Johns Hopkins University

NIH Research Projects · FY 2025 · 2022-04

Abstract Type 2 diabetes and cardiac arrhythmias are both highly prevalent in older age. There is growing awareness that diabetes affects the electrical conduction system in the heart. Asymptomatic arrhythmias are thought to be particularly common in older adults, especially in the setting of diabetes. Many of these arrhythmias are thought to be harmful, but their impact on cardiovascular outcomes and mortality in older adults with diabetes is not clear. Prior research has shown that glycemic variability and hypoglycemia in diabetes contribute to a high burden of atrial and ventricular arrhythmias. However, prior studies have not collected concomitant information on glucose patterns and ECG recordings. We contend the glycemic patterns (low, high, and variable glucose) may acutely contribute to cardiac arrhythmias in diabetes. To address this question, we will conduct continuous glucose monitoring and leadless “patch” ECG monitoring in a population of adults with diabetes aged 60 years and older to assess coinciding variations in glycemia and cardiac rhythm. We will relate these patterns to current health status and long-term clinical outcomes. Our research will inform the role of low, high, and variable glucose in leading to cardiac arrhythmias and subsequent outcomes in older adults with diabetes.

NIH Research Projects · FY 2026 · 2022-04

Summary - Overall To understand HIV-1 reservoir dynamics, we must understand how the reservoir is formed. The overall goal of this research program is to study dynamics of the latent reservoir through single cell analysis of the viral decay processes that determine the composition of the reservoir. Seminal studies by co-investigator Alan Perelson showed that following initiation of combination antiretroviral therapy (ART), plasma virus levels decay rapidly in a striking biphasic fashion. These studies established that in untreated people living with HIV-1 (PLWH), most of the virus in the blood is produced by infected cells that die or transition to a non-productive state of infection very rapidly. The half-lives of the two phases of decay are 0.7 days and 14 days. It is important to note that these decay processes occur continuously throughout untreated infection and are simply revealed when new infection events are blocked by ART. Thus, they are an essential feature of HIV-1 biology. Surprisingly, the identity and fate of the cells that decay with these kinetics have never been clearly defined. Coincident with the initial studies of HIV-1 dynamics by Perelson and colleagues, studies from the Siliciano lab established that HIV-1 could persist in a latent form in resting CD4+ T cells, and it rapidly became clear that the half-live of this latent reservoir was extremely long (3.7 yrs), long enough to preclude cure even with optimal ART. Using an SIV/macaque model, Dr. Dan Barouch showed that this reservoir is established very early in infection. A fundamental hypothesis of this research program is that the latent reservoir is composed of cells that survive the rapid decay processes that eliminate the vast majority of infected cells. We believe that insights into reservoir dynamics can be obtained through analysis of these decay processes. We will analyze these decay processes in coordinated studies in PLWH (Dr. Robert and Janet Siliciano, Project 1) and in SIV-infected macaques (Dr. Barouch, Project 2) with the help of Dr. Perelson and the Modeling Core.

NIH Research Projects · FY 2026 · 2022-04

The primary challenge in curing HIV-1 is the persistence of a latent viral reservoir (LVR) in resting CD4+ (rCD4) T cells that harbor stably integrated latent HIV. Examining changes in the LVR composition is incredibly difficult due to the long half-life. Recent data show that clonal expansion of latently infected rCD4 T cells through a combination of antigenic stimulation, homeostatic proliferation, and integration site promotor disruption are major contributors to LVR maintenance. It is unclear which tissue source is the primary driver of LVR maintenance, as well as what level of contribution each of these three potential mechanisms driving proliferation may play in that process. Solid organ transplantation in people living with HIV and the associated different T cell induction strategies prescribed for prophylactic allograft rejection treatment provide a unique opportunity to examine how the LVR rebounds after a large proportion of the T cell repertoire is destroyed. The HOPE in Action HIV+ kidney organ transplantation trial provides access to >120 matched flash frozen lymph nodes (LN), renal allograft tissue, and longitudinally collected peripheral blood mononuclear cells (PBMC) from PLWH. We hypothesize that the LVR is primarily maintained through antigen stimulation of latently infected cells in micro foci within lymph nodes, which subsequently migrate into the circulation and other tissues in the body, thereby reestablishing the LVR post-T cell depletion therapy. Aim 1: Examine long-term LVR dynamics post-renal transplantation and its association with clinical outcomes. We will measure the HIV LVR annually for up to 10 years using the intact proviral DNA assay (IPDA), which distinguishes fully intact HIV from defective, deleted, and hypermutated proviral DNA, in individuals receiving transplant-related immunosuppressive drugs that are of interest to HIV cure strategies. Aim 2: Develop a tissue specific atlas of the LVR in LN, blood, and organ tissue (kidney) pre-transplantation, and examine reseeding of the circulating, LN, and kidney allograft LVR post T cell induction. We will assemble a multi-modal atlas of HIV+ LN by integrating the CODEX multiplexed immunofluorescence (mIF) platform to phenotype lymphoid cells and laser capture microdissection (LCM) and site-directed next-generation sequencing of the proviruses in cells isolated from distinct LN zones. HIV SMRTcap, a novel HIV-specific single molecule sequencing assay will provide simultaneous resolution of proviral sequences and matched integration sites, to evaluate clonality and intactness of latent provirus within the LN, PBMC and kidney. Aim 3: Determine the relative contribution of homeostatic proliferation, antigenic stimulation, and integration site promoter disruption on LVR maintenance and re-establishment post-transplant. These proposed studies will enable us to characterize the longitudinal LVR spatially, genetically, and phenotypically in multiple compartments. This project will provide critical information on feasibility and mechanisms of potential HIV cure strategies by modeling re-seeding of viral populations in kidney allograft and lymphoid tissues and determining driving mechanisms of clonal proliferation.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT A novel class of oral nicotine pouches that contain a nicotine powder instead of tobacco leaves have recently emerged and fall under FDA’s purview, but there is virtually no research to inform the regulation of these products. These novel pouches are rapidly growing in popularity. For example, in 2020, dollar sales in U.S. convenience stores grew by 470% for ‘Zyn’, a leading brand of these pouches. Our preliminary research indicates that these products are being marketed heavily to consumers, often with advertising tactics that may convey modified risk (i.e., descriptors of “tobacco-free”). These pouches contain non-tobacco flavors (e.g., fruit) with known appeal to youth. Tobacco industry research shows that these pouches deliver similar, or greater, levels of nicotine to users than traditional smokeless oral tobacco products, suggesting that they can produce dependence. Because FDA applies a public health standard when regulating tobacco products, the risks and benefits of novel oral nicotine pouches must be considered for current smokers (a population that may benefit from switching to novel nicotine pouches) and non-nicotine users, especially youth (a population for whom nicotine pouch use would have negative public health consequences). Using human lab studies, marketing surveillance, and web-based experiments, this innovative project will elucidate product features and marketing tactics that may drive initiation and continued use of novel oral nicotine pouches for smokers and non-nicotine users, including youth, addressing FDA CTP’s areas of scientific interest in Addiction/Abuse Liability, Behavior, and Marketing Influences. In Aim 1, smokers will use pouches of different flavors (tobacco; mint; fruit) and nicotine doses (low; high), and their own brand of cigarettes, over 7 lab sessions and pharmacokinetic (PK) and pharmacodynamic (PD) effects (e.g., subjective abuse liability and tobacco withdrawal) will be assessed. In Aim 2, we will surveil advertisements for novel nicotine pouches over 5 years to identify/monitor marketing tactics and examine, via web-based experiments, how common tactics influence product perceptions (i.e., perceived harm, addictiveness, and appeal) and use intentions among cigarette smokers and youth non-nicotine users. In Aim 3, we will conduct a second lab study with smokers and adult non-nicotine users to determine how a common marketing tactic (e.g., “tobacco-free” descriptors) impacts use behaviors and PK/PD effects of these pouches. This project will provide vital new data on product features and marketing tactics that may influence whether smokers and non-nicotine users (including youth) initiate, continue using, and possibly become addicted to novel oral nicotine pouches. This information will allow FDA to make informed decisions about what features should be allowable in novel nicotine pouches, how accessible they should be, and what marketing tactics should be permissible. Ultimately, this research can protect public health by informing polices to mitigate use of these pouches by nicotine-naïve youth as well as policies that may facilitate product switching for smokers.

NIH Research Projects · FY 2025 · 2022-04

Project Summary/Abstract This study is focused on expanding our understanding of post-stroke cognitive impairment and dementia (PSCID). Studies have found that patients who suffer a stroke are at increased risk for developing subsequent cognitive decline. While this has been demonstrated epidemiologically, the mechanism by which this occurs is not known. PSCID is a form of vascular cognitive impairment and dementia (VCID). VCID has been linked to progressive changes in the white matter, referred to as white matter hyperintensities (WMH), that are readily seen on magnetic resonance imaging (MRI). It has been hypothesized that disruption of the blood-brain barrier (BBB) precedes the development of WMH. Thus, imaging the BBB may be a way to determine who is at risk for developing VCID. It is the central hypothesis of this proposal that PSCID is due to acceleration of VCID brought on by the acute ischemic event and is characterized by global disruption of the BBB which precedes the development of WMH. Thus we aim to: 1) Test if BBB disruption detected on routine clinical MRI scans of the brain is predictive of PSCID, 2) Study the mechanism of progressive WMH in post-stroke patients using serial research MRI scans to measure BBB disruption of normal appearing white matter before it progresses to WMH, and 3) Translate a novel MRI method into the clinical setting that uses arterial spin labeling (ASL) to measure BBB disruption without the administration of exogenous contrast. To achieve these objectives patients will be recruited from hospitals in the Johns Hopkins Health System. Patients will be followed with serial cognitive testing to detect cognitive decline over a 3-year period. BBB measurements will be extracted from the MRI scans done at the time of the evaluation for acute stroke. A subset of patients will be followed with serial research MRIs. Research MRIs will be used to track the progression of NAWM to WMH and its relationship to BBB disruption. These research MRIs will also implement a novel ASL method for measuring BBB permeability to determine if this method could be used instead of contrast-based methods. The long-term goal of this research is to validate a biomarker for the pathogenesis of PSCID such that patients at risk can be identified for therapeutic trials and potential therapeutics can be screened for their effect on the pathology.

NIH Research Projects · FY 2025 · 2022-04

Project Summary: Myocardial fibrosis is characterized by the accumulation of extracellular matrix in the myocardium and has been identified as one of the main determinants of age related cardiac remodeling. This can manifest as either increased diffuse interstitial fibrosis or focal fibrosis as a scar and lead to cardiac dysfunction. Cardiac transthyretin amyloidosis characterized by infiltration of the myocardium by misfolded transthyretin protein, on the other hand, has emerged as an important cause of accelerated remodeling leading to heart failure and CVD, and predisposing to frailty and dementia. Importantly, novel FDA approved therapies (tafamidis, inotersen) may allow treatment of cardiac amyloidosis highlighting the need for early detection. We expect this study to establish the pivotal importance of quantifying fibrosis and amyloidosis at the population level to facilitate clinical detection and orient the development of novel strategies to prevent heart failure, atrial fibrillation and complications of CVD in older adults. Therefore, our specific aims are: Aim 1a) determine the cross-sectional associations of presence as well as extent of amyloidosis measured by Tc-PYP, with extent of myocardial fibrosis measured by MRI T1 mapping at MESA Exam 7. 1b) determine cross-sectional associations of presence and extent of amyloidosis as well as fibrosis, with magnitude of cardiac remodeling defined as structural and functional alterations of the left and right heart chambers by cine MRI at MESA Exam 7.1c) construct prediction models for presence as well as for extent of both cardiac amyloidosis and progressive fibrosis at Exam 7, by combining risk factor exposure and subclinical disease trajectories based on phenotypes obtained from all MESA Exams (1-6) prior to Exam 7. In Aim 2a) we will compare the magnitude of ECV change between MESA Exams 5 and 7 in the absence versus presence, as well as extent of amyloidosis measured at Exam 7. 2b) compare the magnitude of 12-14 year changes in 4 chamber cardiac remodeling attributed to amyloidosis versus those attributed to progressive fibrosis. 2c) construct longitudinal predictive models of 12-14 year change in ECV attributed to amyloidosis versus ECV changes attributed to progressive fibrosis, using all phenotypic variables obtained from MESA Exams 1 through 5. We propose to use data acquired during 2010-2012 in 800 individuals (400 men and 400 women) as part of the MESA 5 exam. As part of this proposal, all participants will undergo a repeat MRI exam and Tc-99m-PYP at Exam 7. This study leverages the already acquired MESA phenotypic data to predict amyloidosis and malignant progressive fibrosis leading to adverse remodeling, CVD, frailty and dementia.

NIH Research Projects · FY 2025 · 2022-04

The human proteasome plays an essential role in both protein homeostasis and in the regulation of multiple cellular processes from signal transduction to transcription. It has also become a proven target for developing drugs for treating multiple diseases including multiple myeloma and lymphoma. Several inhibitors of the proteasome, including bortezomib, carfilzomib and ixazomib, have been used in the clinic, responsible for prolonging lives of multiple myeloma patients. However, the existing proteasome-targeted drugs suffer from severe toxicity and rapid emergence of drug resistance, which also limits their potential in treating other types of diseases. We have developed a rapamycin-inspired macrocycle library known as rapafucins by fusing the FKBP-binding domain (FKBD) of rapamycin with a combinatorial peptide library. A screen of the rapafucin library in multiple myeloma cell line NCI-H929 led to the identification of a potent inhibitor, Rapaprotin that induces apoptosis in NCI-H929 cells. Rapaprotin exhibited selective toxicity to cancer cells over normal cells. It also has a unique mechanism of action, requiring activation by an intracellular protease through cleavage of the macrocycle into a linear form, Rapaprotin-L, which inhibits all three types of protease activities of the proteasome. Moreover, Rapaprotin is synergistic with bortezomib and is capable of resensitizing bortezomib-resistant cancer cells to the drug. In this application, we will investigate the mechanism of activation of Rapaprotin by the cellular protease, validating Rapaprotin-L as the active species for its cellular activity. We will obtain a high-resolution cryo-EM structure of the complex between proteasome and Rapaprotin-L. We will optimize the potency and pharmacokinetic property of Rapaprotin through design and synthesis of new analogs. The optimized analogs of Rapaprotin will be assessed for their efficacy in animal models of multiple myeloma and other diseases. The newly developed Rapaprotin analogs will serve as useful chemical probes to facilitate the study of the function and pharmacology of the proteasome and promising leads for developing a new class of anticancer and immunosuppressive drugs with lower adverse effects.

NIH Research Projects · FY 2026 · 2022-03

Due to epidemics of opioid overdose and hepatitis C virus (HCV), the availability of kidneys from HCV-viremic (HCV+) donors is increasing. There are limited numbers of HCV+ transplant candidates, and as a result 500- 1000 HCV+ donor kidneys are discarded each year. A new practice of HCV+ donor to HCV-naïve recipient (HCV D+/R-) kidney transplantation (KT) with direct-acting antivirals (DAAs) has had early success. However, there remains equipoise about whether to give DAAs as prophylaxis or as treatment post-transplant (“transmit- and-treat”). With transmit-and-treat, HCV is cured with 8-12 weeks of DAAs, but complications such as fibrosing cholestatic hepatitis, rejection, CMV, and BK virus are reported. Prophylaxis seems to prevent these complications but data is limited. A direct comparison of prophylaxis and transmit-and-treat has not been done. Determining the best strategy would allow for expansion of HCV D+/R- KT and minimize clinical complications. We propose PREVENT HCV, a multicenter randomized controlled trial comparing DAA prophylaxis with transmit-and-treat in HCV D+/R- KT. We will perform 120 HCV D+/R- KTs over 2 years at 6 transplant centers. Aim 1 will compare the safety and efficacy of transmit-and-treat (SOF/VEL for 12 weeks starting day 14 post- KT) vs prophylaxis (SOF/VEL for 2 weeks started several hours pre-KT). We will also measure clinical complications of HCV D+/R- KT such as liver injury, rejection, and infection with these two strategies. In this trial, the exact timing, size, and genetic composition of the transmitted viral inoculum will be known, providing an unprecedented opportunity to study the earliest events in primary HCV infection. Leveraging this, Aim 2 will characterize the earliest viral dynamics and phylogenetics of early HCV in the liver and blood, as well as the transmitted virome, identifying emerging viruses, including SARsCoV2, some of which have been implicated in rejection. Aim 3 will characterize the innate immune response to primary HCV, measuring cytokines and the transcriptome of innate immune cells. These studies can contribute new knowledge about HCV related to vaccine efforts and deeper understanding of the virome, generalizable beyond transplantation. Our multidisciplinary team includes experts in Transplant Surgery, Infectious Diseases, Nephrology, Epidemiology, Biostatistics, Pathology, Virology, and Immunology. Our team has experience successfully enrolling and conducting multicenter transplantation trials (U01AI134591, U01AI138897) and will leverage existing infrastructure for operations, data management, analysis, and safety monitoring. In summary, PREVENT HCV will quantify clinical risks of HCV D+/R- KT and determine the optimal DAA approach. This could facilitate thousands of additional KTs, contributing to one of the mandates of the White House Executive Order on American Kidney Health. Finally, this trial includes unique mechanistic studies that can generate fundamental insights into the biology of primary HCV relevant to vaccine efforts, and knowledge about the transmitted virome and its significance in immunocompromised hosts.

NIH Research Projects · FY 2025 · 2022-03

ABSTRACT: Retinitis Pigmentosa (RP) is an inherited retinal degeneration caused by one or more of a large number of genetic mutations. It is a major cause of blindness and severe vision loss in people aged 20-60 years. The first symptom in RP is loss of night vision as a result of mutation-caused death of rod photoreceptors. Subsequent loss of cone photoreceptors leads to gradual constriction of visual field and eventually blindness. Currently, there is no treatment for preventing vision loss in RP. NAC Attack is a phase-3 multicenter, randomized, double masked, parallel and placebo-controlled clinical trial to evaluate the efficacy and safety of oral N-acetylcysteine (NAC) in patients with RP. Participants will be randomized to receive either oral NAC of 1800mg/bid or placebo in a ratio of 2:1 and will be followed for 45-months. The Coordinating Center (CC) collaborates closely with the Executive Committee to ensure the success of NAC Attack. The CC contributes to study leadership and provides expertise on trial design, facilitation of recruitment and retention of participants, coordination across all trial entities, implementation and maintenance of a high-quality data management system, statistical analysis, and quality assurance. The CC will:  Enlist and retain Clinical Sites with experienced investigators and sufficient recruitment capacity;  Ensure that Clinical Site personnel complete certification requirements and are in regulatory compliance;  Create and maintain the study database through design and implementation of data collection forms, secure web-based data capture using REDCap, data editing, and data management;  Create and maintain the study cloud-based portal using JHU OneDrive to receive and manage imaging and test files from the clinical sites;  Advise Clinical Sites on resolution of real-time problems and overall strategies for successful implementation of the study protocol;  Provide aids to clinical sites for study management such as appointment schedule, reminders of upcoming visits, missing forms, and incomplete submission of study materials;  Provide regular reports on study progress & performance to Clinical Sites and all study committees;  Design and implement a full program of quality assurance activities including certification of personnel and clinical sites, site visits, and performance monitoring;  Provide interim and final statistical analyses of study data;  Prepare for various committee and study meetings;  Participate and lead in the preparation of scientific presentations and reports. NAC Attack has the potential to identify a pharmacological therapy benefitting all patients with RP, irrespective of the identification of their causative mutation, and thus to impact on the clinical management of RP.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY/ABSTRACT Retinitis pigmentosa (RP), the most common inherited retinal degeneration, causes severe visual disability and has no effective treatments. It is caused by mutations in one of a large number of genes that result in rod photoreceptor degeneration while sparing cones. The loss of rods, which constitute 95% of the cells in the outer retina, results in high levels of oxygen causing oxidative stress which is a major contributor to gradual degeneration of cone photoreceptors. Cone degeneration causes gradual constriction of visual fields and eventual blindness. Compelling laboratory data demonstrate that antioxidants, including N-acetylcysteine (NAC), promote cone survival and function in animal models of RP. A clinical trial testing oral NAC in 30 RP patients showed good safety with a maximum tolerated dose of 1800 mg bid, which resulted in good intraocular levels and caused small improvements in cone function over a 6-month treatment period. This has led to the hypothesis that long-term administration of NAC can promote cone survival and prevent severe visual disability in patients with RP. This project is a large multicenter, randomized, double-masked, placebo-controlled clinical trial designed to test that hypothesis. Ellipsoid zone (EZ) width measured on a spectral domain-optical coherent tomography scan through the fovea corresponds to remaining cones with intact inner and outer segments and thus is a biomarker for cone survival. Approximately 438 RP patients with an EZ width between 1500 and 8000 µm will be randomized in a 2:1 ratio to 1800 mg NAC bid or placebo. The primary efficacy objective is to determine if the cumulative loss of EZ width between baseline and month (M) 45 is significantly less in eyes of subjects in the treatment group versus those in the placebo group. Secondary efficacy objectives are to determine if reductions between baseline and M45 in mean macular sensitivity (measured by microperimetry) or best-corrected visual acuity are decreased by NAC treatment. A novel exploratory outcome will utilize adaptive optics scanning light ophthalmoscopy, which allows non-invasive imaging of the cone mosaic with single-cell resolution, to determine if negative changes in cone density, spacing, regularity, and reflectivity between baseline and M45 are reduced in the intervention group versus the placebo group. All participants will have whole genome sequencing which will allow pharmacogenomic analyses. The safety and tolerability of long-term NAC treatment will be carefully assessed. This clinical trial has the potential to identify a new non-invasive, oral treatment that prevents severe visual disability in patients with RP regardless of the pathogenic mutation, thereby addressing a major unmet medical need. In addition, it will provide the most definitive test yet as to whether oxidative damage plays a major role in cone degeneration in patients with RP and determine if it is a validated therapeutic target for new treatment development.

NIH Research Projects · FY 2026 · 2022-03

Tuberculosis (TB) remains a major global health problem, and advances in the basic and clinical sciences are urgently needed to make progress towards the World Health Organization’s End TB Strategy goal of reducing TB deaths by 95% and new cases by 90% between 2015 and 2035. The Johns Hopkins University (JHU) Center for Tuberculosis Research (CTR) has been a global leader in TB pathogenesis, translational models, diagnostics, drug development, pharmacology, public health interventions, and epidemiological and economic modeling for more than two decades. Research emanating from the CTR and JHU has transformed the treatment of TB infection and disease, elucidated interactions between TB and HIV drugs, validated the efficacy and effectiveness of new diagnostic tools, and contributed to the development of evidence-based policies for global TB control, based on the epidemiology and population dynamics of TB. However, to make further progress in efforts to achieve the END TB goals, additional innovative, cross-disciplinary and impactful research is critical and a new generation of TB scientists must be recruited and trained. In the current JHU TRAC proposal, we have assembled a multidisciplinary team of researchers from multiple departments spanning four JHU schools (Medicine, Public Health, Nursing and Engineering), with complementary expertise in microbial pathogenesis, immunology, animal models, imaging, clinical epidemiology, pharmacology/pharmacometrics, computational modeling and biostatistics, in order to optimize training opportunities for junior investigators and support for new, interdisciplinary collaborations, with the goal of addressing key knowledge gaps in TB research. The JHU TRAC team comprises 58 researchers, including 33 experienced TB researchers (19 current members of the CTR), 14 senior researchers new to the TB field, and 11 Early Stage Investigators (ESI). The overarching mission of the JHU TRAC is to advance TB research by promoting innovative, multidisciplinary collaborations and by recruiting, training and supporting junior Investigators to develop the next generation of leaders in TB research. To this end, the JHU TRAC will focus on these four areas: 1) Enhance the integration, productivity and impact of JHU TB research; 2) Provide mentoring, support, and pilot funding (pilot studies are as of yet undefined but can include those classified as human subjects research and those that include the use of vertebrate animals) for the next generation of TB researchers; 3) Support TB researchers with direct services from a Clinical Core and three Scientific Cores; 4) Contribute to the END TB goals through global engagement, training, outreach, and collaboration with partners in high-burden countries.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY / ABSTRACT This is a proposal for a K24 Midcareer Investigator Award in Patient-Oriented Research for Ami A. Shah, MD, MHS of Johns Hopkins University School of Medicine. Dr. Shah is an Associate Professor of Medicine in the Division of Rheumatology, Deputy Director for the Rheumatology Precision Medicine Centers of Excellence clinical programs, and Co-Director of the Johns Hopkins Scleroderma Center. Dr. Shah has spent the majority of her career and scholarship focused on patient-oriented research in systemic sclerosis (scleroderma) and in investigating the relationship between cancer and autoimmunity. Scleroderma is a complex, multisystem rheumatic disease that manifests very differently among patients with the same diagnosis. There is heterogeneity in symptoms, trajectory of disease, timing of events, and response to therapy. While many risk factors have been identified for specific scleroderma complications at the population level, these have not been easily translatable to clinical practice at the patient level. This has been due to many factors including difficulty (i) capturing multivariate patient-specific disease trajectories, (ii) modeling the complex interplay between organ system parameters over time, and (iii) utilizing knowledge gained from trajectories of other patients who share scleroderma subgroup characteristics. In this proposal, the applicant seeks to harness rich clinical data through the Johns Hopkins precision medicine platform and develop novel computational methods to generate personalized risk estimates of major clinical events in scleroderma. She will utilize an innovative strategy to apply and test these new insights in a clinical setting. By embedding estimated trajectories and probabilities of major events into a patient level data visualization tool that updates in “real-time,” she will test whether these new discoveries can influence provider risk estimation and future diagnostic and therapeutic decision-making. Lastly, she will utilize phenotypic trajectories as a platform to identify candidate biomarkers at baseline that associate with long-term disease progression in scleroderma, as this may provide insight into patient subgroups who could benefit from intensive screening and treatment strategies. These aims will serve as an outstanding vehicle for career development and growth for Dr. Shah’s mentees, opening new fields of inquiry and developing novel precision medicine approaches in scleroderma.

NIH Research Projects · FY 2025 · 2022-03

The stethoscope is a ubiquitous technology used to listen to sounds from the chest in order to assess lung or heart conditions. Despite its universal use, it is considered an unreliable diagnosis tool due to a number of limitations: masking by noise, need for highly trained users and ear to interpret lung sounds and subjectivity in interpreting auscultation sounds. Still, one of the reasons auscultations are a staple of clinical screening is that sound is one the cheapest, fastest and most readily available biomarkers. The simple fact of breathing involves sound traveling through chest cavities that will be affected by presence of obstructions or abnormalities. While the signature of these air flow disruptions may be concealed, the right engineering innovation should not only identify their presence but can be extended as an imaging modality to identify their location, which would be a novel use of breath sounds to image lung cavities. The proposed smart auscultation technology is innovative in three ways: (i) it develops a machine learning architecture that imposes finite-element airway propagation constraints and stochastic variational inference using recurrent neural networks, (ii) a novel piezo-sensing material with tunable acoustic impedance that matches the skin hence eliminating air as transmission medium between the chest and device diaphragm which virtually eliminates pick up of any ambient noise, (iii) an array device that leverages the piezo-sensor to develop an imaging device using passive breathing sounds (instead of radiations or ultrasound probes). The proposed technology is extremely low-cost, deployable under adverse conditions, usable for immediate clinical examination as well as extendable for monitoring as a wearable device. The new technology will be field tested directly in case/control studies at the Johns Hopkins pediatric ER and pulmonary clinics to validate localization accuracy from the auscultation array using physicians’ judgments as gold standard. If successful, this technology will complement alternative, often costly and time-consuming diagnosis schemes (X-rays or ultrasounds which often cost $100-$1000’s) to offer a fast, cheap (few $) and accessible tool that can be widely disseminated from community clinics to hospitals and potentially home-based health monitoring. Given the dire public health need in addressing ALRI challenges, the proposed low-cost and efficient technology can be a game changer as a point-of-care aid to triage cases that require further medical attention.

NIH Research Projects · FY 2025 · 2022-03

Project Summary Ischemic stroke is the leading cause of long-term disability in the United States. Fortunately, the landscape of stroke patient management has been changing by endovascular mechanical thrombectomy (EVT) in recent years. EVT is an interventional procedure to remove a stroke-causing thrombus (clot) from a cerebral artery to induce recanalization. It stands to reason that further improvements of EVT in safety and efficacy will continue to improve stroke outcomes. One key to the success of EVT is patient selection using perfusion imaging that assesses the viability of the downstream vascular bed and collaterals. Salvageable tissue will likely benefit from reperfusion by EVT, whereas the risk of post-recanalization hemorrhagic transformation (HT) is larger when infarct (dead tissue) size is large (>50–70 ml). Cerebral collateral circulation keeps salvageable tissue viable and slows down the infarct core growth; however, the strength of the collateral circulation varies strongly between patients and it is expected to become insufficient over time (even within the time window in which EVT is offered). Therefore, it is essential to assess the risk–benefit ratio of EVT for each patient using perfusion imaging; however, the problem with the current standard of care is an inability to perform real-time, intra-operative brain perfusion imaging. In this project, we propose to develop a novel method called IPEN v2 to perform quantitative brain perfusion imaging in the interventional suite using standard x-ray angiography images. IPEN (Intra-intervention PErfusion with No gantry rotation) will provide the interventional radiologist critical, real-time, information to take multiple steps to perform EVT safely and more effectively. Under an R21 project, we developed IPEN v1 which can assess the 3D tissue perfusion of multiple volumetric regions-of- interest (ROIs) directly from angiography images. A simulation study for liver tumor oncology showed that the perfusion indices were accurate even though ROIs were overlapped in angiography images. Building upon this foundation, Specific Aim 1 of this project is to develop IPEN v2 for brain perfusion assessment. Specific Aim 2 is to validate IPEN v2 using patient data. We will retrospectively access 300 sets of stroke patient data acquired via standard of care and validate IPEN with multiple aspects. Specific Aim 3 is to assess IPEN v2 using computer simulated data. By the end of this project, we will have IPEN v2 fully developed and validated to enable the necessary improvements of EVT. We will then start the conversation with manufactures for implementing IPEN in their angiography systems.

NIH Research Projects · FY 2026 · 2022-03

Project Summary. Anorexia nervosa (AN) is a behavioral disorder marked by self-starvation and fear of weight gain. Weight restoration to a BMI of 19-21 remains the mainstay of treatment for severe AN despite relapse rates in the first year of up to 50%. The mechanisms underlying these high relapse rates remain unknown. Meal- associated anxiety is a striking feature in patients with AN. As the disorder develops, eating behaviors are in- creasingly driven by what appears to be a conditioned avoidance of energy dense foods, known as fear foods, suggesting that exposure-based approaches to treatment may help drive remission. However, in many intensive treatment programs, tube feeding over meal-based nutrition is increasingly the approach. Thus, the need is great for determining what mechanisms and approaches underly the successful treatment of AN and what neurobehavioral factors render individuals responsive versus resistant to treatment. Research: Ex- periments will address the extent to which habituation of learned aversions to fear foods following meal-based exposure generalizes across similar types of foods (Aim 1). Task-based fMRI combined with this behavioral approach will allow the determination of the neural substrates of habituated anxiety responses (Aim 2a). Finally, a machine-learning approach will be used to predict anxiety ratings based on baseline neural activation and identify individuals responsive vs resistant to treatment (Aim 2b). By demonstrating the significance of addressing food-related anxiety as a primary treatment target and examining the neural circuitry activated by fear foods, this project has potential to 1) alter how AN is treated across multiple levels of care and social eating settings, and 2) enhance understanding of the neurobiology that sustains treatment refractoriness. Career Development: The training plan will provide the PI with a) clinically relevant training in the phenomenology of AN, clinical course, and validated instruments used to assess eating disorders important to formulating clinically relevant hypotheses and data interpretation, b) hands-on training in advanced statistical methods for fMRI data, c) opportunity to integrate her training in factors that influence food choice with obtained results, and d) training in grant writing and career development to launch an independent research career. Environment: Johns Hopkins is an excellent environment for collaborative, interdisciplinary, and translational research in healthy and disease states and is focused on mentoring junior faculty. The Johns Hopkins Hospital is ranked #1 in the nation for Psychiatry, with the School of Medicine being the leading research medical institution in the United States and the Eating Disorder Program nationally recognized as a leading program for eating disorder treatment. Career Goal: The proposed research and training program is targeted to meet the PI's overall career goal of becoming an independent academic researcher investigating the biological basis of eating disorders at a university setting by providing the skills and pilot data necessary for larger R01 proposals to examine neural mechanisms underlying the driven nature of eating disorder behaviors with the goal of improving existing treatments and personalizing care.

NIH Research Projects · FY 2026 · 2022-03

Dementia with Lewy Bodies (DLB) is the 2nd most common dementia illness after Alzheimer’s disease, by definition is associated with deposition of aggregated alpha-synuclein in the cortex and is identified as a research priority under the Alzheimer’s Disease Related Dementia’s program. Parkinson’s disease dementia (PDD) is one of the DLB’s and is diagnosed when an individual develops dementia more than a year after onset of the motor symptoms of Parkinson’s disease (PD). Up to 1/3 PD patients will have cognitive impairment (PD-CI) at the time of diagnosis and more than 80% become demented over the course of their disease, having progressed from PD-normal cognition (PD-NC), to PD-MCI (Mild CI) and then PDD. This progression, however, is variable with 20% of individuals with PD-NC or PD-MCI after 15 years and the rate of PDD, amongst those who do develop dementia, is highly variable. PDD is particularly debilitating because patients can also suffer from delusions and hallucinations, together leading to significant cost in quality of life and increased mortality over PD alone. Determining the association between pathological markers and PDD clinical presentation is crucial for understanding the pathogenesis and developing more effective symptomatic and disease-modifying therapies. Pathogenic α‐syn transmission has been strongly implicated in mediating pathology spread in a stereotyped fashion from the gut to the brain, with α‐syn pathology in the cortex driving development of dementia. Recent studies support the notion that pathogenic α‐syn may behave in manner similar to strain-specific prions that exhibit distinct biochemical and pathologic phenotypes. These different strains may underlie the heterogeneity in α‐synucleinopathies, and perhaps the variability observed in the onset and progression of cognition impairment (CI) in PD. However, the association between the properties of α‐syn strains and CI in PD is significantly limited. We propose to use an established protocol to amplify α‐syn aggregates by using the template of pathological α‐syn from the CSF samples of our PD-NC and PDD patients, and identify, define and segregate different α‐syn strains by biophysical and biochemical methods and cellular and animal assays. We will compare the strain properties between different cognitive strata in both a cross-sectional (Aim 1) and longitudinal (Aim 2) analysis, to evaluate the extent to which α‐syn strains change with and predict development of PD-MCI and PDD. We will then apply these same methods to gut and brain autopsy tissue from individuals with PD and a gut-brain alpha-synucleinopathy mouse model (Aim 3). We will determine the association between the properties of characterized α‐syn strains and CI in PD. The overarching goal of this project is to determine if PD-MCI and PDD strains and the strain conversion can be developed as biomarkers for the onset and progression of CI in PD. Successful completion of our Aims will mainly identify new markers for predicting the onset and progression of CI in PD, but also uncover the pathogenesis of dementia in PD, discover promising targets for disease modifying and generating novel experimental models.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY The current project examines the neural basis of Braille reading in proficient congenitally blind adults, late blind readers with varying degrees of proficiency and blind children learning to read, using fMRI and high-density diffusion imaging (dMRI). These studies of Braille literacy provide insights into human brain plasticity and the neural basis of culture. Reading changes the anatomy and function of the human brain. In sighted people, reading experience enhances anatomical pathways within and across visual and language networks. Sighted readers develop a ‘visual word form area’ (VWFA) in lateral ventral occipito-temporal cortex (lVOT), tuned to letters and words. Braille offers insights into the mechanisms of cultural recycling by disentangling which aspects of the reading brain are modality invariant and which are modality specific. The current proposal distinguishes between two alternative hypotheses. According to the task-based hypothesis, blind readers develop the same neural mechanisms for reading as the sighted in the lVOT and show similar connectivity changes, because lVOT is intrinsically predisposed for modality-invariant shape recognition. By contrast, the connectivity-based hypothesis proposes that connectivity and experience heavily influence reading localization. It therefore predicts that blind individuals develop tactile word form areas (TWFAs) in parietal regions with strong connectivity to somatosensory and language networks. It also predicts that Braille literacy enhances anatomical connectivity of these parietal network. Aim 1 investigates the neural changes support this expert reading in congenitally blind adults. Proficient Braille readers can achieve speeds of 200 words per minute and more. What neural changes enable this ability? In a series of fMRI experiments with congenitally blind proficient readers we use MVPA and fMRI adaptation to test our hypothesis that proficient blind readers develop ‘tactile word form areas’ TWFAs in posterior parietal cortex and connected dorsal occipital areas. Aim 2 tests the prediction that individual differences in the connectivity (dMRI) and functional specialization of parietal areas predicts individual differences in reading proficiency among congenitally and late blind adults, whereas individual differences in early visual areas only predict individual differences in the congenitally blind population. Aim 3 tests the key prediction that TWFA specialization and Braille-reading associated connectivity changes emerge as a result of literacy by working with congenitally blind children (dMRI and fMRI) longitudinally, as they learn to read. Uncovering neural markers of successful Braille literacy will test theories of human brain plasticity and facilitate and inform strategies for enhancing Braille literacy among people who are blind.

NIH Research Projects · FY 2026 · 2022-02

PROPOSAL SUMMARY Glucose homeostasis is tightly controlled in animals with plasma glucose levels maintained in a narrow range. While insulin, secreted by the beta cell, regulates by promoting efficient glucose disposal and suppressing glucose release from the liver when glucose levels rise, glucagon, secreted by the alpha cells, counterregulates by facilitating glucose release from the liver through glycogenolysis and gluconeogenesis when levels fall. Epinephrine, cortisol and growth hormone play supporting roles in glucose counterregulation. Impaired counterregulatory responses can lead to hypoglycemia, a potentially fatal condition. Hypoglycemia is frequently experienced by type 1 and late-stage type 2 diabetics, which limits the use of aggressive therapies in disease management. The etiology of this impaired counterregulation is not well understood. On the other hand, alpha cell dysfunction (impaired inhibition of glucagon secretion by glucose) leads to elevated fasting glucose levels and diminished early suppression of glucagon after glucose challenge. This form of impairment exacerbates type 2 diabetes and may contribute to its development and progression. I propose to study both forms of impairment. In oral glucose tolerance tests, diminished early suppression of glucagon followed by greater late glucagon suppression is observed in type 2 diabetics. This leads to worsened hyperglycemia followed by hypoglycemia. If the mechanism behind persistent glucagon suppression and delayed recovery is fully elucidated, it would be possible to protect against hypoglycemic events. I propose to explore the different mechanisms of somatostatin and GLP-1 mediated regulation of glucagon secretion by extending the parsimonious model of glucose-insulin- glucagon dynamics I developed. Reactive Hypoglycemia (RHG) occurs a few hours after ingesting a carbohydrate rich meal. Plasma glucose levels drop below 55 mg/dl and the patient displays neuroglycopenic symptoms which are relieved by glucose ingestion. There is currently no definitive explanation for this behavior. I will extend the glucose-insulin-glucagon minimal model I developed to include the other hormones and validate the model with data from OGTT studies of patients with RHG. I will also investigate the role of insulin in potentiating RHG. An overarching question in type 2 diabetes pathophysiology is the nature of disease progression from normal through prediabetic to overt diabetic state. The critical role of alpha cell dysfunction in disease development and progression has not yet been studied. I will interface the glucose-insulin-glucagon model I developed with existing disease progression models. This will identify the role of alpha cell dysfunction and glucagon action in development and acceleration of type 2 diabetes. I will study the etiology of hypoglycemia in aims 1 and 2 and the impact of alpha cell dysfunction in type 2 diabetes through longitudinal modeling of disease progression in aim 3.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Over 15 million epilepsy patients worldwide have medically refractory epilepsy (MRE), i.e., they do not respond to drugs [1]. Successful surgery is a hopeful alternative for seizure freedom but can only be achieved through complete resection or disconnection of the epileptogenic zone (EZ), the brain region(s) where seizures originate. Unfortunately, surgical success rates vary between 30%-70% because no clinically validated biological markers of the EZ exist. Localizing the EZ has thus become a costly and time-consuming process during which a team of clinicians obtain imaging data (e.g. MRI, PET) and scalp EEG recordings, which is often followed by invasive monitoring involving days-to-weeks of EEG recordings captured intracranially (iEEG). Clinicians visually inspect iEEG data, looking for abnormal activity (e.g. low-voltage high frequency activity) on individual channels occurring immediately before seizures. They also look for abnormal iEEG spikes that last a few seconds occurring in between seizures. In the end, clinicians use <1% of the iEEG data captured to assist in EZ localization (minutes of seizure data versus days of recordings), which begs the question-“are we missing significant opportunities to leverage these largely ignored data sets to better diagnose and treat patients?” Intracranial EEG offers a unique opportunity to observe rich epileptic cortical network dynamics, which are only visible by the naked eye during seizures. But, waiting for seizures to occur is risky for the patient as invasive monitoring is associated with complications including bleedings, infections, and neurological deficits. Further, the costs of monitoring are very high, with one estimate quoting that the cost is at least $5,000 per day. In the proposed study, we aim to leverage iEEG data in between seizures by (ii) testing a new networked-based inter- ictal (between seizure) iEEG marker of the EZ, and by (i) modulating seizure networks with single-pulse electrical stimulation (SPES) and analyzing the associated cortico-cortical evoked potentials (CCEPs). We hypothesize that patient-specific dynamical network models (DNMs), built from each patient’s inter-ictal iEEG and CCEPs data, can characterize brain network dynamics and reveal pathological nodes, i.e., the EZ. The DNM characterizes how each iEEG node (channel) dynamically influences the rest of the network and how the network responds to exogenous stimuli. Our team has expertise in dynamical systems modeling, signal processing of iEEG data, electrophysiology, and surgical treatment of epilepsy, and is uniquely positioned to test our main hypothesis through the following aims: (i) to investigate source-sink properties of DNMs derived from interictal iEEG data to localize the EZ, (ii) to investigate resonance properties of DNMs derived from SPES evoked responses to localize the EZ, and (iii) to test whether stimulating suspected EZ nodes with resonant periodic pulse inputs triggers seizures. If successful, the proposed computational approaches and SPES experiments have the potential to significantly reduce invasive monitoring times, avoiding further risks to patients and reducing costs to hospitals by leveraging access to patient iEEG networks during passive monitoring.

NIH Research Projects · FY 2026 · 2022-02

Project summary/abstract Air pollution research is increasingly adopting emergent cost-effective technologies to measure pollutant levels at spatial and temporal scales finer than that delivered by the geographically sparse network of regulatory monitors. Low-cost air-pollution monitors, while promising, introduce a series of data features like need for field co-location and calibration to eliminate noise, spatio-temporally correlated massive datasets, and repeated mea- sures on exposures. Current statistical methodology for more traditional air-pollution data collection schemes are not optimized to properly exploit the noisy, high-throughput, and spatio-temporally dependent low-cost data. This proposal pursues multi-faceted statistical methods development motivated by the unique features of the low-cost monitoring data to improve the rigor and widen the breadth of scientific findings based on such data. Our first innovation is a spatial-filtering method for calibration of the noisy low-cost data. Regression calibra- tion of low-cost networks using field co-location with regulatory monitors leads to underestimation of air-pollution peaks – a critical flaw from a health perspective. The current practice also fails to exploit the spatial correlation among exposure levels in the network. Our proposed filtering approach mitigates both issues and will be used to produce network-wide calibrated and smooth high resolution spatio-temporal maps of pollutants. Our next set of innovations concern proper utilization of the high-throughput data from low-cost networks. The large low-cost datasets have increased uptake of data-intensive machine-learning (ML) methods like ran- dom forests (RF) for exposure prediction modeling. However, exposure data are spatio-temporally correlated and RF encounters numerous issues for dependent data leading to loss of accuracy. We proposed RF-GLS, a novel extension of RF that explicitly accounts for spatio-temporal correlation to improve predictions. We will develop extensions of RF-GLS for use in the spatial-filtering, for predicting categorical exposure data (like Air Quality Index category), and for estimating exposure effects after accounting for confounders. We will use RF-GLS for predicting personal exposures using the low-cost ambient and wearable network data in Baltimore. We recognize that the rich repeated measures data on exposures from low-cost monitors can be directly used in association studies between health and air-pollution without any ad-hoc and lossy data reduction like using the mean exposure. We propose a scalar-on-distribution-analysis (SoDA) that uses the entire sample of exposures as a distribution-valued covariate in association studies. SoDA is tailored to repeated measures covariates and will be more efficient than the general-purpose SoFR (scalar-on-function-regression). SoDA will be used to directly assess which aspects of an individual's exposure distribution correlate most with their health, which in turn can help re-evaluate and update current air quality standards. The statistical methods proposed here will be applied to analyze low-cost ambient and personal exposure networks in Baltimore. We will also implement the proposed methods in publicly-available user-friendly software.

NIH Research Projects · FY 2026 · 2022-02

Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. Several key enzymes have been identified that modulate cancer metabolism. These include enzymes in glucose, amino acid, nucleic acid, and lipid metabolism, including lactate dehydrogenase A, glutaminase 1, thymidylate synthase, and choline kinase alpha, to name just a few. Ubiquitous mitochondrial creatine kinase 1 (CKMT1) is emerging as a novel key enzyme in creatine metabolism of cancer. Few studies to date have investigated the role of CKMT1 in cancer, and the specific role of CKMT1 in breast cancer migration, invasion and metastasis remains largely unknown. To close this knowledge gap, we seek to investigate reprogramming of creatine metabolism in breast cancer. Our preliminary data show that CKMT1 drives cellular creatine (Cr) and phosphocreatine (PCr) concentrations and activates glycolysis in breast cancer cells. We consistently show in cell lines, mouse models, and patients that creatine metabolite levels along with CKMT1 expression are downregulated in metastatic breast cancer cells and metastatic tumor tissues. Overexpression of CKMT1 in metastatic breast cancer cells reduces migration, invasion, and metastasis, while increasing proliferation and primary tumor growth. Silencing of CKMT1 in nonmetastatic breast cancer cells increases migration and invasion, which occurs through generation of reactive oxygen species (ROS) that upregulate adhesion and degradative factors, epithelial-to-mesenchymal transition (EMT), and signaling pathways. In Aim 1, we will rigorously investigate the cause-and-effect relationships between reprogramming of creatine metabolism, related molecular pathways, and metastasis-driving cancer cell properties. In Aim 2, we will assess if genes/enzymes and related molecular pathways responsible for reprogramming creatine metabolism drive primary tumor growths and metastasis in mouse models of breast cancer. Our preliminary data show that CKMT1 expression was significantly decreased in clinical breast cancer metastases as compared to primary breast tumors. In Aim 3, we will further investigate in unique single-patient tissue microarrays (TMAs) from our rapid autopsy program how creatine metabolic enzyme expression levels and creatine metabolites, as well as related molecular pathways, are affected when breast cancers metastasize in patients. In our three Aims, we will test our overall hypothesis that reprogramming of creatine metabolism participates in driving breast cancer metastasis. Our preliminary findings provide evidence that creatine metabolism, and in particular CKMT1, holds promise as prognostic indicator and potential therapeutic target for metastatic breast cancer. Our proposal will significantly advance our understanding of reprogramming of creatine metabolism in tumor progression and metastasis. We will develop integrated multiplex matrix-assisted laser desorption/ionization imaging and immunohistochemistry approaches to detect creatine enzymes and metabolites in breast cancer specimens for future use in pathology workflows.

NIH Research Projects · FY 2026 · 2022-02

Toward our long-term goal of delivering precision medicine in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE), we plan to develop a methodological framework to classify HIE based on brain MRI evaluation combined with clinical variables to better predict neurological prognosis. In this proposal, we will create an MRI quantification tool to identify various types of lesions, which, combined with clinical variables, will isolate HIE subtypes and subsequent clinical phenotypes to predict prognosis. HIE is the most common cause of acquired brain injury in the neonatal period. It can result in a wide range of neurological complications that affect various functional domains, with heterogeneous severity. Stratification of HIE subtypes and specific prognoses is essential for developing and delivering targeted adjuvant and rehabilitative treatments and is also necessary for medical providers in order to guide the appropriate allocation of resources. Although predictive biomarkers have been highly anticipated, as of yet, there are none validated. MRI has demonstrated strong predictive power for severe neurobehavioral deficits within the context of severe MRI findings. However, predicting outcomes following moderate-to-mild changes or even a normal-looking brain MRI does not guarantee normal neurobehavioral outcomes. With the recent advances in image analysis technologies, we intend to increase the sensitivity and negative predictive value by detecting and quantifying moderate-to-mild pathological changes, which are difficult to evaluate qualitatively. Since individualized prediction cannot be made from a single feature, as each feature weakly correlates with outcomes, we hypothesize that patient stratification, combining brain MRI features and clinical characteristics, will be highly accurate for individualized prediction. We will apply our automated structure-by-structure image quantification (SIQ) pipeline, developed and validated through R01HD065955, to be applied for the MRI quantification in this proposal. The HIE cohort study (R01HD086058) will provide a library of teaching files that consist of MRIs with various types of lesions, from which the SIQ algorithm learns the features of the lesions. The cohort also includes clinical variables, such as serum markers and electroencephalograms, combined with the MRI features and test data for the validation study. For Aim 1, we will create a reference library that includes MRI atlases with various pathological changes due to HIE. Combined with the multi-atlas label fusion and lesion localization algorithms, the library enables a robust SIQ. For Aim 2, we will apply a supervised learning algorithm to the MRI features quantified by the SIQ to identify brain lesions and the severity that is associated with certain outcomes. Aim 3 will use a supervised classification algorithm for the MRI features and clinical variables to determine the HIE subtypes related to the affected functional domains and the severity of the outcomes. This project will provide a methodological framework with which to identify subgroups of infants with HIE who are at risk of developing neurological complications, and who may benefit from current and future early interventions.

NIH Research Projects · FY 2026 · 2022-02

An increasing number of adults in the U.S. develop acute respiratory failure (ARF) requiring mechanical ventilation in an intensive care unit (ICU). To improve patient outcomes, evidence-based guidelines recommend titrating sedatives to allow for patient wakefulness while in the ICU. However, among awake ARF patients, anxiety can be a common and long-lasting problem. Outside of the ICU setting, self-management interventions are established, evidence-based, first-line treatments for patients with anxiety. However, there is limited evidence about the feasibility and benefit of self-management interventions for ARF patients during hospitalization. Hence, this K23 proposal seeks to: 1) conduct a qualitative study in hospitalized patients to refine an existing Self-Management in Acute Respiratory Failure (SMARF) intervention (Aim 1), and 2) conduct a pilot randomized controlled trial (RCT) of the refined SMARF intervention vs. usual care in the ICU and wards to establish its feasibility, acceptability (primary outcome; Aim 2a), and potential efficacy in reducing anxiety symptoms and associated outcomes at hospital discharge (Aim 2b) and at 3-month follow-up (secondary outcomes; Aim 3). Megan Hosey, PhD, a practicing clinical psychologist and Assistant Professor at the Johns Hopkins School of Medicine, has a long-term career goal of becoming an independent, patient-oriented researcher in acute respiratory failure, examining early interventions to reduce psychological symptoms and improve long- term functional outcomes. Through this K23 award, Dr. Hosey will achieve the following career goals: 1) gain expertise in qualitative research via didactic coursework and mentored practical experience, 2) deepen knowledge and experience in patient-oriented research by completing a Master of Health Science (MHS) degree in Clinical Investigation and conducting a pilot RCT, and 3) gain mentored experience with scientific publication and grant writing. This award will result in preliminary data and skills that will lay the foundation for a successful future R-level grant and pathway towards independent investigator status. This award will build upon Dr. Hosey’s extensive clinical expertise in self-management interventions for ARF patients and her research background in the psychosocial aspects of recovery from ARF via providing tailored didactic training and mentored research experience with a world-class team, all occurring in a resource-rich academic environment.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Restoration of craniofacial soft tissues is a major challenge in reconstructive surgery. Soft tissue losses from congenital facial differences, oncologic resection, trauma, and inflammatory diseases affect millions of patients each year. Current solutions to facial soft tissue losses – both autologous and prosthetic-based – suffer from serious limitations. Autologous solutions such as tissue flaps and lipotransfer are hampered by donor site defects and unpredictable survival, often necessitating repeated operations to achieve adequate restoration. By contrast, prosthetic solutions such as hydrogel fillers or polyester implants are plagued by limited volume and duration of restoration, and by fibrosis, device exposure, and infection respectively. There is a critical need for an engineered, off-the-shelf solution that immediately restores missing soft tissue volume while encouraging natural soft tissue development and remodeling over time. Such an approach to creating well integrated, vascularized soft tissue would greatly decrease the burden of care for craniofacial patients. We recently created a biostimulatory nanofiber-hydrogel composite (NHC), comprised of chemically defined polyester nanofiber and hyaluronic acid (HA) hydrogel components, that is capable of inducing host cell infiltration, pro-regenerative conditioning of tissue responses, and progressive remodeling of the injection site into vascularized soft tissue. Our long-term goal is to use NHC in conjunction with the patient’s own cells as a regenerative cell therapy for craniofacial soft tissue defects. The overall objective for this proposed study is to engineer NHC with high biostimulatory activity coupled with allogeneic cells and define the materials properties and cellular responses governing soft tissue remodeling in genetically tractable and established translational models. In Specific Aim 1, we will engineer optimized nanofiber-hydrogel composites (NHC) as biostimulatory matrices to promote immunomodulation, angiogenesis, and tissue remodeling and define their structure-function relationships. In Specific Aim 2, we will examine the potentiation effects of adipogenic progenitor cells on host cell infiltration and conditioning, angiogenesis, and soft tissue remodeling when co-delivered with biostimulatory NHC. In Specific Aim 3, we will demonstrate soft tissue remodeling capacity in a larger volume preclinical model in rabbits using an optimized combination of biostimulatory NHC and adipose progenitor cells. This study will yield a new series of off-the- shelf biostimulatory NHC matrices capable of remodeling into vascularized soft tissue, elucidate the underlining mechanisms by defining the interplay between biomaterials, autologous cells, and host tissue responses, and offer insights into future clinical utility. The proposed biomaterials and autologous cell approach to craniofacial soft tissue restoration promises to significantly improve clinical outcomes – minimizing morbidity, reducing cost, and expanding accessibility to treatment.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Tuberculosis (TB) occurs more frequently in males (~70% of cases) than females. While reduced access to care for females and undercounting of female cases may contribute modestly to this longstanding epidemiologic observation in some countries, both human studies (the Lűbeck disaster and eunuch studies) as well as animal models underscore the fact that biological factors play a dominant role in female resistance to TB. Despite the importance of this sex-bias in TB, it has gone largely neglected by basic science researchers. The central scientific premise of this application is that defining the biological mechanisms of the male bias for TB will enlighten our mechanistic understanding of TB pathogenesis and protective human immune responses in TB. A multidisciplinary team with decades of expertise on sex differences (Klein), TB pathogenesis (Bishai), and sex differences in HIV (Scully) will conduct the project. This proposal will investigate the impact of genetics (X chromosome complement) and sex steroid hormones on TB pathogenesis using cellular tools, animal models, and human samples. A key tool used in Aim 1 will be the novel four core genotype (FCG) mouse model, in which animals with XX genotypes have male gonads/hormone levels and those with XY genotypes have female gonads/hormone levels. This model will enable us to differentiate the impact of genetics from those of the sex steroids on murine control of TB. The X chromosome encodes numerous genes of immunologic importance including the genes that encode for TLR7, TLR8, CYBB, NEMO, CD40L, and FOXP3. The process of X-chromosome inactivation (XCI)--in which one female X chromosome is epigenetically silenced--is designed to provide balanced gene dosing between females and males. Certain genes, however, can escape XCI, leading to a double gene dose in females. The process of gene escape from XCI has not been studied in the context of TB, and advanced molecular tools will be used in Aim 2 to investigate gene escape from XCI as a cause of the male bias in severity of TB. While it is widely known that sex steroid signaling modulates immune function, the impact of sex steroids as a basis for the male bias in TB has not been thoroughly investigated. Testosterone has an immunotolerizing effect, reducing levels of IFN-γ and elevating levels of IL-4. In contrast, estrogen promotes higher levels of macrophage activation and increases in TNF-α levels. In Aim 2, we will carefully dissect the role of sex steroids using adoptive transfer methods as well as gonadectomized mice with selective hormone replacement. Lastly, in Aim 3 we will extend these studies to assess the intersection of HIV infection, a critical risk for TB, and sex differences in immunity. We will assess immune responses in samples from people living with HIV (PLWH) on ART versus healthy controls (HCs), specifically balancing groups for sex. We will evaluate the ability of whole blood and hMDM from PLWH and HCs to contain Mtb growth both alone and in the presence of DHEA. Lastly, we will assess transcriptomic responses in PBMCs from male and female PLWH and HCs following Mtb infection.