Brigham And Women'S Hospital

NIH Research Projects · FY 2026 · 2023-05

Project Summary Heart failure (HF) affects over 5 million adults over the age of 65. Cardiac transthyretin amyloidosis (ATTR-CM) is a cause of HF in ~10% of older adults and leads to significant morbidity and mortality. Musculoskeletal manifestations are common in ATTR-CM and occur 5-10 years prior to onset of HF. Exercise intolerance, a cardinal feature, is traditionally attributed to cardiac dysfunction but contributing systemic mechanisms have not been evaluated. Tafamidis, a transthyretin stabilizer, is the only approved therapy for ATTR-CM. It slows disease progression, prolongs life, and reduces HF hospitalizations. However, it does not improve functional capacity- no therapeutic intervention has been shown to do so in ATTR-CM. The central premise of this proposal is that skeletal muscle dysfunction from amyloidosis and HF severely limits aerobic capacity and, thus, quality of life in ATTR-CM, and that targeted exercise training will improve quality of life by improving skeletal muscle performance and aerobic capacity. Cardiopulmonary exercise testing (CPET) and the short physical performance battery (SBBP), including a leg extensor muscle power assessment will be used to achieve the following specific aims; 1) to compare skeletal muscle performance in ATTR-CM and non-amyloid HF; and 2) to determine improvements in aerobic capacity and quality of life due to 12 weeks of supervised exercise training in patients with ATTR-CM. To achieve the second aim, we use a personalized exercise intervention developed and led by Dr Bhasin’s team at the Boston Older Americans Independence Center (Boston OAIC) at BWH. Dr. Cuddy is an Instructor of Medicine at Harvard Medical School and Brigham and Women’s Hospital (BWH) who is highly qualified and invested in leading this study. She is a cardiologist and an expert in cardiac amyloidosis with a track record of successful research, including publications and awards. Her long-term career goal is to be become a clinician-scientist at the forefront of optimizing quality of life in adults with ATTR-CM. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with the skills needed to become an independent physician-scientist in CV medicine, with a well-qualified mentorship team led by Dr. Sharmila Dorbala. Data collected in this proposal on systemic dysfunction and the efficacy of exercise training in this population will ultimately inform future therapeutic trials. An outstanding mentoring team and advisory committee of established scientists in the fields of CV medicine, CV imaging, Aging, and Function-promoting therapies, will guide the candidate in her transition to scientific independence over the course of the award period.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT Endocytic recycling is critical for a broad range of physiologic events, including nutrient uptake, cell motility and polarity, intracellular signaling, and cytokinesis. We have been studying a coat complex that forms transport vesicles in a recycling pathway, which involves ACAP1 (Arfgap with Coil-coil, Ankyrin repeat and PH domain type 1) acting as the inner component and clathrin as the outer coating. Recently, we have made a remarkable discovery, finding that the protein kinase Akt acts as another component of this coat complex. Akt also possesses a direct ability to bend membrane, a finding that is unprecedented, as no kinase is known to possess this capability. Our recent discovery has also led us to reconstitute vesicle formation by this coat complex. Altogether, these findings lead us to propose three major goals. First, an ultimate understanding of how a protein bends membrane is being achieved through a high-resolution cryo-electron microscopy (EM) approach that solves the structure of the protein assembled on membrane. As this is the functional form of coat proteins, we will collaborate with a group having demonstrated expertise in the EM-based approach to elucidate in molecular detail how coat factors assemble into a protein lattice structure on membrane to achieve membrane bending. Second, whereas protein-based mechanisms of vesicular transport are being intensely investigated, lipid-based mechanisms have been far less explored. Addressing this fundamental shortcoming, we have recently pursued the vesicle reconstitution system to identify lipid enzymes needed for vesicle formation by the ACAP1 coat complex. Thus, we will elucidate the specific stage of vesicle formation that requires a particular enzyme. Moreover, to achieve a more complete understanding of how the lipid product of a particular enzyme acts, we will explore whether the geometry of the produced lipid affects ACAP1 vesicle formation, and also whether a particular lipid geometry promotes the ability of the ACAP1 coat factors to bend membrane. Third, we have recently performed mass spectrometry on the reconstituted ACAP1 vesicles to implicate many cargoes of the ACAP1 pathway. To validate this finding, we will focus on unexpected cargoes for further scrutiny, as confirmation that they use the ACAP1 pathway will provide particularly compelling support that our approach has identified true cargoes of the ACAP1 pathway. Specifically, we will mutate the sequence in these unexpected cargoes recognized by the ACAP1 coat complex and then confirm that sorting into the ACAP1 pathway is inhibited. We will also pursue an unifying explanation for the unexpected cargoes using the ACAP1 pathway by determining whether this transport results in their delivery to invadopodia, which are localized cell-surface structures that concentrate key factors for matrix degradation, a process needed for cell invasion into tissue. We anticipate that the completion of these studies will not only advance a further fundamental understanding of endocytic recycling, but also shed new insights into the physiologic roles served by the ACAP1 pathway.

NIH Research Projects · FY 2025 · 2023-05

Project Summary - The role of macrophages in hepatobiliary development The liver is a vital metabolic organ, involved in nutrient metabolism and detoxification of endogenous and exogenous products. To manage exposure to antigens and microbes, the liver harbors ~80% of the body’s residential macrophages. The role of macrophages in liver development is completely unknown. In our preliminary work we demonstrate that genetic or induced loss of macrophages severely affects hepatobiliary development, reducing biliary tree branching and affecting hepatocyte polarization. The objective in our proposed work is to employ macrophage-deficient zebrafish and transgenic reporter strains combined with high-resolution confocal imaging and novel image analysis methods to determine the importance of macrophages for liver development. Our central hypothesis is that macrophages are attracted to the developing liver bud by a temporal and location-specific expression of TNFα, and that macrophages mediate their effect on hepatobiliary development through modulation of TGFβ signaling. Two Specific Aims are proposed to define the role of macrophages for normal hepatobiliary development development. In Specific Aim 1 we will identify the exact periods during development when macrophages interact with the liver, and how their loss affects normal development and function. Specific Aim2 will define the molecular signals by which macrophages are attracted to the developing liver, and how macrophage-derived TGFβ signaling affects liver development. Our proposed work will provide critical new mechanistic insight into the contribution of macrophages to normal hepatobiliary development, and further elucidate the pathogenesis of developmental biliary defects in childhood.

NIH Research Projects · FY 2026 · 2023-05

Neurodegenerative diseases are common and devastating disorders, which will become increasingly prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still do not have disease-modifying therapies. To provide an alternative approach to studying these disorders and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease. Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation. We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models. Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed, which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia. We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in neurons non-cell autonomously. Given the growing evidence for an important role for glia in neurodegenerative disease, these studies have the potential for significant impact.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract The overall goal of this NCI K08 career development proposal is to facilitate Dr. Miranda Lam’s development into an independent investigator in oncology health policy research focused on understanding factors and policies that impact the quality and cost of cancer care. Her proposed project aims to characterize the variation in radiation oncology spending, utilization, and quality across the U.S. and identify strategies used by high-value radiation oncology practices. The primary objectives are to 1) identify and characterize variation in radiation oncology spending, utilization, and quality for cancer patients undergoing radiation therapy, 2) specifically investigate whether disparities in spending, utilization and quality of radiation oncology exist for dual-eligible patients, who are older on Medicare and low-income or disabled on Medicaid, and 3) elucidate approaches and strategies used by high- vs. low-value practices. A comprehensive evaluation and analysis of variation in spending, utilization, and quality of radiation oncology practices is the first step to optimizing cancer care delivery with radiation treatments across the U.S. Identifying the differences in approaches to care and barriers encountered by high- vs low-value practices are critically important for physicians, patients, hospital leaders, and policymakers. While the current mandatory Radiation Oncology Alternative Payment Model (RO APM) by Centers for Medicare and Medicaid (CMS) is on hold, alternative payment and delivery models are impacting oncology. This project will be timely and provide CMS and practices with valuable data to adjust or inform any future APMs in the future, as necessary to ensure successful transition without negatively impacting the quality of cancer care. Even if the current form of the RO APM is not implemented at this time, understanding variation in high- and low-value practices will still be valuable to determine whether certain practices need additional support to continue to provide high-value care for their cancer patients. In Aim 1 of the proposed study, the investigator will analyze Medicare claims data to characterize the variation in spending, utilization, and quality for patients undergoing radiation therapy for cancer treatments. She will systematically and comprehensively evaluate radiation oncology practices. In Aim 2, she will delve into whether there are differences in spending, utilization, and quality for dual-eligible patients. Finally, in Aim 3, she will perform key informant interviews of high- and low-value practices to elucidate differences in management, leadership, and care delivery.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY The accelerating pace of discovery in the basic biomedical, clinical and translational sciences now provides unprecedented opportunities to transform patient care in gastrointestinal and liver diseases. Over the past 35 years, Brigham and Women’s Hospital (BWH) has made major contributions to the training of academic gastroenterologists and hepatologists seeking cures for digestive diseases. This application from BWH requests support for the research training of 4 basic and clinical/translational research fellows, with BWH providing funding for an additional training slot. Outstanding candidates with strong interests and solid foundations in research will be recruited and trained to apply their knowledge and skills towards addressing important unmet clinical needs in the prevention, diagnosis, and treatment of patients with gastrointestinal and hepatic diseases. Trainees will receive program support for 2 years during which they will follow a structured and rigorous, but individualized training program. This will be a joint effort of 25 eminent preceptors from BWH, Boston Children’s Hospital, Dana Farber Cancer Institute, Harvard Medical School, the Harvard T.H. Chan School of Public Health, Massachusetts Institute of Technology and the Broad Institute. These preceptors constitute a network of collaborative researchers, who are international leaders in fields directly relevant to gastroenterology and hepatology. They have been organized into 4 themed, but interconnected research training units: cell biology, immunology and microbiology; metabolism and bioengineering; genes, stem cells and development; and clinical and translational sciences. These training units will provide content-specific educational programming and will increase the efficiency of administration within the training program. Oversight will be provided by a Research Training Executive Committee including the Program Director and 2 Associate Program Directors, who will also serve as preceptors. Additional members will provide guidance on mentoring and on achieving and maintaining excellence within the training program. An outstanding roster of internal and external advisory board members will evaluate the program and provide specific recommendations that improve its quality, impact, efficiency and value added to the research training of our most promising gastroenterology fellows. This highly personalized training program will include: 1) individual development plans; 2) rigorous research training; 3) hands-on experience in cutting-edge methodologies, and; 4) an integrated curriculum. Trainees will further benefit from the extensive institutional resources and rich intellectual environment of the participating institutions. Based upon the sustained levels of interest in our fellowship program, we anticipate a substantial pool of highly qualified candidates and will maintain a strong focus on recruiting highly qualified candidates. Through its rigorous, structured and highly personalized curriculum, this training program affirms its commitment to training future leaders in digestive disease research who are prepared to translate their findings towards improving patient care.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY Human cytomegalovirus (CMV) is the most common viral infection to complicate cardiac transplantation and is an important risk factor for cellular rejection. While CMV causes damage to native organs through direct viral cytopathic effect, CMV-mediated cardiac allograft rejection is attributed to “immune dysregulation,” the mechanisms for which are not well understood. This information is critical to the field of transplantation, as treatment of cellular rejection, even in cases with concurrent CMV viremia, includes immunosuppression, an approach that confers risk of abrogation of viremic control and precipitation of CMV-related morbidity, including worsening rejection and other opportunistic infections. While cellular rejection is mediated by cytotoxic T lymphocytes (CTL), recent paradigm-shifting work has demonstrated that activated mononuclear-phagocytic (MP) cells also have a critical role in driving allograft rejection through trained immunity. These findings are intriguing in the context of CMV-mediated graft rejection as MP cells are an important CMV viral reservoir. The central hypothesis being tested in this proposal is that CMV-mediated dysregulation of the MP system triggers a unique rejection phenotype that drives the infiltration of distinctly proliferative and alloreactive CTL into cardiac allograft tissue. The objective of this proposal is to leverage multi-omics strategies, including scRNA-seq and CITE-seq, to decode the allograft tissue microenvironment in rejection during CMV viremia, with a focus on understanding how MP cells orchestrate alloreactive CTL responses (Aim 1) and determine if tissue MP and CTL cell states are reflected in the blood (Aim 2). To accomplish this, we will study endomyocardial tissue and paired blood from a cohort of 200 heart transplant recipients at the Massachusetts General Hospital (MGH) Transplant Center. These studies will distinguish CMV-mediated and CMV-independent mechanisms of cellular rejection, allowing for the development of diagnostic tools and rejection treatment strategies tailored to viral or non-viral causes, promoting precision medicine in cardiac transplantation. Dr. Sen will perform the work in this K08 proposal in the Center for Immunology and Inflammatory diseases (CIID) at MGH under the mentorship of Dr. Andrew Luster and Dr. Alexandra-Chloe Villani. The CIID is a state-of-the-art multidisciplinary research center focused on mechanisms of immune-mediated inflammatory diseases and is the foundation for immunology research at MGH. Dr. Sen has devised a career development plan consisting of coursework and hands-on training in single-cell ‘omics,’ bioinformatics, the biology of alloimmunity and tolerance, cardiac tissue microenvironments, in vivo host-pathogen interactions, and human subjects research, as well as organized a Training Advisory Committee, chaired by Dr. Joren Madsen, to provide expertise and assistance in these areas. The K08 award will provide Dr. Sen with the intellectual and technical training necessary to become an independent, R01-funded investigator with expertise in host-pathogen interactions and immune dysregulation in transplantation.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT/PROJECT SUMMARY Impressive advances in gene discovery in the auditory system have occurred in the last decades, making specific targeted approaches for therapeutics realistic goals of great interest in the field of hearing and deafness. Hearing loss (HL) is an increasingly significant health problem in populations worldwide, with a substantial proportion due to genetic causes. Given the health burden and ongoing rapid discoveries, it is now essential to pursue new strategies for specific early interventions that could prevent or mitigate severity and progression of HL. One such disorder is DFNA9, an adult-onset sensorineural HL with balance dysfunction, caused by mutations in COCH, encoding cochlin, the most abundantly detected protein in the inner ear. This disease model is similar to and representative of the majority of genetic HL disorders with a dominant mode of inheritance and with a deleterious gain-of-function of the mutant protein. Aims 1 and 2 of this proposal involve utilization of the powerful and versatile CRISPR-Cas9 gene editing technology for specific targeting and disruption of the dominant missense pathogenic COCH variants p.G88E and p.A449T. We will utilize human fibroblasts from patients with these two variants, and derived pluripotent stem cells and organoids. These biological resources will serve as tools for the development of effective methods for allele-specific gene disruption of the COCH pathogenic variants, while leaving the normal allele intact and functional. The organoids will be assessed as a possible in vitro system for elucidating the biology of COCH aggregates pathognomonic of DFNA9 temporal bones. Furthermore, we will utilize two Coch knock-in (KI) mouse models with these variants for implementation of somatic tissue gene targeting in the inner ear. These approaches will establish methodologies for gene editing not only for DFNA9, but also for a broader category of other HL disorders with a dominant gain-of-function mechanism of pathology, with the ultimate goal of translation to clinical trials and therapeutic intervention.

NIH Research Projects · FY 2026 · 2023-04

Project Summary The natural disease course of chronic obstructive pulmonary disease (COPD) is punctuated by events, termed exacerbations, when symptoms are acutely worse. Exacerbations are costly and burdensome – they are associated with accelerated lung function decline, impaired health status, increased hospitalization, and increased mortality. Evidence suggests that some individuals are particularly susceptible to exacerbations, but heterogeneity remains poorly understood. There is thus an urgent need to better delineate COPD heterogeneity and improve identification of groups at risk for these adverse outcomes as early as possible. Our long-term goal is to use quantitative imaging and trajectory-based subtype analysis to delineate COPD subpopulations, enabling early identification of subpopulations at risk for adverse, long-term outcomes. We have developed CT biomarkers of pulmonary vascular pruning, cardiac morphology, emphysema subtypes, airway thickening, and skeletal muscle wasting in CT imaging. However, we have not performed an integrative analysis of these biomarkers that could better delineate homogeneous subgroups. We have also developed a Bayesian trajectory algorithm that incorporates longitudinal data to identify distinct population subgroups with similar biomarker patterns while accounting for factors such as age and smoke exposure. Our overall objective in this proposal is to use multidimensional trajectory analysis to evaluate novel CT biomarkers in terms of exacerbation risk-stratification. Our central hypothesis is that multidimensional trajectory analysis of pulmonary and extra-pulmonary CT biomarkers can identify subgroups with latent susceptibility to exacerbations. The rationale for this work is that by identifying distinct trajectory subgroups using multiple CT biomarkers, we will better delineate COPD heterogeneity, leading to earlier, more precise risk-stratification – especially amongst those patients for whom CT imaging is the most reliably available data source, such as those who have undergone lung cancer CT screening. Aim 1 focuses on the methodical assessment of our novel CT biomarkers in terms of COPD exacerbation risk stratification using trajectory analysis. Aim 2 focuses on using CT biomarkers and trajectory analysis to identify subgroups within a lung cancer screening cohort that are at risk for hospitalizations due to COPD exacerbations. The approach is innovative, in our opinion, because it shifts focus from disease staging to identifying mechanistically similar subgroups (endotypes). The significance of these contributions will be an improved understanding of CT-assessed patterns of abnormality in cardio- pulmonary and extra-pulmonary systems and how these patterns present in trajectory subgroups at risk for adverse events. In turn, we expect this to better enable detection of early disease manifestations and subtype characterization. We expect these contributions to enable further studies of the mechanistic differences between subgroups as well approaches to preempt costly acute events by identifying the early-stage manifestations of at-risk groups.

NIH Research Projects · FY 2026 · 2023-04

Prostate cancer has the highest estimate of heritability of any cancer, with 58% of variability in prostate cancer incidence attributed to inherited genetic factors. Genome wide association studies have validated 269 single nucleotide polymorphisms that are strongly associated with prostate cancer risk. We found that a multiethnic polygenic risk score (PRS) combining these SNPs demonstrate a 9-fold difference in risk of disease comparing men with high vs. low PRS in a both Black and White men. This proposal aims to translate this prostate cancer PRS into clinical practice by addressing four important questions: 1) Can the PRS be integrated with other tools including MRI and rare genetic variants in DNA damage repair (DDR) pathways as part of an early detection strategy to identify clinically-relevant, potentially lethal prostate cancer? 2) At what point in a man’s life should an early detection program begin if he is at increased genetic risk? 3) What is the optimal interval of imaging to detect clinically relevant cancer in men at high genetic risk? This collaborative U01 proposal addresses these issues in three specific aims. Aim 1 - we will prospectively determine the ability of a prostate cancer PRS integrated with MRI to identify higher-grade, potentially lethal prostate cancer. We will recruit 1500 men (600 Black, 900 White) from the MGB Biobank, the Walter Reed Biobank, and the primary care network at Howard University and Brigham & Women’s Hospital. All men will be stratified into low, average, and high risk on the basis genotyping. PSA, MRI, and DDR variants will be obtained followed by biopsy for elevated PSA or abnormal MRI. We expect to find the PRS identifies a population at risk for prostate cancer while the DDR variants and MRI identifies a subset with clinically relevant disease. In Aim 2, we will evaluate at what point in a man’s life an MRI is clinically useful. Our population will be imaged across 5 year age groups from 40-69 years. In addition, men at the high genetic risk without cancer will undergo serial MRI imaging at the NCI at 2 year intervals. In Aim 3 we will determine if deep learning methods applied to mpMRI and informed by genetic risk can more accurately predict significant cancers. This will be the first in field prospective trial to integrate germline genetics with MRI to identify men at risk of clinically-relevant prostate cancer. The results will have short-term impact by establishing an optimal early detection algorithm and show the utility of incorporating information on the germline into an early detection strategy. It will establish the role of MRI in detecting clinically relevant cancers among those with high genetic risk. The longer-term goal will be to use the knowledge gained to design trials of the at-risk populations with longer follow-up to prove that genetic testing can improve our ability to prevent prostate cancer mortality through targeted screening and prophylaxis. Importantly, men at low risk for clinically significant disease could be spared screening, prophylaxis and treatment. This information can be directly translated into patient populations.

NIH Research Projects · FY 2026 · 2023-04

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline loss-of-function mutations in the TSC1 or TSC2 gene. Renal disease, which includes angiomyolipomas, cysts, and carcinomas, is the second leading cause of morbidity and mortality in TSC. In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human TSC renal cysts and angiomyolipomas. We also demonstrate that B7-H3 promotes TSC2-null cell growth in vivo via a mechanism that requires CD8+ T cells. These and other data lead to our central hypothesis: immunosuppressive macrophages together with B7-H3 expression on TSC2-deficient cells promote renal disease in TSC. A key translational corollary of this hypothesis is that immunosuppressive macrophages and B7-H3 are potential therapeutic targets for TSC. Aim 1: To identify the mechanisms through which macrophages contribute to the renal manifestations of TSC. We will test the hypothesis that immunosuppressive macrophages promote TSC1- and TSC2-deficient cell growth directly, and/or indirectly via inhibition of CD8+ T cell function. Aim 2: To determine how B7-H3 remodels the immune microenvironment of TSC-associated renal disease. We will test the hypothesis that B7-H3 promotes TSC2-null cell growth by inhibiting CD8+ T cell function. Aim 3: To investigate the preclinical efficacy of co-targeting macrophages and B7-H3 in TSC. We will test the hypothesis that targeting both immunosuppressive macrophages and B7-H3 will lead to long-lasting, durable responses in preclinical models of renal disease driven by loss of Tsc1 or Tsc2. We expect this project to have scientific impact by identifying the immune mechanisms responsible for the growth of TSC2-null cells in the kidney. These mechanisms may have broad implications, since macrophages are believed to play a key role in other renal diseases, including autosomal dominant polycystic kidney disease (ADPKD). Our areas of innovation include our novel, translationally relevant hypotheses as well as technical innovation, including CITE-seq, spatial CODEX and nanoString transcriptomic profiling, and a novel, unpublished mouse model of renal disease in TSC (Rosa26-CreERT2 Tsc2f/f).

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to account for ~ 34,500 deaths each year in the United States. Therapeutic options are limited for mCRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially personalized therapies based on genomic alterations in tumors. Recent genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes involved in DNA damage response (DDR) are among the most common genetic events and enriched in mCRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells. Specifically, defects in homologous recombination repair (HRR) would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. BRCA1/2 encode proteins essential for HRR. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of mCRPC patients with HRR mutations (or deleterious BRCA1/2 mutations) based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. BRCA1/2 mutations can predict PARPi response with 50-60% accuracy. However, the degree to which patients with non-BCRA1/2 genomic alterations respond to PARPis remains unclear. Through genome-wide CRISPR screening, we have recently discovered that loss of MMS22L in PCa cells predicts the response to PARP inhibition. MMS22L is required for HRR of replication fork-associated DNA double strand breaks. More importantly, the MMS22L gene is frequently deleted (~14%) in prostate tumors. In addition, the results from our CRISPR screening further suggest that loss of TP53 or RB1 may render PCa cells resistance to PARPis due to upregulation of HRR gene expression, which can be overcome by combining ATR inhibition. Therefore, the goal of this project is to determine (1) to what extent loss of MMS22L confers a cellular response to PARP inhibition in preclinical PCa models; (2) to what extent inactivation of TP53 or RB1 influences PARPi response; (3) to what extent ATR inhibition re-sensitizes resistant PCa cells to PARP inhibition. The successful completion of this project will set the stage for future clinical trials in mCRPC patients with MMS22L and TP53/RB1 alterations and significantly expand the pool of eligible patients for PARP inhibition.

NIH Research Projects · FY 2026 · 2023-04

Abstract Neurovascular diseases, including stroke, aneurysms, and arteriovenous malformations, can cause devastating and life-threatening injury to the brain. Each year these diseases affect nearly 1 million people in the US. Stroke alone kills more than 130,000 Americans each year. Effective treatment of these diseases requires understanding the cerebrovascular architecture, which is complex and patient specific. Existing clinically available methods for imaging blood vessels in the brain are limited by several factors, including spatial and temporal resolution, the need for ionizing radiation or contrast agents, and the lack of availability of some types of imaging during surgical procedures. We propose to generate patient-specific 4D models of cerebral vasculature with unprecedented spatial and temporal resolution from a single pair of 2D Digital Subtraction Angiography (DSA) image sequences. Two important advantages of using DSA are: 1) it has high spatial and temporal resolution; and 2) it is readily available both pre-operatively, for planning surgery, and intra-operatively, for monitoring the surgical procedure. To pursue this goal, we will investigate novel approaches for contouring vessels in DSA images, extracting information about blood flow with high temporal resolution from DSA video sequences, and annotating the contoured vessels with this temporal data. We will expand our recent work on constrained 2D-to-3D reconstruction for generating patient-specific 4D cerebrovascular models that will exploit these annotated vessel contours. The resultant models will support vessels as small as 0.1 mm3 and flow rates up to 15 frames per second, a 10-fold improvement in spatial and/or temporal resolution over models generated from clinically available MRA, CTA and rotational DSA. Finally, we will develop new software for visualizing and interacting with these 4D models and give surgeons the ability to virtually inject a bolus of contrast at any point in the vascular network to observe downstream flow. This software will give neurosurgeons a better understanding of their patient’s cerebral vasculature, allowing them to plan and perform safer and more effective neurovascular surgery.

NIH Research Projects · FY 2026 · 2023-04

Abstract This proposal focuses on the potential role of mast cells in the control of type 2 immunopathology (T2I) elicited by IL-33, a principal effector cytokine involved in the onset and persistence of upper and lower airway inflammation. Preliminary studies demonstrate that mast cells are required to drive type 2 inflammation when the levels of prostaglandin E2 (PGE2) are reduced, but paradoxically shift to an anti-inflammatory role when PGE2 levels are sufficient. We have now found that mast cells are necessary to control the production of soluble ST2 (sST2), a decoy receptor that binds IL-33 and limits its bioavailability in vivo. Moreover, PGE2 upregulates the expression of sST2 while downregulating the expression of ST2L, the cell surface receptor for IL-33. Aim 1 will determine the mechanism(s) by which mast cells protect the lung from IL-33-induced T2I, and identify the mast cell subsets that are responsible. Aim 2 will determine the receptors and molecular mechanisms by which PGE2 alters the expressions of sST2 and ST2L, and Aim 3 will verify the importance of these mechanisms in vivo. The studies have strong translational implications for the pathophysiology of respiratory T2I, and could point the way toward the development of logical therapeutic strategies for asthma and chronic sinus disease.

NIH Research Projects · FY 2026 · 2023-04

R35GM149229 Abstract This is an R35 NIGMS application that is meant to succeed R37GM62437 and concerns the development and application of chemical approaches to enhance our understanding of histone post-translational modifications (PTMs) on Lys residues and the enzymes that attach and remove them (“writers” and “erasers”). Our lab has a record of technical innovation in the chemical biology of histone modifications including bivalent analog design and protein semisynthesis. Our bivalent compound approaches have led to the generation of potent and selective inhibitors of p300 and CBP (p300/CBP) acetyltransferases and the LSD1-HDAC1-CoREST (LHC) demethylase/ deacetylase gene silencing complex. Our latest-generation compounds, A485 for p300/CBP and corin for LHC have become very useful and popular pharmacological probes for analyzing these histone-modifying enzymes in mechanistic and preclinical therapeutic experiments. Our protein semisynthetic methods including expressed protein ligation, engineered sortase-catalyzed histone production, and Cys modification to introduce acyl-Lys mimics have proven to be efficient approaches to furnish site-specifically modified proteins. In recent years we have shown how particular histone modifications influence nucleosome stability and susceptibility to eraser enzymes including deacetylase, demethylase, and deubiquitinase isoforms. Notably, we have discovered a new case of histone mark (PTM) crosstalk—an apparent gatekeeper function for histone H3 acetylation at Lys14 in blocking LSD1 demethylation of H3 methyl-Lys4. In the next phase of our research program, we will develop and apply new chemical methods to more broadly understand the biology of histone mark crosstalk using protein semisynthesis, gene editing, structural approaches, and “cut and paste” mass spec proteomics. We will explore structural and functional features of enzymatic nucleosome interactions in the context of LSD1, PRC1, SAGA, HDAC1, and Sirt6 complexes in part by incorporating chemical warheads into designer nucleosomes. In addition, we will apply a newly engineered version of sortase to isolate histone H3 tails from cellular chromatin to quantitatively readout patterns of PTMs in different cell types and in response to pharmacological agents by employing tandem mass tag mass spectrometry. Upon completion of this research effort, our findings will broaden the knowledge of how histone Lys modifications are “written” and “erased” and how specific PTM patterns regulate gene expression and cell fate. Moreover, these studies should pave the way for new therapeutic strategies to combat epigenetic dysregulation in various diseases. This research program will enable the training of the next generation of biochemical investigators.

NIH Research Projects · FY 2026 · 2023-04

Summary Preserved language function is essential to quality of life. For patients with a brain tumor near putative language cortex, neurosurgeons may use functional magnetic resonance imaging (fMRI) presurgical language mapping to assess and mitigate the risks of surgery-induced permanent language deficits. Critical barriers to clinical deployment of presurgical fMRI are that 1) The validity of conventional fMRI is contingent on the patient’s ability to perform precisely timed phonological and semantic tasks. But up to 50% of patients assigned to fMRI have language or other cognitive deficits that affect task performance and may invalidate the mapping. 2) Expertise in administering language tasks is insufficient in many clinical settings. To tackle these challenges, we propose a single-group clinical trial to test movie fMRI (in which subjects watch short movie clips while being scanned) as a novel diagnostic intervention for language mapping in neurosurgical patients. Our primary hypothesis is that movie-watching relative to task-based and resting-state fMRI can provide comprehensive language mapping in a greater number of neurosurgical patients, especially those with language deficits. Compared to conventional fMRI language mapping tasks, movie-watching is predicted to engage more completely the neural networks supporting language in real life. Movie-watching also improves subject compliance in fMRI scanning. Our preliminary results demonstrate reduced in-scanner head motion, higher mapping sensitivity in receptive language areas, and overall higher language mapping specificity, of movie versus conventional task fMRI, in brain tumor patients undergoing presurgical language mapping (n=34). In this project, Aim 1 will evaluate in individuals with stroke-induced aphasia (n=80) and healthy controls (n=40), the comprehension and expression elicited by movie-watching versus conventional paradigms, as a function of language impairment. We predict that language performance will be comparable, and in most individuals with aphasia superior, for movie-watching relative to the other paradigms. Aim 2 will assess in neurologically-healthy subjects (n=40), the quality of movie fMRI language mapping as a function of movie clip, and relative to conventional paradigms, using indices of language localization sensitivity and specificity, hemispheric lateralization, and proximity to language white- matter tracts. We predict that for clips inducing the most sensitive and specific synchronized fMRI activation, movie-fMRI will produce better language mapping quality indices than the other paradigms. Aim 3 will similarly evaluate movie-fMRI in neurosurgical patients with frontal or temporoparietal gliomas (n=80), as a function of baseline language function, against the gold standard intra-operative electrocortical stimulation language mapping, and relative to post-operative language outcome. We predict that movie-fMRI will produce better language mapping in a large proportion of patients, especially those with language deficits. Study materials will be publicly released, including optimal movie clips for certain language deficits and fMRI analysis routines.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract Heterozygous truncating variants in the essential sarcomere protein titin (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM), dilatation and contractile dysfunction of one or both ventricles of the heart. DCM often progresses to heart failure (HF), a devastating disorder associated with high morbidity and mortality including death in 50% within 5 years after the first HF hospitalization. While an exact mechanism of how TTNtv leads to pathogenesis of DCM is still under investigation, insufficient amount of TTN protein caused by TTNtv significantly disrupts cardiac physiology and contributes to development of DCM. To define therapeutic strategies for DCM caused by dominant truncating variants in TTN (TTNtv DCM), Dr. Kim first developed an efficient model system: isogenic wild-type (WT) and mutant human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying heterozygous TTNtv. TTNtv/+ hiPSC-CMs have decreased TTN expression and impaired contractility, similar to human patients with DCM. Additionally, by comparative analyses of sequence conservation and transcriptional activation signals during cardiomyocyte differentiation of hiPSCs, Dr. Kim identified a transcriptional enhancer of TTN, when deleted from WT hiPSC-CMs, markedly reduced TTN expression and disrupted sarcomere formation and function. Furthermore, Dr. Kim’s preliminary work demonstrated that transcriptional activity of the TTN enhancer can be increased by modifying its sequences and by directing clustered regularly interspaced short palindromic repeats (CRISPR)-mediated activator to the TTN locus in human cells. Based on these preliminary data, Dr. Kim formed the hypothesis that increasing TTN gene expression by modulating endogenous TTN regulatory elements and by introducing exogenous transcriptional activators will improve function of cardiomyocytes in TTNtv DCM model systems. In this proposal, Dr. Kim plans to test her hypothesis in three specific aims. In Specific Aim 1, Dr. Kim will identify regulatory genetic elements of TTN gene expression, which are currently unknown. In Specific Aim 2, Dr. Kim will modulate regulatory elements of TTN via genome editing to augment TTN expression. In Specific Aim 3, Dr. Kim plans to assess effects of increased TTN expression in TTNtv DCM model systems. This work will take place in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital (BWH), a core teaching hospital of Harvard Medical School (HMS). Dr. Kim will perform the research under the mentorship of Dr. Christine Seidman, the Thomas W. Smith Professor of Medicine at HMS and director of Cardiovascular Genetics Center at BWH, and Dr. Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS. Dr. Kim’s goal is to become an R01-funded independent clinician-scientist with expertise in genetics of cardiomyopathy. Dr. Kim plans to use her K08 award to strengthen her skills and knowledge in gene regulation and genome editing, which will serve as a foundation for her R01 application where she will apply genetic engineering technologies to develop therapeutic strategies for DCM.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT I am interested in developing novel treatment strategies for maintaining muscle mass and function in the elderly population. My lab utilizes murine models of aging to investigate mechanisms on how aging-associated loss of hypoxia signaling in skeletal muscle affects two key factors in maintenance of muscle mass and function: (1) skeletal muscle regeneration and (2) adaptation to aerobic exercise. Prolyl hydroxylase domain enzyme (PHD)2 increases profoundly in skeletal muscle with aging and is a key regulator of the hypoxia signaling pathway. This increase in skeletal muscle PHD2 leads to loss of hypoxia inducible factor (HIF)-1, a central transcription factor responsible for downstream hypoxia pathway signaling. Using a murine model of aging and genetically modified mice, we have demonstrated that a muscle specific increase in PHD2 recapitulates diminished skeletal muscle regeneration and loss of aerobic exercise adaptation as seen in aging. Building on these intriguing pilot data, the central goals of this project are to (1) mechanistically define the role of PHD2 and its impact on muscle regeneration in aging, (2) determine whether PHD2 inhibition preserves skeletal muscle myogenic potential with aging, and (3) evaluate if increased skeletal muscle PHD2 in aging limits muscle adaptation in response to aerobic exercise. Importantly, transcriptome analysis in humans also demonstrates decreased hypoxia signaling in old skeletal muscle, suggesting translational potential for hypoxia signaling targets. As FDA approved PHD2 inhibitors are available, an improved mechanistic understanding of hypoxia signaling as it relates to skeletal muscle regeneration and exercise response may offer therapeutic opportunities for elderly patients suffering from loss of muscle function with aging.

NIH Research Projects · FY 2026 · 2023-03

One of the biggest challenges in rare diseases is accuracy and timeliness of patient diagnosis. On average it takes 6 years for an accurate diagnosis, delaying treatment and creating substantial burden at the levels of individual, familial and healthcare systems with an estimated $750 billion spent on unnecessary procedures. Therefore, there is an urgent need to improve diagnosis. Genetic risk predictions can improve diagnosis, with particular clinical utility in the specific setting where large barriers to diagnosis exist, such as rare sleep disorders. The rare sleep disorders narcolepsy and circadian rhythm sleep wake disorders face large hurdles to diagnosis, where 20% of primary care physicians are unaware that sleep medicine exists as a specialty, routine screening for sleep disorders is nearly absent, diagnostic tests require overnight visits to a limited number of specialized clinics, and insurance coverage for common diagnostic tests is non-existent. In contrast to the current diagnostic landscape for sleep disorders, genetic risk prediction is relatively inexpensive and easily accessible. In order to integrate genetic risk into the diagnosis and treatment pipeline, we must first have broadly applicable, reliable genetic predictors of risk. To address the challenge of timely patient diagnosis in sleep disorders, we propose to leverage large exome sequence repositories to generate rare variant risk scores, expand the current known common polygenic scores, and ultimately test the ability of both the rare and common polygenic scores to predict risk of rare sleep and circadian disorders in a large-scale hospital database with the goal to integrate flags in patient records.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Recent largest GWAS identified HAVCR2 (TIM3) genetic risk factor for late-onset Alzheimer’s disease (LOAD). Our laboratory discovered and cloned Tim3 as an inhibitory molecule that induces T cell exhaustion in cancer1. Blocking antibodies to Tim3 are being approved for the treatment of cancer. However, we have now identified that Tim3 is not only expressed on T cells, but also on myeloid cells and dendritic cells, where TIM3 restrains dendritic cell function and regulate anti-tumor immunity2. In the CNS, HAVCR2 was identified as one of the top 100 enriched transcripts and is specifically expressed in both mouse and human microglia3-5, but its role and function in microglia is unknown. Our long-term goal is to define the role of TIM3 in regulation of microglia in neurodegeneration. We made the following observations: 1) Tim3 inhibits microglial activation and phagocytosis: deletion of Tim3 in dendritic cells boosted antigen presentation and we find that TIM3 also regulates microglial activation and phagocytosis; 2) TGFb-Tim3 axis regulates microglia phenotype switch in neurodegeneration: we find that TGFb is the key driver for the induction of Tim3 and once expressed it synergizes with TGFBR to potentiate TGFB signaling, loss of Tim3 switches M0-homeostatic microglia to an MGnD-nondegenerative phenotype; and 3) TIM3 deletion in microglia reduces plaque burden in 5xFAD mice. These data support the genetic linkage studies and show the importance of Tim3 in regulating disease pathology in AD by modulating microglial function. Based on these studies, we hypothesize that TIM3 is a key regulatory molecule in microglia that inhibits their response to neurodegeneration, migratory and phagocytic functions and thereby inhibit plaque clearance resulting in promotion of Ab deposition, development, and progression of AD in aging brain. Based on this hypothesis we have proposed three aims: Aim 1: Define how TIM3 regulates phenotype and functions in 5xFAD and P301S mouse AD models. We propose to study the effect of microglial deletion of Tim3 in neurodegeneration and brain tauopathy using the mouse models of AD. Aim 2: What is the role of TGFb signaling in the regulation of Tim3 expression and function in microglia and development of AD? Since TGFb plays a critical role in maintenance of the homeostatic phenotype in microglia, we propose to study how TGFb signaling induces Tim3 expression and promotes homeostatic behavior of microglia by cooperating with TGFb receptor signaling. Aim 3: Define the role of TIM3 in the regulation of human microglial function in AD. Determine how TIM3 impacts human iPSC-derived microglia activation and functions. We will examine whether genetic or pharmacologic inhibition of TIM3 has a similar effect on iPSCs-derived human microglia expressing the MGnD phenotype by utilizing a humanized chimeric mouse model of AD for treatment with human anti-Tim3 antibody IN SUMMARY, targeting TIM3 in microglia may provide a novel approach for therapeutic modulation of innate immunity in AD and dementia.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT The prevalence of and mortality from cirrhosis have increased dramatically over the past twenty years. Atrial fibrillation (NVAF) disproportionately affects 15% of patients with cirrhosis and leads to substantial morbidity and mortality, including 5-fold higher rates of stroke. In the general population with NVAF, the risk-benefit balance typically favors initiation of oral anticoagulants (OAC). In contrast, over 50% of patients with cirrhosis and NVAF are not anticoagulated despite their markedly increased risk of stroke, due to concerns about bleeding, poor anticoagulation quality and falls. These concerns also complicate selection of an optimal OAC regimen, which involves choosing between warfarin and direct oral anticoagulants (DOAC: apixaban, rivaroxaban, dabigatran and edoxaban). While DOACs have potential benefits over warfarin in patients with cirrhosis, they have variable hepatic metabolism (between 20%-75%) and they are largely untested in cirrhosis, because such patients were excluded from all prior DOAC randomized controlled trials (RCTs) for NVAF. Moreover, RCTs are unlikely to recruit and retain vulnerable patients with advanced, decompensated cirrhosis or cognitive impairments in a manner representative of routine care. Thus, for patients with cirrhosis and NVAF – who are at higher risk of both bleeding and thrombosis – there is a pressing need for robust data regarding the optimal OAC strategy. This proposal seeks to define the comparative effectiveness and safety of warfarin and DOACs in a population- based cohort of over 250,000 U.S. adults with established cirrhosis and NVAF diagnosed between 2011-2019 (including over 100,000 new OAC initiators), from 4 healthcare databases (Medicare, Medicaid, Truven MarketScan and Optum Clinformatics). Within this cohort, we propose: (Aim 1) To define the effectiveness and safety of use vs. non-use of OACs (including warfarin and specific DOACs); (Aim 2) To define the comparative effectiveness and safety of initiating (2a) warfarin vs. DOACs; and (2b) specific DOACs (i.e. head-to-head comparisons of, apixaban vs. rivaroxaban vs. dabigatran vs. edoxaban); and (Aim 3) To identify key subgroups for whom OACs are particularly beneficial or hazardous – including patients with advanced or decompensated cirrhosis, high fall risk or poor predicted anticoagulation quality. To minimize confounding and optimize study validity, we will use innovative methods developed by our team, including: (i) high-dimensional propensity scores; (ii) our novel, validated algorithms for phenotyping cirrhosis severity, fall risk and anticoagulation quality; and (iii) linkage of a subset of our cohort with rich clinical information and laboratory data from electronic health records (EHR), for external adjustment and propensity score calibration. Completing these studies will provide the necessary evidence base for providers to optimize OAC selection and stroke prevention in vulnerable patients with cirrhosis and NVAF, yielding an immediate and direct public health benefit. This work will also produce a readily generalizable infrastructure for robustly detecting drug effects in patients with chronic liver disease.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Secondary lymphedema is a morbid condition affecting over 5 million patients in the United States. Patients with this condition develop lymphatic retention, which progresses to irreversible subcutaneous fibroadipose deposition in the affected extremity. As a result, patients experience chronic pain, decreased mobility and function, open wounds, and overall reduced quality-of-life. In Aim 1, I will examine how a stimulation of a signaling mediator which augments adipocyte differentiation may reduce overall fibroadipose deposition by preventing the proliferation of pathologic stem cell populations. In Aim 2, I will examine how inhibition of a pro-survival signaling mediator may impact adipocyte and pre-adipocyte survival. In the process, I seek to understand whether specific subsets of these cells are more likely to undergo apoptosis. Finally, in Aim 3, I seek to develop a local cell therapy which obviates the systemic adverse effects of therapies which modify cell differentiation or survival. In the process, I will have developed a therapy which is capable of secreting microRNA, paving the way for a new class of cell therapeutics. The career development award is indispensable for my maturation as a physician-scientist, to serve as a scientific and clinical leader performing research which is inspired by the challenges my patients face, rigorous in its evaluation of the underlying pathogenesis of this condition, and translational in its consideration of treatment strategies. I am supported by a team of mentors with expertise in stem cell and adipocyte biology, clinical lymphedema management, and in academic plastic surgery leadership. I am also supported by a team of additional scientific advisors with expertise in lymphedema biology, cell therapy, and translational medicine. The institution is committed to my success, with protected time for activities proposed in this award, laboratory space, salary support, and laboratory funding. During the 5-year career development award, I will build on my previous expertise with monitoring stem cell fate using lineage-tracing mouse models, and add new scientific expertise to my armamentarium with single-cell RNA sequencing and bioinformatics analysis. I will engage in workshops and seminars to build on my technical skillset, and develop essential laboratory leadership skills. Upon completion of my 4th year of the career development award, I will submit for my first R01 submission, with the goal of further advancing findings obtained during my career development award. Upon completion of the 5-year award period, I will expect to have established my scientific expertise in adipocyte biology, cell therapy, and lymphedema, and established my technical expertise in lineage-tracing and RNA sequencing, to contribute broadly to the scientific environment in my institution.

NIH Research Projects · FY 2026 · 2023-03

Project Summary Cancers take many years to develop, and death due to a cancer may occur many years after diagnosis. Therefore, it is important to use innovative methods of analysis to make optimal use of all exposure data both before and after diagnosis. We propose four types of innovations in the current application. Lethal cancer models: Of highest public health interest is what risk factors predispose a disease-free subject to die due to a specific cancer in the future. We have previously developed models for lethal cancer by integrating models for cancer incidence with models for prognosis after a cancer diagnosis. In this application, we propose to extend this approach in the case of colorectal cancer (CRC) by considering three stages in the carcinogenic process: (a) development of advanced polyp, (b) development of incident CRC after advanced polyp have been identified and removed, and (c) death due to CRC among patients with incident CRC. Latency models: Some prospective studies have risk factor data available at several points in time. One issue is how these data should be optimally used to predict cancer incidence. One approach is to use the most recent exposure; a 2nd approach is to use the total duration of exposure; a 3rd approach is to introduce a lag between exposure and outcome assessment. In this application, we propose a latency model to estimate the optimal weighting of previous exposures to predict cancer incidence; these models enhance understanding of biological mechanisms for specific risk factors. Cure Models: There have been many studies of risk factors predicting mortality among cancer patients. However, for some cancers, if patients do not die from their cancer over a given period of time (e.g., within 5 years for CRC), then they are unlikely to ever die due to their cancer, and will probably die due to another cause (i.e., they are cured). But what are the risk factors that predict cure? Although cure models have been used before, they mostly are based on post-diagnostic risk factors. To our knowledge, this is the 1st proposal to consider pre-diagnostic risk factors as predictors of cure. Assessing Effects of Screening on CRC risk models: Colonoscopy is the current standard for CRC screening. It is unique, in that if pre-cancerous lesions (i.e., adenomas) are found, then they are removed, and the natural history of CRC progression is interrupted. However, even if these lesions are removed, for some subjects, these lesions are more likely to develop again at a future time. Thus, it is challenging how to control for effects of screening in CRC risk models. In this application, we propose an innovative approach to control for screening by both assessing effects of a risk factor on adenoma incidence, and effects of adenoma incidence on CRC risk.

NIH Research Projects · FY 2025 · 2023-02

Project Summary - The role of liver progenitor cells in liver regeneration Acute and chronic liver disease causes liver failure and is a growing cause for morbidity and mortality. The COVID-19 pandemic has further increased the magnitude of this problem. The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. In our preliminary work, we describe a near-total hepatocyte ablation model in zebrafish where organ regeneration is derived from biliary epithelial cells. Our objective here is to characterize the functional implications and molecular mechanisms of EAE to affect organ development. Our central hypothesis is that severe hepatocyte injury will reveal the facultative stem cell potential of biliary epithelial cells. This process appears to be driven by EGFR, PI3K, and mTOR signaling. Two Specific Aims are proposed to define the generation and contribution of facultative hepatic stem cells. In Specific Aim 1 we will utilize single-cell transcriptomic and high-resolution imaging analyses after near-total hepatocyte ablation to investigate whether and when biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. In the process, we will generate an inventory of all liver cells in the zebrafish and determine evolutionary conservation of cell identity and function by comparison to murine and human liver datasets. Specific Aim2 will determine the degree of biliary epithelial cell proliferation hepatoblast transcription factors gene expression prior to hepatocyte differentiation and define the signaling pathways involved in the generation, function and proliferation of this facultative stem cell population. Identification of a signal like EGFR that can cause biliary epithelial cells to become hepatocytes has significant therapeutic potential for patients with liver failure.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract: A lack of diagnostics that rapidly and accurately identify bacterial pneumonia drives excessive empiric antibiotic prescribing in patients with acute respiratory infections – 30-60% of these antibiotics are unnecessary. Clinicians are under pressure to make rapid treatment decisions, usually without real-time diagnostic information that reliably differentiates patients with bacterial pneumonia from other conditions with similar clinical presentations. While time to effective treatment is a critical determinant of clinical outcome, many patients with pneumonia receive inadequate empiric antibiotics due to rising rates of antibiotic resistance in bacterial pneumonia pathogens. In contrast to bloodstream, gastrointestinal, or urinary tract infections, the lung is a particularly challenging space to access without invasive diagnostic procedures. We have established proof of concept in murine models that there are clear, bacterial species-specific breath volatile metabolite signatures in pneumonia, and that microbial breath volatile metabolites have markedly different responses to antibiotic exposure within a few hours in phenotypically susceptible vs. non-susceptible organisms. In close collaboration with a team of engineering, biostatistical, antimicrobial resistance, and regulatory experts, we will apply an advanced, portable, miniaturized gas chromatography-differential mobility spectrometry (GC-DMS) diagnostic platform to the rapid, noninvasive, point-of care diagnosis of bacterial pneumonia. We will derive breath volatile metabolite signatures that differentiate bacterial pneumonia from other clinical syndromes with a similar clinical presentation, identify the underlying bacterial species directly from metabolic fingerprints in the breath, and provide phenotypic information about antibiotic susceptibility, harnessing early differential metabolic responses to effective vs. ineffective antibiotic therapy. This assay will sharply reduce diagnostic delays in patients with pneumonia, both facilitating early administration of appropriate antibiotics and curtailing unnecessary antibiotic use.