individuals with lifetime, cumulative exposures to interpersonal violence and mental health symptoms. Its scalable digital format may offer a cost-efficient model for addressing health and safety needs in settings where traditional services are difficult to access due to geographic, logistical, or personal barriers, and may reduce reliance on high-intensity or crisis-based services, such as long-term behavioral health treatment.

NIH Research Projects · FY 2025 · 2023-09

Anastasis: A Novel Cell Survival Mechanism Project Summary Anastasis is a newly discovered cell recovery mechanism that rescues apoptotic cells from the brink of death. Challenging the classic view of irreversible apoptosis, we have discovered robust reversibility of apoptosis in three types of mouse/rat primary cells, twelve human cancer cell lines, and egg chambers in fruit flies. What are the physiological functions, pathological roles, and therapeutic potentials of anastasis? Anastasis could be an unexpected cytoprotective mechanism for preserving terminally differentiated cells and tissues that are difficult to replace, such as cardiomyocytes and neurons. If true, enhancing anastasis may be beneficial for treating heart failure and brain injury. Besides, anastasis could be an unrecognized escape tactic enabling cancer cells to survive cancer therapy, thereby contributing to disease recurrence. If confirmed, suppressing anastasis in dying cancer cells may promote cancer cell death and reduce the chances of recurrence. Anastasis may also play important roles in limiting apoptosis during embryonic development and normal homeostasis. If identified, understanding its regulation can provide new insights into the control of cell death and survival in physiological conditions. However, there are several challenges of testing these hypotheses. It is difficult to track anastasis, especially in vivo, because cells that have reversed apoptosis are morphologically indistinguishable from healthy cells. There are no anastasis-specific hallmarks identified, and the regulators of anastasis remain undiscovered. Here, we will overcome many of these challenges by developing a novel and highly specific tracking system to label anastatic cells for mammalian studies, and to identify the key regulators of anastasis. To mark anastatic cells, we will create an anastasis biosensor that can tag anastatic cells with permanent expression of a fluorescent protein only after they have recovered from both mitochondrial outer membrane permeabilization (MOMP) and caspase-3 activation, the two most recognized apoptotic events, making this biosensor system highly specific to anastasis. We will establish anastasis biosensor stable cell lines to determine reversibility of apoptosis in vitro, and will employ biosensor xenografts to interrogate anastasis in vivo using clinically relevant mouse models. To elucidate the mechanism of anastasis, we will identify its key regulators, through proteomics, genetics, and pharmacological approaches. We will identify which genes exhibit up- or down-expression (potential anastasis regulators, and therapeutic targets) during different stages of anastasis, determine whether specific post-translational modifications distinguish anastatic cells, establish whether cells that recover from different cell death inductions share similar molecular features, and investigate how interfering with anastasis regulator candidates could modulate the reversibility of apoptosis. We will identify small molecules that target the candidates by bioinformatics, and test their efficacy in promoting or suppressing anastasis in vitro. Successful completion of this project will generate essential tools and knowledge for studying anastasis, thereby laying a strong foundation for developing revolutionary new therapeutic approaches by controlling anastasis.

NIH Research Projects · FY 2026 · 2023-09

Project Summary Black cisgender women (hereafter, Black women) carry a disproportionate HIV burden than women in other racial and ethnic groups. Despite its promise, there is an unmet need for pre-exposure prophylaxis (PrEP) among Black women. Intimate partner violence (IPV) and gendered racism may exacerbate racial disparities in PrEP access and also curb potential real-world effectiveness. IPV reduces PrEP uptake among women. Black women also experience unfair treatment due to deeply ingrained stereotypes by healthcare systems. As such, Black women may feel uncomfortable discussing PrEP with a provider or provider biases may prevent PrEP access. Integrating trauma-informed care into community health centers that serve Black women may enhance PrEP adoption. Trauma-informed care can help providers understand IPV, medical mistrust and gendered racism within the context of Black women’s experiences. System policies can also be modified to be trauma-informed for both staff and Black women clients. In addition to changing health systems, peer navigation could be a successful model of care to improve PrEP engagement. Peer navigation can build self-efficacy in patient-provider communication and decrease medical mistrust offsetting the impact of socio-structural barriers. The proposed research aims to address this gap via the implementation and evaluation of a trauma-informed multilevel intervention designed to increase PrEP initiation among Black women. This intervention includes a trauma- informed PrEP Implementation Toolkit for staff in community healthcare clinics in addition to a trauma-informed peer navigation model. We propose a hybrid type 2 effectiveness-implementation study with clinical staff, peer navigators, and clients. Aim 1 includes adapting an existing trauma-informed peer navigation for PrEP-eligible Black women. Qualitative data from semi-structured interviews with 20 Black women clients will be used to adapt the peer navigation. Aim 2 includes assessing the effectiveness of the trauma-informed multilevel intervention. The toolkit will be employed in clinics using a stepped wedge design with monthly aggregated clinic data collected 8 months before and after toolkit implementation in each clinic. Toolkit effectiveness will be assessed using within- and between-clinic changes in PrEP initiation. Staff will complete baseline, immediate post, and 3-month post surveys to assess mechanisms of change. In a parallel two-arm trial, 300 Black women clients will be randomized to receive either peer navigation (intervention arm) or support group only (control arm) and will complete baseline, 1-, 3-, and 6- month post-randomization surveys. The primary client outcomes will be 1-, 3-, and 6-month PrEP initiation. Aim 3 includes assessing the implementation of the multilevel intervention. Adoption, acceptability, appropriateness, and sustainability will be assessed with 3-month post-toolkit staff surveys; and at 1-, 3-, and 6- month client post-randomization surveys. Intervention costs will be computed using an ingredients-based approach. Fidelity will be assessed with the fidelity-monitoring approach for multilevel trials.