Brigham And Women'S Hospital

NIH Research Projects · FY 2026 · 2023-02

Alzheimer’s Disease and Related Dementias (ADRD) along with other age-related neurodegenerative diseases contribute to significant morbidity and costs for the aging population worldwide. Advances in this field have uncovered that bilingualism is a protective factor that delays onset of ADRD and may enhance cognitive reserve. Still, little is clearly known about the direct impact of bilingualism on cognitive reserve and ADRD progression; multiple, entangled confounding variables, such as lifestyle and psychological resilience, complicate the relationship between bilingualism and cognition and warrant further investigation. Other major shortcomings in previous studies include small sample size, lack of population heterogeneity and insufficient data on relevant covariates. We aim to address these critical gaps via the following specific aims. In Aim 1, we will leverage advanced informatics and longitudinal electronic health records (EHRs) from millions of patients across three geographically disparate sites (i.e., MGB [Boston, MA], UTHealth [Houston, TX], and UC Davis [Sacramento, CA]). We will develop robust algorithms to identify potential monolingual and bilingual cohorts and their phenotypes. We will disseminate reproducible informatics methods to support research cross-institutionally. In Aim 2, we will conduct a prospective cohort study to evaluate the dynamic cognitive changes in monolingual and bilingual older adults. We will explore potential pathways by which bilingualism impacts cognitive decline over time using comprehensive instruments and surveys to repeatedly measure cognitive resilience, cognitive reserve, and related factors, including social support, psychological resilience, and physical activity. In Aim 3, we will develop and validate machine learning algorithms to identify onset of age-related cognitive decline and dementia using EHR data. We will apply the validated language classifier for all participating EHR systems to examine the role of bilingualism in relation to the progression of cognitive decline and the effect of other factors recorded in EHR data. By integrating multiple disciplines to explore the influence of bilingualism on cognitive reserve, this proposed design will address major gaps and challenges in this field. Such research has the potential to transform the current understanding of neural and behavioral pathways in relation to language, culture, and environment. Furthermore, the knowledge gained may translate to improvements in existing interventions and novel therapeutic approaches for ADRD.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract Our research proposes to elucidate local and systemic immune dysregulation in rosacea with the long-term goals of developing novel preventative and therapeutic targets and improving overall health outcomes for rosacea patients. Rosacea is a common inflammatory skin disease with unclear etiology affecting over 14 million people in the United States alone.1 Toll-like receptor 2 (TLR2) is a microbe-sensing mechanism that maintains immune homeostasis in the skin through communication with commensal microbes.2-4 Therefore, we suspect that understanding the skin microbiota-host interaction is critical to elucidating the pathogenesis of rosacea. Moreover, the immune dysregulation in rosacea does not appear to be localized to the skin. There is a growing body of epidemiological evidence demonstrating that rosacea is associated with a wide range of systemic co- morbidities.40-51 Thus, it is also important to elucidate potential systemic immune dysregulation that can explain the overall disease burden in rosacea patients. Aim 1: We aim to test the hypothesis that skin dysbiosis induces transcription and expression of the components of the innate immune response implicated in the pathogenesis of rosacea. To that end, we will perform multi-omics data integration of the microbiome, transcriptome, and proteome from rosacea skin in order to delineate the microbiota-host interaction. Aim 2: We aim to test the hypothesis that there is shared immune dysregulation between the skin and systemic circulation that can explain the burden of systemic co-morbidities in rosacea patients. To that end, we will perform multi-omics data integration of the transcriptome and proteome from the skin and blood/serum in order to characterize shared molecular pathways. Dr. McGee’s career goal is to become a physician scientist with the unique expertise to apply multi-omics, data-driven, personalized strategies to treat inflammatory skin diseases and their associated systemic co-morbidities. To achieve this goal, she will undertake a combination of formalized coursework, workshops, and hands-on training in bioinformatics, computational biology, human subjects research, and clinical trials. She will also engage in career development activities by participating in a grant writing course and a K-R transition program. Dr. McGee’s research and career development will be guided by a mentoring team with several decades of combined experience in successfully transitioning their mentees to research independence. Dr. McGee’s training will take place at two prominent academic institutions: 1) Beth Israel Deaconess Medical Center, a major teaching hospital of Harvard Medical School which supports ~250 principal investigators and offers 16 institutional and 12 departmental core facilities, and 2) Harvard T.H. Chan School of Public Health, which hosts the consistently ranked #1 biostatistics program in the country and supports computational research initiatives to answer multidisciplinary questions.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY The 5 million Americans living with systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are at increased risk of poor COVID-19 outcomes. SARO treatment with immunomodulators may lead to blunted and dysregulated immune responses to vaccination and infection. SARDs are characterized by a predisposition to autoantibody formation and fibrosis. These factors may place SARDs at risk for poor short-term outcomes (e.g., breakthrough infection, prolonged viral shedding) and post-acute sequelae of COVID-19 (PASC), characterized by prolonged COVID-19 symptoms (>/=28 days). PASC is of high clinical and

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY CD4+ IL-17-producing T helper cells (Th17) are known drivers of central nervous system (CNS) autoimmune inflammation in multiple sclerosis (MS), yet not all Th17 cells drive disease. Indeed, two major Th17 subtypes have been described in both mice and humans: homeostatic or non-pathogenic (npTh17) that maintain the steady state in tissue and inflammatory or pathogenic Th17 (pTh17) that drive destructive tissue inflammation. Importantly, npTh17 are precursors of pTh17 and IL-23 is known to be the switch factor for conversion of npTh17 to pTh17. However, the mechanisms by which IL-23 drives this conversion are not well understood. Identifying these mechanisms will provide critical insight for the development of novel therapeutic interventions for MS. Genetic variants in TCF7, the gene encoding the transcription factor TCF-1, have been associated with disease susceptibility in MS in genome-wide association studies, but the underlying mechanisms remain unknown. Notably, TCF-1 has been implicated in Th17 biology, but its role remains unclear due to conflicting data generated in models that have either defective T cell development or that study TCF-1 indirectly. Using mice that conditionally delete Tcf7 only in mature T cells, and thus have normal T cell development, we have found that TCF-1-deficient Th17 cells may not require IL-23R signaling for acquiring pathogenic potential. Indeed, we have found that TCF-1 is differentially regulated in npTh17 and pTh17 in vivo and that IL-23 shuts down TCF-1 expression. Our preliminary data further uncover a putative regulatory circuit that links IL-23, TCF-1, and endogenous glucocorticoid (GC) signaling. We have found that npTh17 are steroidogenic. They can produce GCs, which in turn, sustain TCF-1 expression, oppose IL23R signaling, and restrain Th17 pathogenicity. In contrast, IL-23 shuts down steroidogenesis in npTh17 cells. Accordingly, we hypothesize that a TCF-1- glucocorticoid regulatory circuit determines IL-23-driven pathogenicity in Th17 cells. We have generated several novel conditional knock-out mice with which we can study the role of TCF-1, the glucocorticoid receptor (GR), and cell-intrinsic steroidogenesis specifically in mature T cells. We will use these tools to mechanistically dissect this novel regulatory circuit. We propose the following aims: 1) Define the role of TCF-1 in opposing IL- 23-driven Th17 pathogenicity; 2) Determine how glucocorticoid signaling regulates TCF-1 expression, IL23R signaling, and Th17 pathogenicity; and 3) Determine the role of cell-intrinsic steroidogenesis in opposing Th17 pathogenicity. Our proposed investigation is highly clinically relevant given the association of genetic variants of TCF7 with susceptibility to MS and the use of GCs to treat relapses in patients with relapsing-remitting MS (RR-MS).

NIH Research Projects · FY 2026 · 2023-01

Abstract Out of hospital cardiac arrest (OHCA) produces an early systemic inflammatory response associated with significant neurological injury and mortality. Unlike sepsis, OHCA offers an opportunity to intervene at the earliest stages of the immune response. However, the immunology of cardiac arrest is understudied. To address this, we started the multi-center Immunology of Cardiac Arrest Network (I-CAN), a collaboration applying single-cell approaches to a unique biobank of cryopreserved, viable peripheral blood mononuclear cells (PBMC) from OHCA patients. Our premise is that cardiac arrest triggers endogenous, compensatory mechanisms that promote the resolution of inflammation, limit injury and improve survival. Our preliminary studies identified that monocyte and NK cell states expressing immune checkpoints were expanded in patients with poor neurological outcomes. Interactome analysis identified cytokines (IFNγ, IL-10) that mediate cross-talk between Nectin-2+ monocytes and Tim-3+ TIGIT+ NK cells. Subsequent ex vivo studies on PBMC from OHCA patients demonstrated that Nectin-2 is a brake on production of IFNγ by NK cells. IFNγ-deficient mice in experimental cardiac arrest and resuscitation had reduced neurological injury and mortality. These findings suggest our hypothesis that Nectin-2 monocytes are a protective response to ameliorate inflammation and neurological injury after OHCA. Here, we propose to define the mechanisms that resolve inflammation after cardiac arrest. In Aim 1, we perform deep immunophenotyping of OHCA patients at single-cell resolution. In Aim 2, we define the immune checkpoint profile of OHCA and its association with neurological outcomes. We then define the function of immune checkpoints in OHCA, with a focus on Nectin-2+ monocytes. In Aim 3, we test targeting of immune checkpoint receptors as a therapeutic strategy in a mouse model of cardiac arrest and resuscitation. Together, these aims define a new therapeutic approach: augmentation of endogenous, protective mechanisms to reduce inflammation after cardiac arrest. Further, our multi-center and multi- disciplinary team in the Immunology of Cardiac Arrest Network (I-CAN) establishes the resource of a two-site biorepository of clinical cardiac arrest with deep immunophenotyping of the subjects.

NIH Research Projects · FY 2026 · 2023-01

Abstract Thrombosis, the obstruction of blood flow due to the formation of clot in blood vessels, accounts for 1 in 4 deaths worldwide. In particular, venous thrombi occur in deep veins most often in the legs or arms and is commonly known as deep vein thrombosis (DVT). DVT and pulmonary embolism are collectively referred to as venous thromboembolism (VTE) in which a part of the venous thrombus breaks off, travel to the lungs, and lodge in pulmonary arteries. VTE is the 3rd leading cause of cardiovascular-related deaths globally with estimates of >500,000 deaths in the United States every year. VTE is reported to be the leading cause of disability-adjusted life years lost in hospitalized patients. Despite the large amount of capital invested in drug development, very few drugs are ultimately proven useful in humans. Such a low yield occurs largely because planar cell culture and animal models for testing the drugs oftentimes fail to reflect human physiology/pathology. In contrast, three-dimensional (3D) human cell-based in vitro models have been increasingly adopted to improve drug testing by recapitulating physiological and pathological parameters of their human counterparts. In addition to the development of engineered human- based microtissues, real-time, in situ, non-invasive volumetric monitoring of the behaviors of the engineered vascular models and their responses towards viral infection/drug treatment is a key capacity to achieve high(er)-throughput and accurate in vitro screening of promising drug candidates. Here we propose to harness our unique expertise in engineered in vitro human vascular tissue models and high-speed label-free imaging of thrombosis with further aid by strong experiences in clinical hematology and anticoagulation management in patients. Together, we will create an enabling and first-of-its-kind high(er)- throughput real-time imaging-integrated thrombosis-on-chip model to study thrombosis and potential therapeutic agents, taking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a timely example to instruct future preparedness for pandemics and other vascular disorders.

NIH Research Projects · FY 2026 · 2023-01

Summary/Abstract Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death worldwide, resulting in an immense public health burden. The clinical manifestations of COPD are extremely heterogeneous, and disease course is affected by numerous endogenous and exogenous factors. Finding groups of patients with similar pathobiology is crucial for the accurate prediction of disease progression and the development of personalized treatments. Currently, clinical research has been divided in the discrimination of patients based on either their phenotypic features, such as lung function, exacerbation frequency/intensity, presence of emphysema (clinical subtyping), or on the molecular compositions of their biological samples, as assessed through multi-omics assays (molecular subtyping). Despite providing some insights on different groupings of COPD patients, little agreement has been found between these two classification approaches. As such, the connection between pathophysiological processes, exposures, and their phenotypic consequences is currently unclear. In this application we propose to use deep neural network architectures to integrate phenotypic and genomic data of COPD subjects and construct integrated patient profiles that describe both the phenotypic and molecular features of the patient simultaneously. These profiles will be used to cluster patients to find joint clinical and molecular subtypes (endotypes) for COPD and to predict disease outcomes across a 5-year time span. We will extract the characteristic clinical and molecular features of each endotype to obtain endotype- specific biomarkers and connect them to clinical manifestations of COPD. Finally, we will develop network- based approaches to understand the key molecular pathways and regulators associated with each endotype. Achieving the objectives proposed in this plan will require a unique set of skills that span biology, network science, machine learning, and lung disease biology. Although Dr. Maiorino’s past career trajectory has prepared him well for the proposed research, advancing our current understanding of COPD heterogeneity is a challenging task that will require further training in specific areas. Dr. Maiorino has developed a comprehensive training program focusing on pulmonary disease biology, omics data integration, and high-dimensional statistics. Dr. Maiorino will take advantage of the rich intellectual environment offered by the Channing Division of Network Medicine and Harvard Medical School to attend courses and participate in regular meetings with his mentors and advisory board members. Altogether, Dr. Maiorino’s training and research plan will enable him to expand his current skillset and to develop into an independent investigator contributing to the advancement of precision medicine in COPD.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT Hypertension is a major risk factor for cardiovascular (CV) morbidity and mortality. Increased CV risk remains even if blood pressure (BP) is controlled, suggesting there are additional factors associated with hypertension (influenced by, but independent of, BP per se), which contribute to adverse CV outcomes. This application focuses on two potentially interrelated CV pathophysiologic processes: 1) impairment in myocardial oxygen delivery (manifested as coronary microvascular dysfunction, a known predictor of CV morbidity/mortality) and 2) impairment in cardiac efficiency (manifested as inefficient coupling of myocardial oxygen consumption and cardiac work). There are no established treatments for coronary microvascular dysfunction or abnormal cardiac efficiency—a critical knowledge gap. Individuals with hypertension and left ventricular hypertrophy (LVH) have coronary microvascular dysfunction and excess mineralocorticoid receptor activity. Our overall hypothesis is that, in individuals with hypertension and LVH, mineralocorticoid receptor blockade will improve coronary microvascular function and cardiac efficiency, independent of changes in BP; and these improvements will lead to improved myocardial structure and function and ultimately to improved CV outcomes. We propose a randomized, controlled, basic experimental study involving humans. Men and women with hypertension and LVH on enalapril (angiotensin-converting enzyme (ACE) inhibitor) will be randomized to treatment for 9 months with eplerenone (mineralocorticoid receptor antagonist) or chlorthalidone (thiazide-like diuretic) + potassium. We will use cardiac PET/CT to quantify changes in coronary microvascular function (i.e. myocardial flow reserve - ratio of stress/rest myocardial blood flow) and cardiac efficiency (i.e. myocardial external efficiency - ratio of myocardial work to oxygen consumption); echocardiography to assess changes in myocardial structure and function; and 24-hr BP monitoring. This study will test the hypothesis that, in patients with hypertension and LVH on ACE inhibition, treatment with mineralocorticoid receptor antagonist, as compared with a thiazide-like diuretic, improves: • Coronary microvascular function, i.e., myocardial flow reserve (Specific Aim 1) • Cardiac efficiency, i.e., myocardial external efficiency (Specific Aim 2) We anticipate that improvements in these outcomes will associate with improvements in myocardial structure and function (peak global longitudinal strain, tissue Doppler mitral annular early diastolic relaxation velocity [e’], and ratio of mitral E velocity to e’ [E/e’]).

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY With the rapidly aging population and improved survival rate, the number of breast cancer survivors in the U.S. is projected to reach 4.4 million by 2030, among which more than 60% of them will be aged ≥65 years. A key issue facing older cancer survivors is the impact of cancer and its treatment on their cognition. Cancer and brain aging have both common and distinct etiologies. For example, shared germline genetic heritability was identified between breast cancer and Alzheimer’s disease (AD) in large cross-trait genetic analyses, while other studies showed differential regulation of p53 and Pin1 in cancer and AD. Compelling clinical and observational studies report deficits in cognitive functioning in women diagnosed and treated for breast cancer over the short-term (<2 years), and consistently support acute toxicity of chemotherapies on cognition (i.e., chemo-brain). In contrast, population studies, often with long follow-up (>10 years), show lower incidence of AD in cancer survivors compared with cancer-free controls. While these inverse associations have persisted in studies with attempts to reduce diagnostic and competing risk biases, the possibility of survival bias, which would increase with time since cancer diagnosis, cannot be ruled out. Until we can determine how breast cancer and its treatment (chemotherapy, radiation, and hormone therapy) affect cognitive trajectory, we will not be able to improve quality of life and care for breast cancer survivors. However, most previous research is limited by a lack of (a) consideration of both the short- and long-term effect of breast cancer on cognition (which may reduce survival bias for breast cancer with a 5-year relative survival rate of 90%); (b) repeated global and domain specific cognition measures before and after treatment; (c) focus on the role of post-diagnostic lifestyles in the treatment- cognition relation; (d) investigation of gene-treatment interactions; (e) and identification of shared and distinct molecular etiologies of cancer and AD. The overarching goal of this proposal is to comprehensively determine the association of breast cancer diagnosis and treatment with cognitive trajectory over time, and identify the intersection of cancer hallmark pathways with AD to inform targeted intervention. This proposal leverages the unique resources from the Nurses’ Health Study with follow-up of 3,120 breast cancer survivors for >30 years, and repeatedly collected objective cognitive assessments; and the Gene Expression Omnibus with 2,520 human brain transcriptomics on AD patients and controls, and addresses the following hypothesis: (1) Women diagnosed and treated with cancer experience more rapid cognitive decline over the short-term, and (2) Cancer hallmarks of genomic instability, oxidative stress and inflammation are shared mechanisms between cancer and AD, but the hallmarks of proliferation and cellular pluripotency are differentially regulated. Dr. Peng plans to receive training in areas of aging research, cancer survivorship, advanced statistical modeling, and professional skill development. Together, the scientific and training components of this K01 will position Dr. Peng to become an independent interdisciplinary investigator specialized in the integration of aging and cancer research.

NIH Research Projects · FY 2026 · 2022-12

ABSTRACT Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two devastating chronic lung diseases associated with aging and with a common environmental risk factor, cigarette smoking, but with differing physiology and pathology, which may be due to genetics. Our group has led two large-scale COPD genome-wide association studies (GWASs), identifying five loci (near FAM13A, DSP, MAPT-KANSL1, ZKSCAN1, and STN1) where the genetic variant alleles associated with an increased COPD risk are associated with a decreased IPF risk. These opposite risk loci may reside in regulatory elements that act as “molecular switches” in disease-relevant cell types that impact gene expression to shunt biologic processes toward producing a COPD or IPF end-phenotype. However, GWASs do not directly implicate the functional consequence of genetic variants or the effector genes, cell types, or gene regulatory networks through which the genetic variants are acting. MicroRNAs, which have been implicated in the pathogenesis of both COPD and IPF, modulate gene expression levels and may impact the gene regulatory networks at the opposite risk loci. The goal of this project is to define COPD/IPF opposite risk loci and describe the functional mechanisms, effector genes, and relevant lung cell types through which these opposite risk loci are acting. We hypothesize that opposite risk genetic loci for COPD and IPF are due to shared causal variants acting as molecular switches through regulatory elements affecting gene expression in specific lung cell types. Furthermore, we hypothesize that these molecular switches are marked by discrete microRNA and RNA differences as well as divergent gene regulatory networks in COPD compared to IPF lung tissue. To address these hypotheses, we propose a series of investigations starting by refining the five known COPD/IPF opposite risk loci and identifying new opposite risk loci using expanded COPD and IPF GWASs and TOPMed WGS data. Next, we will perform joint single nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) and snRNA-seq in COPD and IPF lung tissue from the Lung Tissue Research Consortium (LTRC) to predict the disease-specific and lung cell-type- specific regulatory elements and effector genes at each of the COPD/IPF opposite risk loci. We will use CRISPR interference genome editing in implicated cell types to functionally validated predicted relationships of regulatory elements to effector genes. Next, we will generate microRNA sequencing data in IPF lung tissue from the LTRC and build disease-specific gene regulatory networks integrating genetic, microRNA, and RNA data at each opposite risk locus. We will highlight therapeutic opportunities by assessing these gene regulatory networks for drug-related pathway enrichment. We will then examine the COPD- and IPF-related cellular phenotypes that result from perturbations (CRISPR interference, CRISPR activation, and microRNA targeting) of the genes in the opposite risk loci gene regulatory networks. This study will help define the pathobiology and improve our understanding of the susceptibility for the two most deadly chronic lung diseases.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY Parkinson's Disease (PD) is considered a “man-made” pandemic, triggered in part by industrialization that has entailed increased production needs and exposure to toxicants resulting from that growth. Despite the discovery of important genetic risk factors, a substantial amount of etiologic risk for idiopathic PD is environmental, with pesticide exposure being a clear and documented risk factor. As a result, understanding the interaction between genetic drivers and environmental risk factors has significant potential to inform etiology and treatment of PD. This project will investigate how environmental factors, specifically pesticides, influence the development of PD at the level of effects on midbrain dopaminergic (mDA) neurons, a cell type whose loss is the hallmark of PD pathology. The work is informed by a paradigm in which highly quantitative pesticide exposure data from a large PD cohort in California is linked to a screening platform using patient stem cell (iPSC)-derived mDA neurons. Fifty-three pesticides were linked to PD with this method and ten proved directly toxic to mDA neurons. The proposed work will: (1) deeply dissect mechanisms of mDA neuron toxicity for top hits with a focus on mitochondrial and cytoskeletal consequences of trifluralin exposure; (2) explore the role of glia in modulating toxicity using a triculture approach to ask how other PD-associated pesticides alter astrocyte and microglial biology to influence mDA neuron pathology; and (3) use population-level modeling of sporadic PD in a dish to build a platform that will stratify cells from ~100 donors functionally based on responses to pesticides and then use computational methods to reconstruct which cell lines are disproportionately affected. This will identify shared phenotypes among genetically disparate samples. The career development plan is designed to support the candidate's goal of becoming an independent investigator at an academic medical center, treating PD patients in clinic while concurrently leading a research team studying their disease. A strong mentorship and collaborative team in a vibrant research environment is led by a supportive neurology chairperson (Batchelor), outstanding physician scientists with expertise spanning from neurodegeneration (Khurana, Selkoe) to public health and epidemiology (Ritz) to translational neuroscience (Rubin, Studer, Powell). This mentorship team, along with extensive research training and relevant coursework, will position the candidate for success. The institutional resources available through Brigham and Women's Hospital, and Harvard University will support the candidate's career in an environment that makes high impact contributions and collaborative endeavors achievable. The successful execution of this proposal will position the candidate along a path for an independent career as a physician scientist studying the interplay of gene-environment interactions in PD to better treat and prevent this disease.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY Mitochondrial dysfunction is a prominent element of many leading causes of disability, namely cerebrovascular and neurodegenerative diseases. The function and stability of mitochondria are tightly regulated by the mechanisms of mitochondrial dynamics and quality control (QC). The dynamic nature of mitochondria is maintained by the balancing forces of fission and fusion. These processes of mitochondrial dynamics operate to preserve the functional architecture of the mitochondrial network. The mechanisms of mitochondrial QC, including mitophagy, proteostasis, and biogenesis, work to regulate the components of the mitochondrial network through synthesis and degradation. These forces actively control the functionality of the mitochondrial network to ensure efficient energy production. In cerebral ischemia/reperfusion (I/R) injury, the processes of mitochondrial dynamics and QC become dysregulated, contributing to metabolic dysfunction and neurological damage. The F99 phase of this proposal aims to identify the phases of disrupted mitochondrial dynamics and QC in cerebral I/R injury, and their respective molecular mechanisms. Utilizing advanced technologies related to machine learning, computational modeling, and live cell imaging, I have created an agent-based model of mitochondrial dynamics for these investigations. This model allows for the simulation of the dynamic actions of individual mitochondrial units to culminate in the complex patterns normally observed in mammalian cells. Live cell imaging of mouse primary cortical neurons from novel transgenic reporter lines (i.e., MitoTimer, MitoQC) and conditional knockout lines will be utilized to observe the respective contributions of individual dynamics proteins to the patterns of mitochondrial morphology. Knockout neurons will be exposed to oxygen glucose deprivation (OGD), an in vitro model of I/R injury, and mitochondrial parameters (i.e., morphology, oxidation) will be imaged in real time to generate a mechanistic timeline of mitochondrial dynamics. These live cell recordings will be used to optimize and expand our agent-based model to allow for in silico experimental manipulation of mitochondrial proteins. Our expanded model will have the ability to test hypotheses regarding the basal and pathological rates of mitochondrial dynamics and quality control, as well as inform future experiments with decreased costs and increased efficiency. In the K00 phase of this proposal, I will transition from studying mitochondrial quality control in I/R to its study in neurodegeneration. Utilizing the technical skills acquired in the predoctoral phase, I will investigate age-related changes in mitochondrial proteostasis and critical long-lived mitochondrial proteins at the synapse. The K00 phase aims to determine how aging affects the turnover of synaptic mitochondrial proteins, with specific emphasis on the roles of intramitochondrial proteostasis and the integrated stress response. I intend to determine the contribution of mitochondrial proteostasis to synaptic stability and related neurodegeneration. This work has significant implications in aging and neurodegeneration research, as synaptic loss and mitochondrial dysfunction are both hallmarks of age-related neurological diseases.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Despite assumptions that inter-hospital transfer (IHT, the transfer of patients between acute care hospitals) is done to provide patients with necessary specialized care, IHT also exposes vulnerable hospitalized patients to the risks of discontinuity of care. Our recent research suggests that a subset of transferred patients may experience harm during IHT without clear benefit; however, we currently lack data on how to identify in which patients harm outweighs benefit of transfer, i.e., experience inappropriate IHT. The long-term objective of this research is to rigorously define and evaluate the incidence and patient safety impact of potentially inappropriate IHT among hospitalized medical patients, identify patients at risk for inappropriate transfer, and develop an intervention toolkit to reduce potentially inappropriate IHT. To achieve this, we will work with diverse stakeholders involved in IHT, including patients/families, accepting and admitting clinicians, transferring clinicians, and hospital leadership to define potentially inappropriate IHT. We will then determine the incidence and patient safety impact of potentially inappropriate IHT via standardized adjudication of 1800 hospitalized medical patients from 18 US hospitals that participate in a national research collaborative (HOMERuN) and contribute data to a benchmarking and purchasing organization (Vizient). Adjudication tools will be based on those used in similar prior research and will be informed by stakeholder definitions of potentially inappropriate IHT. We will incorporate rigorous adjudicator training and continuous review to ensure reliability across sites, adjudicators, and time. We will then use standard modelling techniques to retrospectively characterize a population(s) of potentially inappropriate patient transfers based on several patient, transfer process, and system-level factors. This will be followed by advanced machine-learning methods to prospectively identify patients at risk for potentially inappropriate IHT and validation of the model's performance. Finally, we will utilize key results from the above analyses and stakeholder input to create a prototype intervention, refine the prototype based on feedback from participating sites using a mixed methods approach, and develop a toolkit of best practices to prevent potentially inappropriate IHT (e.g., by replacing it with a safer alternative) for future dissemination. This research will establish a foundation from which healthcare systems can achieve excellence in providing patients with the right care, in the right setting.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Guigen Liu, Ph.D., is a mechanical and optical engineer whose overarching career goal is to develop and translate optical fiber based biomedical optical imaging and sensing technologies. The research, entitled “Four- dimensional multi-modality microimaging-microdevice system for high throughput drug screening in vivo”, combines the advanced optical microimaging system with an emerging microdevice, which has the huge potential impact on drug development, individualized health care, and fundamental biomedical research. Candidate: Dr. Liu is an Instructor at the Radiology Department of Brigham and Women’s Hospital, Harvard Medical School. During his previous postdoctoral training, he and colleagues pioneered a silicon-tipped fiber- optic sensing platform featuring high speed and high resolution, which earned the 2015 Alan Berman Research Publication Award from the U.S. Naval Research Laboratory. While Dr. Liu has shown a successful track of record in engineering, his training in biomedical research is limited. Through the career development plans: 1) Gain more experience in two-photon fluorescence and Raman microimaging; 2) Learn to design and implement the microimaging-microdevice system; 3) Establish in vivo drug delivery and tissue response testing skills; and 4) Enhance leadership and career development skills, Dr. Liu will launch his independent career in the new field. Mentors/Environment: Dr. Liu has assembled a strong team of mentors to guide him through the proposed training and research activities. The proposed career development plan includes the rich resources available through Brigham & Women’s Hospital and Harvard Medical School, the Tearney Laboratory at the Wellman Center for Photomedicine, and the Laser Biomedical Research Center at Massachusetts Institute of Technology. Research: The research seeks to build an in situ multi-modality optical histological laboratory for the biomedical microdevice, through four specific research aims: 1) To implement quantitative 4D multi-color two-photon fluorescence microimaging; 2) To test drug efficacy in vivo using the 4D two-photon fluorescence MI-MD system; 3) To develop label-free MI-MD system using Raman microscopy; and 4) To investigate microimaging through long and flexible GRIN probes. Completion of these aims will push the microdevice a big step toward potential clinical adoptions in the future. Summary: Innovation of the proposed research is the integration of 3D microimaging and microdevice for 4D testing of drug efficacy and tissue response in vivo, which will meet the pressing needs of high throughput drug screening. The candidate has identified a group of experts who provide complementary training and mentoring on all the aspects for him to complete the proposed research and develop an independent research career.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY Chronic ulcers, defined as wounds that fail to heal within a three-month period, are associated with age-related dysfunction in skin stem cells that not only has potential to blunt tissue repair, but also accounts for skin fragility, atrophy, and the "aging phenotype" that itself has clinical as well as psychosocial implications. Non-healing ulcers in aging individuals represent a multibillion dollar burden in the United States and to society globally, both through utilization of health care resources as well as through reduction in productivity. Nonetheless, it is recognized that "the basic biology and the influence of age-associated changes on wound healing are poorly understood, and there are numerous research questions still to be answered". To address this important issue, we have 1) assembled a highly collaborative and multidisciplinary team of investigators with established track records in skin pathology, regenerative and stem cell biology, wound healing, bioinformatics, and the pathobiology of aging; 2) leveraged the resources of seven Harvard Institutions to develop a unified and state- of-the-art approach to decipher the role skin stem cell deficiency in age-related defective wound healing; and 3) generated data-based hypotheses and identified inter-project synergies that will maximize productivity and translational focus. Our fundamental hypothesis is that identification and interrogation of three major, inter- related, and therapeutically targetable/reprogrammable pathways relevant to age-related skin stem cell dysfunction, a) metabolic, b) epigenetic, and c) membrane transporter/receptor, will pave the way for combinatorial (multicomponent) therapies necessary for more robust healing and regenerative responses to skin injury. We will pursue this goal through six strategies that have been developed by the key personnel of this PPG: 1) discovery of biomarkers for epidermal and dermal stem cell identification and manipulation; 2) determination of metabolic regulators required for epidermal progenitor activity and maintenance; 3) identification of novel epigenetic pathways that govern skin stem cell function and vitality; 4) development and evaluation of unique murine models that permit study of human wound healing in vivo; 5) deployment of lineage tracking technologies that facilitate detection of experimentally-manipulated stem cell fate in healing wounds; and 6) generation of new animal strains and for epigenomic induction of premature aging and methods for genomic restoration of stem cell youth and pluripotency. Our overall aims seek to answer the following questions: 1) How can one map the key metabolomic, epigenetic, and cell receptor stem cell pathways that drive age-related wound healing dysfunction?; 2) What are the therapeutically-accessible nodes for stem cell-directed multicomponent combinatorial targeting within these pathways?; and 3) What are the agents that likely will affect restoration of robust and regenerative stem cell-driven responses to wound healing and support physiologic cutaneous maintenance and health? Success in this endeavor could be transformative in understanding how aged stem cells may be restored to functional vigor implicit to normal tissue integrity and regenerative potential.

NIH Research Projects · FY 2024 · 2022-09

The goal of this project is to create an interoperable care transitions application (Care Transitions App) for patients with multiple chronic conditions that will bridge the care transition between hospital, home, and primary care clinic in order to reduce adverse events in the first 30 days after discharge. We propose to develop a Care Transitions App which will engage patients and caregivers at the two trial sites, Brigham and Women’s Hospital and Vanderbilt University Medical Center, in both inpatient and primary care settings. The Care Transitions App will incorporate components from our prior work, specifically falls-reduction content. We propose to create three new modules: 1) a digital post-discharge transitional care plan, 2) modules for multiple chronic conditions (MCC: diabetes, congestive heart failure, and/or chronic kidney disease), including condition-specific post-discharge care plans with relevant lab values and medication education, and 3) a module for patients to enter their questions and their own goals for recovery prior to the post-discharge clinic visit. This project will include usability testing and integration of the application with Epic via the fast healthcare interoperability resources (FHIR) and SMART on FHIR technology at Brigham and Women’s Hospital (BWH) in Year 1. Aim 1: Utilize participatory design to develop the Care Transitions App and a multi-component intervention, including person-based and task-based interventions delivered by a Digital Navigator. Aim 2: Pilot test the Care Transitions App at BWH and disseminate to VUMC. 2a. We will pilot test the Care Transitions App and use the RE-AIM framework to iteratively refine the intervention before launching the clinical trial at BWH in Aim 3 (Y2). Later, we will pilot test the Care Transitions App at VUMC (Y5). 2b. We will disseminate the Care Transitions App at VUMC (Y5) and use the RE-AIM framework to understand barriers and facilitators at VUMC. Lessons learned at both sites will inform a dissemination toolkit. Aim 3: Evaluate the effectiveness of the Care Transitions App through a cluster randomized trial enrolling patients over the age of 65 years old with MCC including diabetes, congestive heart failure, and/or chronic kidney disease. We will test the following hypotheses: a. The Care Transitions App will be associated with a decrease in the primary outcome, post- discharge adverse events (falls, adverse drug events, other adverse events) within 30 days of discharge. b. The Care Transitions App will be associated with improvements in secondary outcomes: 30-day readmissions, completion of post-discharge phone calls, and completion of post-discharge primary care clinic visits. c. The Care Transitions App will be associated with improvements in patient-centered outcomes: global health, self- efficacy for managing chronic conditions, out of pocket costs, Care Transitions Measure 3, patient experience. Outcome: Our team will develop, evaluate, and disseminate a multicomponent intervention including a Care Transitions App and Digital Navigator training aimed at supporting safe care transitions for patients with multiple chronic conditions and a toolkit to support widespread dissemination.

NIH Research Projects · FY 2024 · 2022-09

Clinical decision support (CDS) systems can enhance the diagnostic process by minimizing diagnostic errors and delays, which are major components of patient safety. Recent federal regulations, including the Protecting Access to Medicare Act (PAMA), encourage CDS adoption and use by requiring that ambulatory providers consult with evidence-based Appropriate Use Criteria through qualified CDS mechanisms for ordering certain advanced imaging exams (e.g., CT, MRI). Optimally implemented, PAMA is a unique opportunity to improve the quality of diagnostic imaging care. However, if poorly executed, it could create interruptive electronic health record (EHR) workflows and low value clinical alerts, with little or no impact on diagnostic imaging utilization. The Harvard Medical School Library of Evidence (HMS-LOE) led a multi-disciplinary team of clinicians and medical informaticists to represent and grade clinical evidence in an effort to create CDS-consumable knowledge artifacts, which are publicly available at the HMS Countway Medical Library. Public domain sources of clinical evidence are represented as a Clinical Evidence Logic Statement (CELS) of “If-Then” form and graded using a system developed by the Oxford Centre for Evidence-Based Medicine for strength of evidence. 18% of the CELS in the HMS-LOE are also fully represented in standardized syntax and formats (e.g., Nomenclature of Medicine-Clinical Terms [SNOMED CT], Fast HealthCare Interoperability Resources [FHIR] and Clinical Quality Language [CQL]). CELS are specifically designed to be CDS-consumable and will greatly facilitate representation and public dissemination and sharing of artifacts. In this study, we will: 1) Assess the technical capability of FHIR, CQL and SNOMED CT to represent three patient-centered outcomes research (PCOR) guidelines from the HMS-LOE in a higher-level, structured representation, specifically a) Using Breast MRI (instead of or in addition to mammography) to diagnose a second breast cancer in women with previous breast cancer, b) Using CT scan for Pulmonary Embolism, and (c) Physician education for those at Risk for Pulmonary Embolism. In addition, we will: 2) Validate PCOR CELS represented in a structured representation at our healthcare system (Brigham and Women’s Hospital), and (3) Scale previously developed CDS artifacts to a different healthcare system (Covenant Health Inc.) with a different EHR implementation and health information technology (HIT) platform. Implementing transparently graded and represented knowledge artifacts will promote widespread dissemination and interoperability across varied HIT platform, end-users and workflows. In addition, validation and evaluation of the CDS artifacts, including usability and impact on clinical practice, will enhance widespread adoption. Ultimately, the goal of CDS for diagnostic imaging is to enhance evidence-based, effective care delivery.

NIH Research Projects · FY 2025 · 2022-09

Abstract We plan to establish a Diagnostic Center of Excellence that will focus on reducing diagnostic errors related to diagnostic imaging in two ways. We will: 1) implement a highly reliable and resilient system to enhance safety by reducing failures in timely performance of clinically necessary diagnostic imaging examinations and interpretative errors (Safety 2), and 2) improve diagnostic precision by building consensus using available evidence around four common causes of diagnostic errors – findings that may lead to a diagnosis of lung, prostate, pancreas and adrenal cancer. The DCE will build on strong pre-existing research and operational collaboration between a team of safety scientists, biomedical informaticists and health services researchers at the Massachusetts General Brigham (MGB) Health System. MGB is comprised of 2 tertiary academic hospitals, 7 community acute care hospitals, 3 specialty hospitals, multiple ambulatory care and outpatient imaging facilities serving patients in ambulatory, inpatient and ED settings, with a provider network of over 10,000 employed and affiliated primary care and specialty care physicians. Recent integration at MGB has prioritized clinical integration, creating a single Office of the Chief Operating Officer, a single Office of the Chief Medical Officer, and a single Enterprise Radiology governance including for quality and safety. We will enhance a set of pre-existing limited implementation information technology-enabled functions and workflows before MGB-wide expansion to address multiple types of diagnostic errors, including those leading to missed, incorrect, or delayed diagnoses. Enhancements will improve EHR-integration, monitoring and learning capabilities of our Clinical Dashboard to better address health disparities, to help advance an equity-informed resilient system and associated workflows. Another system for Peer Learning will also be implemented to target interpretive errors in diagnostic imaging. Finally, we will convene a multispecialty team of clinicians to build consensus on recommendations for diagnosis and management of findings that may lead to lung, prostate, pancreatic and adrenal cancer based on available evidence using a Modified Delphi process. Evidence that are agreed upon will be embedded in a clinical decision support system that will be integrated with the electronic health record. All specifications for systems and workflow processes, consensus results, and lessons learned will be disseminated broadly through national conferences and meetings, a public website, networks of clinical practice and institutions, and social media.

NIH Research Projects · FY 2025 · 2022-09

Delays in the diagnosis of cancer are too common. For patients diagnosed with advanced stage cancers, particularly those with symptoms or findings that may represent missed opportunities for earlier diagnosis, this can be devastating. These concerns are complicated by the nonspecific nature of cancer symptoms, hindsight bias, controversies around over-diagnosis and over-testing, and now delays in screening and care due to COVID. Some patients experiencing a delayed diagnosis may face additional challenges resulting from social determinants of health, racism, language barriers, or inadequate health insurance. Prior studies examined system factors associated with delayed cancer diagnosis, but progress on reducing these delays has been elusive. The patient voice has been missing, even though it is likely the one voice with the most to say about how the delay occurred and opportunities for improvement. In our prior work, we learned patients are frequently aware of problems in their care but hesitate to speak up for fear that it might adversely affect their care. Silence around the delayed cancer diagnosis extends to all members of the healthcare team, given the fear of malpractice litigation and the ingrained resistance to addressing problems in care transparently. We propose a Diagnostic Center of Excellence (DCE) that will seek out and transparently address cases and causes of delayed diagnosis of cancer by bringing together national experts on diagnostic safety (Brigham and Women’s Hospital/Harvard Medical School) and on Communication and Resolution Programs, or CRPs (University of Washington). CRPs are systematic processes for responding to problems in healthcare with transparency, accountability and learning. The project will target delays and disparities for historically marginalized patients with breast, lung, colorectal, and prostate cancer, each of which has recommended screening guidelines. The project encompasses the following specific aims: Specific Aim 1: Create a DCE to design and implement a program to identify and learn from patients who experienced delays in diagnosis of 4 leading cancers. We will partner with existing organizational resources and help to optimize them by bringing together multiple streams of data to facilitate real-time identification of patients, particularly those from marginalized populations, who may have experienced a delay in the diagnosis of cancer. Specific Aim 2: Engage and learn from patients who have experienced delayed cancer diagnoses. We will identify 240 recently diagnosed cancer patients at Dana Farber Cancer Institute and Fred Hutchinson Cancer Center. Using a novel patient advocate intervention, we will conduct serial interviews to develop trust and learn about potential missed opportunities for earlier diagnosis. We will then analyze these cases for improvement opportunities using existing validated tools. Specific Aim 3. Implement and evaluate generalizable interventions to improve the cancer diagnostic process. Our Advisory Committee will review ideas to improve cancer diagnosis emanating from Aims 1 and 2. We will test promising system solutions using plan-do-study-act (PDSA) cycles. We will develop a robust, multifaceted Improving Cancer Diagnosis Communication Toolkit designed for dissemination. By engaging patients and families who have a front row seat to the full diagnostic process, we will harness novel insights to improve timely diagnosis of cancer.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Each year, over 63,000 U.S. infants are born very preterm, below 32 weeks of gestation. With >90% now surviving to discharge from the neonatal intensive care unit (NICU), reducing the short- and long-term morbidities has become the highest priority. Neurodevelopmental impairment is a burdensome long-term morbidity that affects 50-60% of very preterm infants after NICU discharge. Nutrition is a cornerstone of clinical care in the NICU and represents a highly modifiable strategy to support healthy brain development during a critical period, thereby reducing long-term impairments. Previous studies have highlighted nutrient accretion into tissues as a key driver of healthier brain development and better neurodevelopmental outcomes. A current gap is in accurate, specific, and feasible strategies to assess and monitor nutrient accretion over time. The overall aim of this study is to investigate fat-free mass accretion as a dynamic bioindicator of nutritional status in the NICU. The specific aims involve establishing a new fetal reference for fat-free mass that covers the entire spectrum of preterm gestational ages, from 23 to 35 weeks, and using this reference to define targets for fat-free mass accretion that are based on neurodevelopmental outcomes. This study applies the innovative concept of “growth quality” to NICU nutrition research. Innovative approaches include the application of bioimpedance analysis to measure body composition in the NICU setting, and the use of quantitative brain magnetic resonance imaging (MRI) and electroencephalography (EEG) as early biomarkers of neurodevelopment in this population, in addition to standard behavioral measures. Our overarching goal is to improve long-term health and developmental outcomes of very preterm infants through pragmatic, evidence- based innovations in nutritional assessment and care during the NICU hospitalization. The results of this study will lay the foundation for fat-free mass-driven dietary interventions in the NICU setting. This study has strong potential to provide an impactful paradigm shift in the approach to the assessment and monitoring of nutritional status and ultimately the leveraging of nutritional strategies during a critical window in development to improve outcomes for this vulnerable population.

NIH Research Projects · FY 2025 · 2022-09

Total knee replacement (TKR) is commonly used to reduce pain and improve function in patients with advanced, symptomatic knee osteoarthritis (OA). While more than 80% of patients undergoing TKR report improved pain and functional status, growing evidence suggests that post-TKR physical activity (PA) does not surpass pre-TKR levels. Given the substantial time and financial investment associated with TKR and the rich evidence supporting health benefits of PA, the effectiveness and cost-effectiveness of TKR could be meaningfully enhanced if TKR recipients would be more physically active. The period following acute TKR rehabilitation provides a unique window of opportunity for these patients to transform their lifestyles. This proposal addresses whether introducing behavioral strategies that incorporate both intrinsic and extrinsic motivators can help TKR recipients engage in sustained, meaningful PA. Telephonic active coaching with motivational interviewing (TAC(MI)) uses regular conversations to resolve ambivalence and identify means of overcoming barriers to PA. Financial incentives (FI) address the temporal delay between completing healthy behaviors and receiving long-term health benefits by offering immediate rewards contingent on activity and performance. With these behavioral, psychological and economic principles in mind, we propose KArAT (Knee Arthroplasty Activity Trial). The long-term objective of this research is to determine the most effective and cost-effective behavioral interventions post-TKR to help patients develop a sustained commitment to becoming physically active. We plan to conduct a three-arm parallel RCT to establish the efficacy of personalized intervention built on the principles of behavioral science and behavioral economics in improving PA among patients who have undergone TKR. The three arms will include: Arm 1: Usual Care (UC); Arm 2: Attention Control (AC); Arm 3: Telephonic Active Coaching (Motivational Interviewing) + Financial Incentives (TAC(MI)+FI). In general, RCTs focus on either treatment-specific effect or total treatment effect. In this application, we propose a design that will permit us to estimate both. By including a ‘usual care’ arm, we will be able to estimate the overall effect of the intervention, which is relevant to estimating the value of the intervention and understanding the impact on clinical practice. The primary outcome will be the proportion of individuals engaging in at least 150 minutes per week of moderate-to-vigorous physical activity (MVPA) at ≥3 METs by the end of the six-month intervention. Change in average daily step count from pre-TKR to the end of the six-month intervention; change in weekly minutes of MVPA; reduction in sedentary time; and sustainability of efficacy at 12, 18 and 24 months post-TKR will be secondary outcomes. The results from KArAT will help clinicians, patients and policymakers make evidence-based decisions about improving PA after TKR, one of the most common orthopedic surgeries.

NIH Research Projects · FY 2025 · 2022-09

Summary Transfer RNA (tRNA) is traditionally viewed as an adaptor molecule that helps ribosomes synthesize proteins by decoding nucleotide triplets linking mRNA sequence to amino acid sequence of protein. Recent findings demonstrate that tRNAs also serve as a major source of small non-coding RNAs, so called tRNA-derived fragments (tRFs). The emerging concept in molecular biology is that these tRFs perform regulatory functions, although relatively little is known about their precise roles in cell physiology. Work from our and other laboratories has shown that in response to a variety of abiotic stresses (e.g. oxidative or nutrient stress), the vertebrate-specific ribonuclease (RNase) angiogenin (ANG) is activated to target the anticodon loops of tRNAs to produce a specific subclass of tRFs, known as tRNA-derived stress-induced RNAs (tiRNAs). Since their discovery in 2009, tiRNAs have been found to play roles in stress adaptation, cell survival and apoptosis. One of the relatively well studied roles of selected subset of tiRNAs (derived from tRNAAla and tRNACys) is inhibition of translation initiation via interference with functions of the cap-binding complex eIF4F (Ivanov et al. Mol Cell 2011). This proposal will further investigate functions of novel, previously unexplored, tiRNAs in regulation of translation. Our preliminary data suggest that alternative mechanisms of translation modulation exist that are different from the mechanisms used by tiRNAAla/Cys. In Aim1, we will dissect the molecular mechanisms of tiRNA- mediated regulation of translation. Our preliminary data strongly support a model in which multiple non- overlapping mechanisms are used by specific tiRNAs to mediate both inhibition and stimulation of mRNA translation. In Aim 2, we will identify and characterize mRNA targets of tiRNAs by employing candidate and unbiased proteomic and ribosome profiling approaches. Our preliminary data suggest that specific tiRNAs target specific pool of mRNAs thus reprogramming cellular translation. Our proposal is highly innovative and will broadly impact RNA biology. Successful completion of the proposed studies will result in characterization of novel translational control mechanisms acting during stress. Our studies are also important from a therapeutic point of view because multiple pathophysiological conditions are linked to changes in tiRNA production. Mutations affecting the RNase activity of ANG are found in patients with the neurodegenerative diseases Amyotrophic Lateral Sclerosis and Parkinson’s disease. Also, ANG is over- expressed in multiple cancers and its expression correlates with misbalanced tiRNA production, indicating a necessity to understand the function of tiRNAs. Finally, this proposal will generate many resources for the entire RNA/tRNA community and we will ensure that these resources are available for future use.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ ABSTRACT Autoimmune tissue inflammation is dictated by a balance between effector and regulatory T cells. During an autoimmune reaction, effector T cells hyper proliferate, produce pro-inflammatory cytokines and suppress expansion and generation of regulatory T cells resulting in inflammation. Cytokines play a key role in the process, but other factors such as metabolism and physical factors like oxygen tension, pH and space in tissue microenvironment play an equally important role in regulating effector vs. Treg balance. However, the analysis of T cell metabolism in tissue is challenging due to limitations of available cell numbers and current metabolic techniques. We developed a novel computational algorithm called Compass that can predict metabolic state of cells using single cell RNAseq data. Facilitated by this tool, we identified polyamine metabolism as a major driver of pathogenicity of Th17 cells. Herein we observed that Odc1 inhibition can regulate mitochondrial function by increasing mitochondrial complex stability genes with potential consequences in effector T cell function. Further, our preliminary data suggests a connection between the polyamine pathway (rate limiting enzyme, Odc1) and an epigenome modifier, JMJD3/Kdm6b. We also provide evidence that inhibition of the Odc1-JMJD3 axis by chemical inhibitors or genetic deletion modifies the transcriptome and epigenome (genome accessibility) of Th17 cells in favor of Tregs with relevance in tissue inflammation in CNS in experimental autoimmune encephalomyelitis (EAE). Based on these data we hypothesize that polyamine pathway is a critical metabolic and epigenetic regulator of effector vs. Treg differentiation and thereby affects development of tissue inflammation. The key element of the pathway, Odc1- JMJD3 axis is a checkpoint that can be regulated by cytokines and can sense environmental cues such as hypoxia and subsequently adjust metabolic and epigenomic state of T cells to regulate effector vs. regulatory T cell balance. We will test this hypothesis in two aims: 1) determine how polyamine biosynthesis restricts mitochondrial oxphos and promotes reverse electron transport to impact effector vs. Treg development in inflamed CNS during EAE; 2) determine whether polyamine metabolism enzyme Odc1 interferes with JMJD3 function to modulate the genome accessibility of T cells favoring Th17 over Treg development during EAE development. The polyamine metabolism pathway likely has broader implications in T cell biology. Hence, we will focus on the relevance of the Odc1-JMJD3 axis in inflamed CNS in the context of Th17/Treg balance. The proposed study is highly relevant in human diseases as reflected by a significant overlap (about 25%) between multiple- sclerosis risk variants and genes that differentially regulate effector Th17 vs. Treg differentiation.

NIH Research Projects · FY 2025 · 2022-09

Project Abstract This project is focused on developing an automated clinical decision support tool for predicting Intimate Partner Violence (IPV) risk and severity based on historical imaging and clinical data. Despite the high prevalence and urgency of this critical public health issue, there is currently no objective tool to diagnose IPV. The challenges in detecting IPV in the health care setting are due to multiple factors, including the patient’s feelings of shame and fear of consequences and physician’s lack of awareness and fear of offending the patient and partner. While imaging plays an essential role in diagnosing nonaccidental trauma in children because of clear well- established patterns of abuse on imaging studies, a lack of evidence-based research on IPV related imaging patterns has led to under-recognition and underdiagnosis of IPV. By recognizing location and imaging patterns specific to IPV on current and previous radiological studies, radiologists can help identify IPV when the victims are not forthcoming. Our hypothesis is that a multidimensional clinical support tool including imaging and clinical findings harvested from the electronic medical record can provide an accurate and comprehensive calculation of IPV risk. The automated IPV risk and severity predictions can then be integrated to transform the care plan for survivors and make the “invisible” visible. Aim 1: To define IPV related imaging patterns and severity by analyzing radiological studies of known IPV survivors and matched controls Aim 2: To determine IPV risk and severity prediction by developing a clinical decision support tool derived from historical imaging and clinical predictors. Aim 3: To validate the IPV prediction model on new datasets and evaluate the integration of results in radiology workflow using a safe repository. If our hypotheses are correct, established IPV related imaging patterns, a CDS tool derived from historical imaging and clinical predictors integrated into clinical care will be able to diagnose IPV objectively.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract Circadian rhythms, our 24 daily biological rhythms, control nearly all our basic biological functions and are sensitive to the environment. Directing both environmental and pharmacological interventions at disrupted circadian rhythms has untapped potential to treat many conditions including cancer, psychiatric conditions, and cardiometabolic disorders. We first need, however, to understand the molecular mechanisms involved in circadian rhythms, particularly those linking the human circadian system to downstream disorders. Human genetics can provide insights important to address this gap in knowledge. The overall vision of this research program is understanding the underlying mechanisms of the human circadian system and its role in human health leading to integration of the temporal axis of our biology into preventative clinical care and treatment using a multifaceted and innovative approach. My research program spans from genetic discovery to functional follow-up to translational applications with the goals for the next five years to 1) use existing biobanks to identify individuals with extreme circadian behavior for rare variant studies resulting in identification of genes and pathways involved in circadian rhythms; 2) develop scalable human circadian phenotyping methods to enable detailed investigations of circadian behavior in large-scale populations well-powered for genetic studies; and 3) create novel circadian function follow-up cellular assays with the potential to interrogate the impact of gene knock out in a variety of environmental and genetic backgrounds and pair this novel functional screen with drosophila behavioral assays of circadian behavior. I am well-positioned to lead this research program as my background is in human genetics with experience in circadian rhythms and cellular screens for downstream functional assays with a proven-track record of success. As well, I have current and future collaborators positioned to contribute their expertise to this research program, with specific expertise in population genetic studies, circadian phenotyping in humans, and cellular circadian assays. Expected outcomes are: 1) genes, pathways, and cell types that contribute to circadian physiology particularly mechanisms beyond the core molecular circadian clock; 2) Tools for circadian risk prediction and stratification with utility in the workplace, educational environments, and clinical care; 3) Easy to implement and dynamic circadian phenotyping for research and clinical use across a broad range of study and care; and 4) Novel pharmaceutical targets for circadian rhythm disorders and causally linked disorders. These findings will allow for the development of novel therapeutics for rare circadian rhythms disorders and increase our understanding of the basic mechanisms of circadian biology in humans, and ultimately shed light on how circadian rhythm dysregulation predisposes to more common associated neuropsychiatric and cardiometabolic diseases.