Brigham And Women'S Hospital

NIH Research Projects · FY 2026 · 2025-03

Recent advances in stem cell research over the past decade have sparked considerable interest in their therapeutic potential for treating gastrointestinal and hepatic disorders. By reprogramming somatic cells to pluripotency and differentiating them or directly reprogramming cells between somatic states via transcription factor (TF) overexpression, we can produce clinically valuable cells from abundant sources like skin fibroblasts. Despite its potential, direct reprogramming often leads to low yield and incomplete specification of target cells, limiting its practical use for therapy or disease modeling. Further, while many protocols to derive hepatocyte-like cells in mouse and human exist, there is a current unmet need to derive intestinal-like cells via reprogramming. Building on our previous five years of R01-funded research, we aim to answer why reprogramming is inefficient and how we can guide engineered cells toward a more defined identity and functionality. The conversion of mouse embryonic fibroblasts to induced endoderm progenitors (iEPs) represents a prototypical reprogramming strategy, producing cells that can functionally engraft the liver and intestine. Our work to date has demonstrated heterogeneity in this reprogramming process, revealing defined conversion trajectories to distinct cell populations. In our proposed research, we aim to; 1) Characterize reprogramming origin gene regulatory state, charting exogenous TF engagement in successful fate conversion. By understanding a) where ectopic TFs bind upon reprogramming initiation and b) the genetic regulatory barriers to this binding, we will reveal fundamental mechanistic knowledge that can be used to enhance the fidelity and efficiency of reprogramming; 2) Characterize hepatic and intestinal potential of iEPs. Our current data suggest that iEPs are a heterogeneous population of cells harboring hepatic and intestinal potential. By employing multiomic single-cell lineage tracing to characterize the heterogeneity of iEPs, we will track their successful engraftment into the liver and intestine to define their cellular potential. Further, we will track iEP differentiation within these target organs to establish a comprehensive blueprint for in vitro cell maturation; 3) Assess and optimize human direct reprogramming to induced endoderm progenitors. While many TF cocktails directing cells to hepatic identity have been reported, there is currently an unmet need to derive reprogrammed intestinal identities. Our preliminary data suggest that akin to mouse iEPs, human hepatocyte-like cells harbor intestinal identity. We hypothesize that the pioneer TF-based cocktails used in human reprogramming install this broad potential. By applying our innovative genomic technologies, we aim to unlock unforeseen potential in these engineered cells, paving the way to produce functional human liver and intestine cells through reprogramming.

NIH Research Projects · FY 2026 · 2025-03

Summary Transcranial magnetic stimulation (TMS) is an FDA-approved treatment for several brain diseases, such as major depressive disorder, obsessive-compulsive disorder, migraine with aura, and smoking cessation. However, the response rate varies significantly across subjects related to several suboptimal treatment parameters such as stimulation intensity and brain target for individual patients. To overcome the limitations, we will develop novel software and computational techniques that integrate real-time navigated electric-field mapping and source- space electroencephalogram (EEG) analysis during TMS to significantly improve the accuracy of targeting and dosimetry for individualized subjects to enhance treatment efficacy. We propose a novel subject-specific target localization method that integrates diffusion MRI tractography and resting-state functional brain networks to select target regions in the dorsolateral prefrontal cortex (DLPFC) and the inferior parietal lobule (IPL) of the frontoparietal network. We will use the electric field and source space EEG mapping techniques to guide the stimulation of the target regions and examine related changes in cognitive control functions. We will complete the proposed work with three aims. In Aim 1, we will further develop the SlicerTMS software from our previous work to provide real-time E-field mapping and quantitative measures during TMS treatment. In Aim 2, we will incorporate real-time source-space TMS-EEG measures in SlicerTMS2.0 to provide real-time feedback for target engagement and brain activity. In Aim 3, we will validate SlicerTMS2.0 online measures by comparing them with standard offline analysis methods with TMS-EEG experiments using the proposed DLPFC and IPL targets. We will also examine TMS-related changes in the choice reaction time in modified multi-source interference tasks. The outcomes of this grant will provide new tools to improve TMS stimulation targeting and dosimetry, which can significantly enhance TMS treatment response for brain diseases.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Cardiovascular diseases constitute a tremendous health care burden, and despite increased attention, cardiovascular mortality continues to increase in the United States and worldwide. While immune activation and inflammation are critical to atherosclerotic cardiovascular disease pathogenesis, a significant gap remains in understanding how these pathways cause vascular dysfunction, a central upstream pathophenotype. There is increasing recognition that immune and inflammatory mediators may act by impairing endothelial cell metabolism, causing endothelial injury, and thereby triggering the development of vascular dysfunction. We have recently identified the immune mediator CD70 as a critical regulator of endothelial biology. In this K08 Mentored Clinical Scientist Development Award application, we seek to build on these findings and propose to comprehensively investigate how CD70 regulates key endothelial and metabolic pathways to serve as a potential novel therapeutic for atherosclerotic cardiovascular disease. In addition to this overall scientific goal, the K08 Award Application outlines a detailed career development plan that will enable the principal investigator (PI), Dr. Arvind K. Pandey, to establish himself as an independent physician-scientist in the field of vascular biology and immuno-metabolic regulation of endothelial and vascular function. We have identified that loss of CD70 significantly impairs bioactivity of the key endothelial messenger, nitric oxide (NO), while enhancing cellular and mitochondrial oxidative stress. Our new preliminary data explore a potential mechanism by which CD70 regulates endothelial nitric oxide synthase (eNOS), elucidate how CD70 impairs endothelial metabolism, and demonstrate that CD70 knockdown in mice leads to endothelium-dependent vascular dysfunction. We hypothesize that CD70 regulates vascular dysfunction and inflammation through control of bioactive NO generation and endothelial metabolism. The studies outlined in this proposal will elucidate: 1) CD70 regulation of eNOS through direct protein-protein interaction; 2) mechanisms underlying CD70-induced metabolic and mitochondrial network disruption; and 3) the role of CD70 in exacerbating vascular inflammation and dysfunction in a mouse model of atherosclerosis. Concurrent with these scientific aims, the PI has devised a robust training program to acquire the necessary scientific skillset, training in the responsible conduct of research, and laboratory management skills to transition into an independent investigator with an R01-funded research program by the end of the training period. The PI will receive dedicated mentoring under the direction of his Primary Mentor, Dr. Joseph Loscalzo and Co-Mentor, Dr. Thomas Michel, and the PI’s professional development will be supplemented by his scientific advisory group and focused didactics. The proposed research and training activities will take place at Brigham and Women’s Hospital and Harvard Medical School, which have an excellent environment to support the scientific and training aims. The PI has 75% protected research time and has already been allocated institutional resources to support his research program.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Dr. Xinyuan (Cindy) Zhang’s long-term goal is to become an independent and active researcher in the field of cancer molecular epidemiology that contributes to the development of novel strategies for cancer prevention and early diagnosis. Hepatocellular carcinoma (HCC) is highly lethal, without an effective early detection method. Chronic inflammation has been observed in HCC, but neither the genomics nor proteomics signatures of inflammation have been examined in the context of HCC etiology or lifestyle-based prevention. Leveraging the wealth of resources from eight population-based prospective cohorts, Dr. Zhang will integrate molecular data into epidemiology studies to address gaps in understanding HCC risk and improving risk assessment. In Aim 1, Dr. Zhang will use computational biology and system biology skills to examine pre-diagnostic plasma proteomics of incident HCC cases compared to matched non-HCC controls. She will use machine learning methods to develop and validate Inflammatory Proteomics Signatures for HCC early detection. In Aim 2, Dr. Zhang will analyze genomics and proteomics data by mapping inflammatory protein quantitative trait loci and performing Mendelian Randomization analysis for HCC risk. Findings on inflammatory proteomics and genomics will be further compared against current tests in a clinical cohort of liver cirrhosis patients who are currently undergoing HCC screening. In Aim 3, Dr. Zhang will develop a hypothesis-driven empirically derived Anti-Inflammatory Lifestyle Score by regressing health behaviors and factors against inflammatory multiomics markers. In preliminary studies, Dr. Zhang has shown that a dietary score weighted by traditional inflammation markers was associated with HCC risk and has identified a protein biomarker model for HCC prediction, suggesting that further improvement in predictive performance is feasible. Successful completion of the novel research aims will be supported by a well-tailored training plan with three specific objectives in (1) advanced multiomics analytics, (2) cancer biomarkers, and (3) molecular epidemiology study design and management. The outstanding mentoring team with complementary expertise, rigorous training activities, and rich resources will equip Dr. Zhang with the knowledge, skills, and data necessary for research success and transition to independence under this NCI Early K99/R00 award.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with varying contributions of emphysema and large and small airway disease. COPD patients also differ in the natural history of the disease, with some patients experiencing frequent episodes of acute exacerbations and/or rapid decline in lung function. There is an unmet need for biomarkers for COPD progression, exacerbations, and response to therapy, to fulfill the promise of precision medicine. There is a need to train physician-scientists in the full range of activities necessary for large genetic epidemiology studies: enrolling subjects, conducting detailed lung disease phenotyping, collecting biospecimens, and performing bioinformatics analysis. Dr. Craig Hersh, the Principal Investigator of this proposal, has experience directing the COPDGene clinical center at Brigham and Women’s Hospital. He has expertise in using RNA-sequencing to identify gene expression signatures associated with COPD phenotypes. This proposal will expand the PI’s skills in developing and implementing a novel study protocol to identify blood and bronchoalveolar lavage fluid biomarkers for phenotypes and acute exacerbations of COPD, in subjects undergoing bronchoscopic lung volume reduction (BLVR) and other bronchoscopy procedures. Furthermore, he has mentored multiple MD and PhD scientists in genetic epidemiology studies in COPD. Through this proposal, he will devote significant time to mentoring physician-scientists in all aspects of patient-oriented research in new and ongoing COPD studies, as well as augment his own mentoring and leadership skills. Specific aims: (1) COPD bronchoscopy biomarkers study. We will develop and implement a protocol for biospecimen collections before and after bronchoscopic lung volume reduction (BLVR). We will test the hypothesis that post-BLVR respiratory events can be used as a novel model for COPD exacerbations. In addition, we will enroll stable subjects with and without COPD undergoing other bronchoscopy procedures to study a wide range of disease severity phenotypes. Plasma proteomics will be used to identify blood biomarkers. (2) Biomarkers for progression in clinical subtypes COPD. We will test the hypothesis that COPD progression will vary depending on COPD subtypes and that large scale omics analyses will provide blood biomarkers for progression. In the COPDGene Study, we will identify clinically relevant COPD subtypes, test for disease progression using longitudinal data, and analyze RNA- sequencing and proteomics data. (3) Mentoring in COPD biomarkers research. Through this proposal, the PI will mentor physician-scientists in subject enrollment, phenotyping, sample collection, and omics data generation and bioinformatics analysis. The Channing Division of Network Medicine has an extensive history of genetics and epidemiology studies in respiratory disease, including a long-standing T32 program in systems genetics and data science in lung diseases. This proposal will complement the T32 by stressing patient-oriented research coupled with data science. The PI and his trainees will have access to educational and mentoring resources, including expertise in patient-oriented research, at BWH, Harvard Medical School and nationwide through ongoing collaborations.

NIH Research Projects · FY 2026 · 2025-02

Acute heart failure (AHF) is the second most common cause of hospitalization in the United States. Pulmonary congestion, resulting in dyspnea, is the primary reason why patients present to the hospital seeking care. Relief of congestion is a key goal of therapy. Incomplete decongestion increases the risk of short-term death or re- hospitalization three-fold. Despite this, nearly 50% of patients are reported to leave the hospital congested. There is a critical unmet need to accurately monitor congestion. While traditional measures of congestion – physical exam, body weight, urine output, natriuretic peptides – remain important, patients continue to be discharged with congestion. An accurate, reliable, efficient, and facile method to measure congestion is needed. Lung ultrasound (LUS) is a novel, low-cost, easy to use, bedside tool with superior accuracy for detecting congestion compared to conventional measures. Preliminary data from our clinical studies BLUSHED-AHF and CARVD-AHF suggest: 1) daily LUS detects changes in congestion severity more rapidly compared to conventional measures, and 2) guiding decongestive therapy based on LUS results is feasible. Our preliminary findings provide validation for the link between inadequate decongestion, as evaluated by LUS, and an increased incidence of clinically significant adverse events. Furthermore, our data highlights a notable challenge in the field of LUS-based congestion monitoring, which is the necessity for a human rater to ensure accurate and consistent quantitative scoring. Our long-term goal is to improve the measurement of decongestion for AHF patients. In this project we propose to automate LUS congestion scoring using innovations in AI/ML methods and a unique high-quality dataset of heart failure patients. We will use the results to investigate the additive benefit of AI-automated LUS congestion scoring to the current clinical practice of utilizing physical exam, history, blood tests, and chest radiography reports. Successful completion of this work would change clinical practice. The current limitations of congestion monitoring, including with LUS, are reliability and objectivity related to rater experience and information loss across transitions of care. If successful, this work would significantly impact AHF management, elevating the role of LUS. An open-source prototype of the AI software for congestion measurement, PulmoX, would be publicly released for use in future clinical trials for novel decongestion therapies.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) and emphysema are globally significant chronic lower respiratory diseases that represent a major cause of morbidity and mortality worldwide. COPD is diagnosed via spirometry, which detects airflow obstruction that is not completely reversible, while emphysema is defined on pathology as the permanent enlargement and destruction of alveolar walls and can also be measured on computed tomography (CT). Despite advancements, pharmacologic therapies for COPD lack efficacy in altering disease progression or improve mortality. Recent CT imaging studies have highlighted the significance of pulmonary vascular endothelial damage in the pathogenesis of these diseases. Evidence suggests that the pulmonary vasculature may be significantly compromised in patients with COPD and emphysema, indicating a fundamental role of pulmonary vascular injury in disease etiology and progression. However, despite advancement in macro-vascular imaging, understanding of the microvasculature’s role in COPD progression remains limited. While new imaging modalities have emerged for detecting microvasculature perfusion, their availability is often limited in large-scale epidemiological studies, hindering accurate investigations into disease etiology and progression. To address this gap, we developed an AI-based algorithm for robust assessment of vascular perfusion from single energy non-contrast CT scans, which enables the definition of novel image-based markers of pulmonary microvasculature alterations in large epidemiological studies. The proposed research, carried out via a secondary analysis of subjects in the COPDGene cohort, aims to develop and validate a quantitative marker of pulmonary microvascular injury and to explore the correlation between microvascular volume loss and the longitudinal progression of COPD and emphysema in smokers with and without COPD. In Aim 1, we will extend the validation of our AI-based method for generating perfusion maps from single energy non-contrast CT scans. Our preliminary analysis on a non-COPD specific dataset demonstrates the effectiveness and reliability of our approach. As part of Aim 1, we will further validate this technique through a comparative analysis between our synthesized perfusion maps and dual energy CT perfusion imaging. This analysis will be conducted using subjects diagnosed with COPD, both with and without PH, for which single energy non-contrast CT images, DECT scans, and perfusion maps are available. In Aim 2, we will estimate perfusion information from subjects in the COPDGene Phase 2 study to define a quantitative marker of microvascular volume. This marker will serve as a tool to investigate the relationship between pulmonary vascular damage and clinical outcomes, COPD, and emphysema development. Through these efforts, we aim to create an image-based quantifiable feature of pulmonary vascular injury, facilitating new research studies on the etiology and evolution of COPD in smokers.

NIH Research Projects · FY 2026 · 2025-02

7. PROJECT SUMMARY This proposal addresses an unmet need in public health by evaluating the role of Medicaid coverage for treatment of periodontal disease (TPD). Periodontal disease negatively impacts oral health and quality of life. Prevalent among all adults, periodontal disease is even more common in low-income populations served by Medicaid, causing tooth loss and dental pain and representing a significant public health challenge. TPD with scaling and root planing followed by maintenance therapy is the standard of care, but state Medicaid programs are not obligated to offer dental coverage to adults, leading to considerable inter-state variability in coverage for TPD. TPD may improve clinical outcomes and be associated with improving control of chronic diseases like diabetes, but observational data evaluating these effects is considerably confounded. Better evidence is needed on the relationship between providing coverage for TPD with health outcomes, especially for at-risk populations like those covered by Medicaid. State Medicaid programs have initiated coverage for TPD at various times, resulting in a natural experiment that allows us to evaluate the treatment effect of TPD coverage on both oral and comprehensive health. By leveraging a quasi-experimental design using the comprehensive source of all Medicaid claims data from 2016 through 2023, the Transformed Medicaid Statistical Information System (T-MSIS), we will evaluate the effect of implementing Medicaid coverage for TPD across states that implemented this benefit at discrete points in time, allowing us to isolate the treatment effect of TPD specifically while accounting for staggered policy adoption and state and time fixed effects. Our first aim is to evaluate the effect of TPD coverage on tooth loss, emergency department (ED) use for dental problems, and oral healthcare costs. We hypothesize that coverage for TPD will result in a decrease in tooth loss, ED dental use, and dental costs among all Medicaid beneficiaries in affected states. Our second aim will evaluate the impact of TPD coverage on the short-term and long-term complications of diabetes among beneficiaries with diabetes. We hypothesize a reduction in complications such as hyperglycemic crises, diabetic ulcers, retinopathy, and nephropathy. The proposed work builds on prior analyses of Medicaid dental benefits by focusing on a specific procedure with more established implications for comprehensive health, by our use of a novel difference-in- differences estimator that is robust to the realities of Medicaid dental policy adoption and by incorporating both oral health and comprehensive health outcomes. Our proposal is of high relevance to Medicaid policymakers as well as health systems and clinicians by guiding decisions on oral health coverage to improve health in at- risk populations. Our findings will provide important evidence on the contribution of TPD on the health of Medicaid beneficiaries and help develop further oral health coverage and interventions for the Medicaid population.

NIH Research Projects · FY 2026 · 2025-01

SUMMARY New therapeutic approaches are desperately needed for highly malignant brain tumors, glioblastomas (GBMs), where standard therapy has shown limited to no efficacy. In our previous studies, we have developed mouse tumor models of GBM resection and extensively demonstrated that engineered “off the shelf” mesenchymal stem cells (MSC) encapsulated in biocompatible synthetic extracellular matrix (sECM) have therapeutic benefits post-GBM surgery. Engineered T cell based therapies have demonstrated impressive clinical efficacy in hematological cancers, however their success has been limited in solid tumors like GBM, particularly due to evasive and inhibitive tumor micro-environment (TME) and chronic antigen triggering in the presence of suppressive signals in the TME. In order to address the issues related to excessive engineering and exhaustion of T cells, we took advantage of the homing and allorecognition avoidance properties of MSC and engineered them to release bi-specific T cell engager (BITEs) consisting of nanobodies (vHH domain of a heavy chain antibody) simultaneously targeting over-expressed EGFR and specifically expressed EGFRvIII variant in GBM and a CD3 specific scFv (MSC-ENb-BiTE). Our exciting preliminary data indicate that MSC-ENb-BiTE redirect wild type blood derived untransduced T cells to tumors and induce tumor regression in GBM mouse models. These results although promising, have raised fundamental questions for our engineered MSC and naïve T cell therapeutic strategy to target multiple antigens and simultaneously enhance the immunomodulatory function of T cells in mouse tumor models that mimic clinical settings of resected GBM tumors and present nodular and invasive phenotypes? In this proposal, we will develop a broad platform of MSC releasing BiTEs targeting EGFR/EGFRvIII and IL13Rα2 and twin (Tw)-BiTE that simultaneously targets EGFR/EGFRvIII and IL13Rα2 and extensively test their therapeutic efficacy post transplantation of sECM encapsulated MSC-BiTE/Tw-BiTE and intraventricular delivery of T cells in mouse GBM models of resection. Based on the hypothesis that interleukin (IL)-12 will improve the potency of T cell therapy and blocking PD-1 on recruited T cells will result in effective eradication of residual GBM cells, we will co-engineer MSC- Tw-BiTE to express IL-12 and immune-check point inhibitor and assess their efficacy with T cells in GBM models of resection derived from primary GBM lines representing distinct tumor nodular and invasive phenotypes. To ease clinical translation, we will assess the mechanism underlying efficacy of encapsulated engineered MSC and T cells in humanized mouse GBM models. The integration of the kill switch in engineered MSC will ensure safety of our approach and the incorporation of genetically engineered imaging markers into both MSC and GBMs will allow us to follow fate and efficacy in vivo and thus to fine tune the proposed approaches. We anticipate that our findings will have a major contribution towards developing novel cellular therapies for GBM and are likely to define a new treatment paradigm for patients with other cancers.

NIH Research Projects · FY 2026 · 2025-01

The proposed investigations focus on identification of biomarkers associated with nasal polyp recurrence in patients with aspirin-exacerbated respiratory disease (AERD) who fail endoscopic sinus surgery and aspirin therapy after desensitization. Nasal polyps are inflammatory outgrowths of sinonasal mucosa that lead to significant medical resource consumption, impairment in quality of life, and are particularly severe and rapidly recur after endoscopic sinus surgery in AERD, even with adjuvant treatment with aspirin therapy after desensitization which can prevent nasal polyp recurrence in some patients. This proposal details proteomic analysis of both Type (T) 2 and non-T2 biomarkers in the sinonasal tissue and non-invasively sampled nasal fluid of patients with AERD. The investigators have observed that non-T2 proteins including oncostatin M, interleukin 10, and macrophage colony stimulating factor are elevated in the nasal mucus of patients with AERD who have rapid post- endoscopic sinus surgery nasal polyp regrowth despite aspirin therapy after desensitization. Additionally, the investigators have identified nasal tissue macrophages as a likely source of the proteins associated with nasal polyp recurrence. Employing proteomic, lipidomic and cellular techniques, the investigators will test the hypotheses that complex T2/non-T2 inflammatory interactions within the respiratory tract drive post-surgical NP recurrence and that a combination of T2/non-T2 markers can be used as a predictive model for NP recurrence, and also that an activated phenotype of macrophages drives nasal polyp recurrence in AERD. The aims are to: 1) Establish a biomarker-based predictive model of NP recurrence in patients with AERD based on polyp tissue samples, utilizing levels of T2 and non-T2 markers of inflammation, and 2) characterize the macrophage subsets that produce tissue proteins associated with nasal polyp recurrence, specifically oncostatin M and interleukin 10, and establish relationship between macrophage phenotype and nasal polyp severity in patients with AERD. These studies will advance our understanding of the pathogenesis of AERD leading to the identification of novel therapeutic targets for this disease.

NIH Research Projects · FY 2026 · 2025-01

BRCA1 mutation carriers have a very high life-time risk of developing basal-like breast cancer (BLBC), which is a breast cancer subtype that has unfavorable outcomes and limited treatment options. Thus, there is an urgent need to develop novel strategies to prevent or intercept BRCA1 breast cancer initiation, which would benefit from a better understanding of its early stages of development. BRCA1 BLBC may originate from luminal mammary epithelial cells (MECs), particularly, luminal progenitors (LPs). To study BRCA1 mammary tumor initiation from LPs, we developed a novel mouse model that faithfully recapitulates initiation and progression of BLBC from genetically marked BRCA1-deficient luminal MECs. Characterization of this model revealed growing DNA damage and the related luminal to basal and mesenchymal cell fate change during BRCA1 mammary tumorigenesis. Our studies so far from this mouse model as well as human breast cell lines supported that the aberrant basal/mesenchymal gene expression in BRCA1-deficient MECs may be caused by insufficient repair of interstrand crosslink (ICL) DNA damages. Furthermore, single cell analysis of chromatin accessibility (scATACseq) of premalignant MECs revealed the potential acquisition of a fetal mammary stem cell (fMaSC)-like epigenetic state in premalignant LPs with BRCA1-loss, which may be responsible for their increased expansion and luminal-to-basal/mesenchymal cell fate change. Based on these preliminary findings, we hypothesize that accumulation of DNA damages (particularly ICLs) in BRCA1- deficient luminal MECs enables cell fate plasticity by inducing a fMaSC-like developmental program in them; this stemness program is necessary for breast cancer development from luminal cells and can thus become a target for interception of BRCA1 breast cancer initiation. To test this hypothesis, we propose three Specific Aims. In Aim 1, we will study whether BRCA1-deficient luminal MECs acquire a fMaSC-like program via a key fMaSC-related transcription factor, SOX10, by transplantation and organoid culture assays. In Aim 2, we will determine whether inadequate repair of ICL DNA damages induces stemness in BRCA1-deficient luminal MECs in a SOX10-dependent manner and whether developmental pathways such as Wnt and FGF signaling (both control SOX10 expression/activity during neural crest development) play any key role in this process. In Aim 3, we will focus on Wnt signaling, which is required in BRCA1 tumor-initiating cells (TICs) and may constitute a key component of the potential DNA damage-related stemness program; we will determine if Wnt pathway activation is necessary for BRCA1 mammary tumor initiation genetically and if we can intercept formation of BRCA1 TICs and/or progression of BRCA1 precancer to frank malignancy by using a novel narrow-spectrum Wnt inhibitor that blocks binding of the FZD1/2/7 subfamily of Frizzled (FZD) receptors to Wnt ligands. If successful, we expect that this project may lead to novel targets and agents to prevent or intercept breast cancer initiation from BRCA1-deficient luminal MECs, particularly in high-risk individuals.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Therapy-related myeloid neoplasms (t-MN) arise following the administration of chemotherapy or radiation and are a devastating complication of treatment given to cure cancers and treat other inflammatory conditions. There remains a gap in our understanding of how t-MNs arise and, thus, how we can better identify patients at the highest risk of developing them and prevent their development. Many t-MNs evolve from pre-existing clonal hematopoiesis (CH), a pre-malignant state, that develops or expands in the setting of cytotoxic therapy exposure. The long-term goal is to understand better the processes that drive clonal selection in the hematopoietic system, thus the development of CH and evolution to t-MN. The overall objective in this application is to understand how mutations in SRCAP, a gene recurrently mutated in CH among therapy-exposed patients (t-CH), promotes hematopoietic cell expansion and pre-malignancy. SRCAP encodes for a conserved ATPase that deposits the histone variant H2AZ on chromatin and plays essential roles in the epigenetic regulation of transcription and DNA repair. The central hypothesis is that loss of SRCAP dysregulates the DNA damage response (DDR) by altering deposition of H2AZ at sites of DNA double-strand breaks and at the promoters of genes involved in the DDR and thus confers resistance to cytotoxic agents leading to the clonal outgrowth of mutant hematopoietic stem and progenitor cells. Guided by robust preliminary data and the development of a novel conditional knockout mouse model, this hypothesis will be tested by pursuing three specific aims: 1) Study the role of SRCAP in hematopoiesis during normal and stressed states using a novel conditional mouse model; 2) Determine how SRCAP regulates the response to DNA damage; 3) Determine how Srcap mutations influence the evolution and clonal expansion of t-CH. In the first aim, a novel conditional Srcap knockout mouse has been generated and will be used to study the role of SRCAP during normal hematopoiesis and during cytotoxic therapy-induced stress. This mouse is currently in the lab and available for use. In the second aim, the role of SRCAP in regulating the response to cytotoxic therapies and the DNA damage response pathway in both human and mouse cell lines will be evaluated. Finally, in aim 3, the evolution of t-CH will be assessed by generating mice with mutations in Srcap and other genes recurrently mutated in CH and myelodysplasia to evaluate effects on hematopoiesis. The approach is innovative because it utilizes a novel conditional mouse model and provides the opportunity to study both the regulation of the DDR and epigenetic regulation of hematopoietic stem and progenitor cells, two processes known to be essential mediators of disease in CH and myeloid malignancies. The proposed research is significant because it will expand our understanding of how hematopoietic cells evolve in the setting of cytotoxic therapy and the role of SRCAP in normal and stressed hematopoiesis. Ultimately, this knowledge may provide new opportunities to develop strategies for the early detection and prevention of t-MNs.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Analyses of rheumatoid arthritis (RA) synovium have shown that the clinical heterogeneity of the disease is in part explained by heterogeneity in which cell types predominate in the synovium. However, we lack an understanding of how these key cell types work together in space, and in particular whether they form “functional units” of co-localizing cells that interact to create specific immune milieus. Identifying whether these functional units exist, how they differ across disease subtypes, and how they relate to the immune aggregates seen in other diseases could improve our mechanistic understanding of synovial inflammation, enable better disease subtypes, and drive new therapeutic hypotheses. Emerging high-dimensional spatial datasets hold the key to addressing this challenge, but analyzing them properly poses significant difficulties. My prior work and preliminary data show that rigorous spatial analysis of inflamed synovium is imminently possible. Specifically, a statistical tool I developed for multi-sample single-cell datasets turns out to be extendable to the spatial realm, where it appears powerful and is able to detect spatial correlates of known RA subtypes even on pilot data. Additionally, I have found that artificial intelligence (AI) can be used to accurately sort small patches of tissue into groups with similar biological content, enabling comprehensive cataloging of the types of cellular aggregates in inflamed synovium and comparison to other diseases. Here, I propose to systematically characterize spatial synovial heterogeneity in RA by applying cutting-edge computational methods to spatial datasets from RA and other autoimmune diseases. In Aim 1, I will use advanced statistical techniques to identify the spatial underpinnings of known RA subtypes defined from single- cell data, and then to define new, spatially informed RA subtypes. In Aim 2, I will use AI to build a map of the different types of immune- and immune-tissue aggregates in inflamed synovium, and then to identify which are also present in other autoimmune diseases. These aims will identify the spatial building blocks of synovial inflammation and relate them to heterogeneity across the spectrum of disease in RA. This proposal will build important new expertise for me in immunology and spatial methods, and it will enhance my existing expertise in clinical rheumatology and scientific leadership. I will pursue it in an excellent training environment with mentors and collaborators who will provide valuable access to key datasets and methodologic expertise. This training will leave me poised to become an R01-funded investigator who uses AI and advanced statistics to improve our understanding of rheumatoid arthritis.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Cancer is one of the leading causes of death in the USA. The study examines the role of Mixed Lineage Kinase 2 (MLK2) in tumor angiogenesis, a process vital for cancer growth. Hypoxic condition in solid tumor activates stress pathway of MLK2. MLK2, abundantly present in the endothelium, is shown to be essential for endothelial proliferation, migration, and angiogenesis. Lack of MLK2 impairs tumor growth in mouse models and increases miR-146a levels, which suppresses angiogenic factors like VEGF, adversely affecting angiogenesis and endothelial cell proliferation. Given that miR-146a overexpression in endothelial cells leads to similar deficiencies, the study suggests that MLK2's regulatory effect on miR-146a is crucial for endothelial functions and tumor angiogenesis.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis affecting 1% of the population and confers 1.5-2-fold excess risk of atherosclerotic cardiovascular disease (ASCVD) compared to the general population. Identifying the true at-risk population for ASCVD in RA for primary prevention remains a challenge despite efforts to tailor existing population based CV risk estimators. While a subset of RA patients at high ASCVD risk can be identified based on traditional CV risk factors, e.g., hypertension, hyperlipidemia, from clinical studies, we have observed evidence of substantial ASCVD in patients categorized with lower risk. Prior studies have observed a higher prevalence of high sensitivity cardiac troponin (hs-cTn) among RA patients compared to the general population. A marker of myocardial injury clinically used in the diagnosis of myocardial infarction (MI), hs-cTn is a promising biomarker for CV risk stratification in RA. Aim 1 will recruit RA patients, age>40 with ≥1 CV risk factor for hs-cTn testing and concurrently screen for coronary artery calcium (CAC). We hypothesize that including a step measuring hs-cTn in a subgroup of RA patients could improve identification of patients who would benefit from primary prevention with statin therapy, defined as having detectable CAC, compared to identifying patients based on ASCVD risk estimators alone. In Aim 2, the study will revisit the established association between RA and increased risk of CVD to understand potential biases in artificial intelligence (AI) algorithms developed using electronic health record (EHR) data to identify patient populations. Over the past decade, EHR data have become an alternate source of clinical data generally with a more diverse population than cohort studies assembled through recruitment, enabling studies of associations across populations. However, similar to other types of observational data, great care is needed to understand and correct potential biases. Thus, in Aim 2, we seek to rigorously evaluate for bias in existing algorithms for RA and MI by developing algorithms specifically for the self-reported Black population. We will then compare the performance of the algorithms trained with the Black population with the general EHR population for accurately identifying RA and MI in the Black population. Notably, these algorithms have also been applied to support recruiting efforts for RA patient-oriented research (POR) studies. We will use recently published guiding principles from the Agency for Healthcare Research and Quality, and the NIH. This proposal will support the candidate, a mid-career physician scientist, in creating unique training opportunities at the intersection of rheumatology and cardiology, and clinical research with bioinformatics. The candidate is located at a vibrant academic hospital and medical school campus with numerous training opportunities. Together with the studies outlined above, the proposal will serve as a foundation to mentor the next generation of clinical investigators studying rheumatology and musculoskeletal conditions, and concurrently provide training in state-of-the-art bioinformatics methods highly relevant to POR and clinical epidemiologic studies.

NIH Research Projects · FY 2026 · 2024-12

Globally, populations are experiencing increases in diseases attributable to overnutrition, but child undernutrition also persists at high levels. This “double burden of malnutrition” commonly appears as maternal overweight/obesity and child stunting in the same household. Poor nutrition during the critical life stages of the pregnancy, the postpartum period, and early childhood increases life-long risk for nutrition-related non-communicable diseases such as diabetes, hypertension, and dyslipidemia for both mother and child. Evidence-based interventions exist that promote optimal weight gain during pregnancy and postpartum weight loss or prevent undernutrition among children, but little is known about implementing them as integrated, scalable, intergenerational, and affordable solutions. The overall goal of this project is to assess the effectiveness, implementation, and cost-effectiveness of an integrated intervention to reduce the double burden of malnutrition among pregnant/postpartum women and their children. We will conduct a type 1 hybrid effectiveness-implementation trial in rural Guatemalan Indigenous communities that have among the world’s highest prevalence of the double burden of malnutrition. Our project will have three parts. In Part 1, we will conduct an individually randomized hybrid type 1 effectiveness-implementation trial with 766 pregnant mothers and their children, including both food supplementation and counselling to optimize mothers’ gestational weight gain and limit postpartum weight retention. Our primary evaluation will focus on maternal weight and child length at 12 months after birth. In Part 2, we will assess barriers and facilitators to implementation of the integrated DBM intervention and develop strategies to promote widespread implementation. In Part 3, we will conduct an economic evaluation on the integrated nutrition intervention. To our knowledge, this aim will generate the first evidence of costs and cost-effectiveness of interventions to address DBM at the household level, providing crucial information to policymakers and stakeholders for future implementation and budgeting. Overall, this project will generate globally relevant implementation evidence on interventions for the double burden of malnutrition. Results will have implications for nutrition and NCD policy not only in Guatemala but also globally. A major feature of the project is a focus on pragmatism and enrolling more vulnerable families who stand most to benefit from the intervention but who are commonly excluded from clinical trials.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a common and often devastating condition following allogeneic hematopoietic stem cell transplantation, causing injury to small vessels, particularly in the kidney. HSCT-TMA occurs in 13-40% of patients post-HSCT, and is associated with a considerably higher risk of kidney replacement therapy (KRT) and death. There is a dire need to identify early markers of HSCT-TMA, as well as treatments to prevent morbidity and mortality. In Aim 1, we will examine whether markers of endothelial injury and complement overactivation are early predictors of HSCT-TMA. We will leverage Dana-Farber Cancer Institute’s Pasquarello Sample Bank, which contains plasma and serum samples from >3000 adult allogeneic HSCT patients. In a nested case-control study, we will obtain serum from 50 adults with HSCT-TMA and 50 without HSCT-TMA. Samples will be obtained prior to HSCT and at day 7 following HSCT. In Aim 1A, we will examine whether baseline-adjusted markers of endothelial injury (von Willebrand factor, soluble fms-like tyrosine kinase 1, and thrombomodulin) are elevated at day 7 in patients with vs. without HSCT-TMA. In Aim 2A, we will test for complement-mediated cell death in patients with vs. without HSCT-TMA at the same time points using the modified Ham test (primary exposure), a validated, cell-based assay, in collaboration with hematologists at Johns Hopkins with expertise performing this test. We will also measure other markers of complement activity (annexin 2, factor D, properdin, complement factor H) at each time point as secondary exposures. In Aim 2, we will examine whether treatment with eculizumab, a terminal complement inhibitor, is associated with improved renal and overall outcomes in patients with HSCT-TMA. Using data from >12,000 patients treated with HSCT at 4 major cancer centers, we will test whether early treatment of HSCT-TMA with eculizumab (i.e., within the first month of diagnosis) is associated with a lower risk of KRT or death compared to later or no treatment with eculizumab. We will apply the principles of target trial emulation to address common biases in observational studies. This proposal builds upon the PI’s expertise in onconephrology and expands on newly-obtained skills in biomarker and causal inference analyses. It also proposes a new direction focused on HSCT recipients, who are at high risk for kidney-related complications. The results of the proposed projects will have important implications for HSCT-TMA, as they will lay the foundation for larger prospective studies designed to develop and validate a larger panel of predictive markers, and for randomized clinical trials testing the efficacy of therapies for HSCT-TMA.

NIH Research Projects · FY 2026 · 2024-12

The ability to predict the optimal therapy for an individual patient is a major unmet need in the treatment of cancer and other diseases. The majority of therapies in clinical cancer treatment, particularly cytotoxics and immunotherapies as well as combinations of multiple drugs, have no reliable predictor of response. This uninformed therapy selection is highly inefficient and likely leads to reduced therapeutic success rates, increased side effects and excessive economic expenditures. We have developed a “lab-in-a-patient” implantable microdevices (IMD) which release spatially discrete microdoses of up to 20 different drugs into locally confined regions of the patient’s tumor, and measures the response to each localized treatment using a range of histological, immunological, transcriptomic and other tumor-drug response markers. Each drug-tumor readout measures drug efficacy in a concentration- dependent manner, and identifies predictive biomarkers of response and resistance directly within each treatment zone. Our group has developed the IMD technology from ideation through prototyping, animal testing and into early clinical testing, where the IMD has been tested for safety and feasibility in eight cancer types and across multiple institutions. We have shown in two landmark publications that IMD readouts may be capable of predicting responses to chemotherapy in glioblastoma patients, and that IMD readouts are capable of predicting immunotherapy responses in breast cancer models and can be used to efficiently screen for novel and highly effective therapies. This project proposes an academic-industrial collaboration which builds on the technical and early clinical advances made to date, in order to transition the IMD technology from a demonstration of possibility to a status useful for therapy selection and patient stratification in the clinical oncology and drug development setting. We will conduct a clinical study in head and neck squamous cell carcinoma (HNSCC) patients that serves to validate the performance of the IMD in a statistically significant cohort to effectively predict patients’ clinical response to first and second line immunotherapy and chemotherapy. This data will be pivotal towards regulatory approvals and broader clinical uptake of the technology which will be led by our commercial partner Kibur Medical. Secondly, we will use several reservoirs of the IMD to test key in situ pharmacodynamic properties of a novel antibody cytokine conjugate (provided by our industry collaborator Scare, Inc.) directly in patients with HNSCC, in order to dramatically expedite the development of this potentially game-changing treatment class. This aim validates a key aspect of successful IMD commercialization, namely the ability to serve as a platform for early in vivo testing of novel drug candidates, and will serve as a blueprint for uptake by other drug developers. Thirdly, we will enable clinical use of the IMD in harder- to-reach lesions in order to make the platform suitable for end users across a broad range of cancer types. Taken together, the proposed project spans technical, translational and regulatory development that support broad clinical deployment and commercialization of the IMD technology.

NIH Research Projects · FY 2026 · 2024-12

Abstract Intra-arterial blood pressure (ABP) monitoring is essential for the diagnosis and management of hypertension, hypotension, and altered hemodynamics but is less commonly used in neonates due to its invasiveness and associated risks. While commonly used in the neonatal intensive care unit (NICU), intermittent oscillometer BP monitoring lacks precision and reliability, especially in hemodynamically unstable infants. Cuff-based continuous non-invasive arterial blood pressure (CNAP) devices used in adults are not precise at low blood pressure and are not recommended for use in young infants. On the other hand, cuffless devices employing optical sensors (photoplethysmography, PPG) are increasingly being explored as a potentially promising technology but with limited applications in newborns. This underscores the urgent need for safe and accurate CNAP monitors tailored for the neonatal population. We have recently built a low-cost, wearable wireless LED-based Near Infra-Red Spectroscopy (NIRS) device, called FlexNIRS, able to acquire pulsatile signals at a large source-detector separation (NIRS-PPG) with a high signal-to-noise-ratio (SNR) at a 266 Hz sampling rate. Using this device in adults, we demonstrated that the time derivative of the optical pulse waveforms, d/dt(NIRS-PPG), is related to pulsatile blood flow, and specific morphological features of the d/dt(NIRS-PPG) signal collected on the forehead showed a strong correlation with changes in blood pressure. Preliminary data collected in newborns show that the NIRS-PPG signals and their time derivatives have similar morphological features to the ones measured in adults. Using the head as a measuring site has the advantage of avoiding common issues like motion artifacts and peripheral influences in limb-based measurements. This project aims to develop a neonatal wearable optical device (CNAP-FlexNIRS) able to collect high temporal resolution NIRS-PPG pulsatile waveforms. We will test the device in 20 NICU inpatients of different gestational ages and medical conditions, undergoing intra-arterial blood pressure monitoring for clinical care. Finally, we will optimize the NIRS-PPG waveform analysis by training and testing deep-learning models for blood pressure estimation. The ultimate goal is to develop a reliable, low-cost continuous non-invasive arterial blood pressure monitor for both hospital and at-home use in at-risk neonates. This device has the potential to revolutionize neonatal care by eliminating high-risk invasive procedures and providing real-time data for prompt intervention. This technology will empower clinicians with safe and reliable vital information to personalize management for infants at risk of blood pressure fluctuations, leading to improved outcomes.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Given the high cost of MRI, there is a need to maximize the value of these exams in order to make them as worthwhile to society as possible. Value can be increased in a number of ways, such as improving accessibility or increasing the impact on patient management. The present project takes aim at one of the most common types of MRI exams, brain exams. The overall goal is to develop a time-abbreviated exam whereby greater amounts of information are obtained in a smaller amount of time. While faster exams can help increase acces- sibility on a given fleet of scanners, an increased information content can potentially have a positive impact on patient management. Brain exams represent up to 40% of all MRI exams, and typical time slots are 20- to 30-min long. Most brain MRI exams involve a gadolinium (Gd) contrast injection, and much of the time is spent acquiring data with several different MR image contrasts before and/or after the injection. The present project is ambitious in scope; it aims to reduce exam duration by roughly three-fold, while capturing quantitative and qualitative MRI contrasts, as well as the Gd-based enhancement. The duration of the proposed exam is primarily determined by the dynamics of the contrast agent, rather than by the demands of MRI. It takes roughly 5 to 10 minutes for the Gd agent to work its way through normal and abnormal anatomy and, therefore, our proposed exam dura- tion is 8 min. As for contrast types, current clinical exams typically capture only qualitative (i.e., no quantitative) contrasts, and only pre- and post-enhancement phases (i.e., the Gd-based enhancement is not resolved in time). Quantitative contrasts and time-resolved enhancement curves, captured in our proposed approach, will increase the diagnostic information content of individual exams. In contrast with abbreviated protocols that re- duce scan time by cutting sequences and/or increasing slice thickness, the proposed exam adds valuable in- formation over the full-length exam rather than reducing it. We developed a new 3D multi-pathway multi-echo (MPME) MRI sequence and associated machine- learning contrast translation to convert information-rich MPME signals into a variety of contrasts. Signals will be acquired in a continuous manner over the 8-minute exam, generating a series of 3D whole-head images. Re- constructed MRI contrasts include: T1-weighted, T2-weighted, proton density weighted, susceptibility- weighted, T1 maps, T2 maps, T2 FLAIR and MPRAGE images. A total of 200 patients will receive our time- abbreviated multi-contrast exam, both for neural network training/validation and for testing. Qualitative and quantitative quality metrics, as well as diagnostic outcome, will be used for validation. An additional twenty-five healthy volunteers will also be recruited, for a repeatability study. In summary, a fast, comprehensive brain MRI technique is being developed based on our MPME sequence and machine-learning contrast translation. This project fits into a larger body of work aimed at increasing the overall value of MRI as an imaging modality.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Neuroimaging research has revolutionized our understanding of the biological factors that are contributing to psychiatric illness, particularly schizophrenia (SZ). One of the most intriguing recent imaging findings in SZ is an increased extracellular water volume (Free Water - FW), particularly in early phases of this disease. The extracellular nature of FW increase suggests that it could be associated with extracellular matrix and/or blood brain barrier (BBB) permeability. FW relationship with peripheral inflammation points to immunological brain response. The biological nature of the FW increase in SZ, however, is still not clear. In this application, we propose to investigate the neurobiological correlates of this phenomenon. Specifically, we will utilize a novel, thoroughly validated animal model (Gclm knockout) in which oxidative stress and neuroinflammation are mediated by a feedforward loop induced by matrix metalloproteinase 9 (MMP-9), and test whether the phenotype associated with this model correlates with FW increase. We will characterize this relationship in two ways - first, we will use large, already collected, multi-site and multi-modal patient data to test for the relationship between neuroimaging, blood biomarkers, and cognition. Then, we will test this relationship in a transgenic animal model using Gclm knockout mice and oxidative stress and MMP-9 modifiers. We expect that upon successful completion of this project, we will have developed a clinically-feasible analytic paradigm that will propose and validate novel noninvasive biomarkers to mechanistically link oxidative stress and neuroinflammation to cognitive deficits observed in SZ. If successful, our proposal would potentially add a new biological target for the treatment of cognitive deficits prevalent in SZ and provide a noninvasive tool to monitor such treatment.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Responsive neurostimulation (RNS) is used as a treatment for epilepsy that does not respond to medication. However, its effectiveness varies significantly from one patient to another. While it can render some patients almost completely seizure-free, others see no improvement. Additionally, some patients may take years to achieve a reasonable benefit. This project aims to identify factors that determine a patient’s response to RNS, focusing on three specific objectives. Aim 1: Connectivity This aim will utilize patient-specific white-matter connectivity, structural imaging, and stimulation field modeling to identify networks crucial for positive RNS outcomes. Aim 2: Stimulation Timing Given that neuroplasticity likely underpins the gradually improving efficacy of RNS but is hindered during periods of frequent epileptiform activity, this aim will investigate whether periods free from prolonged epileptiform episodes (states with a low risk of seizures) correlate with better long-term RNS outcomes. It will also assess whether delivering stimulation during these low-risk states enhances RNS effectiveness. Aim 3: Background Rhythms This aim will explore circadian fluctuations in background neural activity as a potential predictor of patient response to RNS. Successfully achieving these aims will not only enhance our understanding of neuromodulation in epilepsy but also inspire new trials of innovative closed-loop stimulation algorithms, network-based targeting methodologies, and prognostic tools. In the future, these advancements set a foundation for improving neuromodulation outcomes, accelerating how quickly worthwhile benefits are achieved, and sparing patients unnecessary and ineffective surgeries.

NIH Research Projects · FY 2026 · 2024-12

Gene therapy has had an exciting last decade with many novel FDA approved therapies reaching the clinic. These treatments have not only been fruitful in cancer treatment, but also for genetic diseases and, more recently, in COVID-19 vaccines. Unlike macromolecules or small molecules, nucleic acids (DNA or RNA) require an efficient engineered delivery vehicle for effective treatment owing to either their high negative charge or high degradation rate which hinder cellular entry and systemic circulation, respectively. Although challenging to deliver, nucleic acids have a highly modular payload given that, with similar biophysical properties, they can transcribe or translate into a wide range of products, making the way for a truly modular platform for therapeutic delivery. Compared to systemic macromolecule administration, the delivered nucleic acid cargo can promote local and long-lasting production of a target therapeutic such as a cytokine for immunotherapy. Further, many promising gene modulation approaches exist beyond the delivery of a gene for transcription or translation such as RNA interference, gene silencing, antisense therapy, and gene editing. Consistent with the goals of nanotechnology for cancer treatment provided by the NCI, this project will focus on designing and characterizing the stability of lipid nanoparticles (LNPs) to induce an anti-tumor immune response. The target immune response will be mediated by B cell responses via CMTR2 depletion, an exciting new pathway to induce anti-tumor immune responses. Combination strategies using CMTR2 depletion with other immunomodulatory treatments will also be explored to further enhance the B- cell responses.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The overarching goal of this project is to understand the mechanisms underlying brain-immune interactions at the blood-brain barrier and thereby generate novel targets for immunotherapy in neuroinflammatory conditions. To achieve this goal, I will use an innovative approach that combines genetic manipulation of the brain vascular endothelium in an animal model of viral encephalitis, creating an atlas of immune signaling at the blood-brain barrier, and validation in human tissue. This project will address how inflammatory signals coming from the brain parenchyma are translated across the blood-brain barrier endothelium, and where along the brain vasculature these important immune interactions are occurring. A fundamental understanding of the mechanisms underlying immune cell recruitment to the brain will open the door to novel therapeutics that specifically target immune signaling pathways in the brain. In completing this project, I will gain the critical training and skills necessary to fill the gaps in my current skill set as I transition to an independent investigator. The training goals in this proposal have been carefully crafted to form the foundation for a successful career in basic and translational scientific investigation in neurobiology, immunology, and virology. This plan includes developing expertise in immunophenotyping, single-nucleus and single-cell sequencing, animal models of disease, mouse genetics, and human tissue assays. My training plan also includes specific resources, mentorship, and courses to support my career development as a physician- scientist. To achieve these goals, I have assembled an outstanding mentorship team with scientific expertise in complementary aspects of this project and exemplary track records for training independent investigators and physician-scientists. In addition to my primary mentor Dr. Chenghua Gu, Dr. von Andrian will provide mentorship in vascular biology and immunology. Dr. Quintana will complement these areas of expertise with mentorship in innate immunology, neurobiology, RNA sequencing, and animal models of neuroinflammation. Dr. Knipe will provide expertise in innate immunology and virology, and Dr. Chitnis will continue her outstanding mentorship in human tissue studies and career development as a successful physician-scientist. The institutional resources available through Harvard Medical School and Brigham and Women’s Hospital are world-class and will support my career in an environment that fosters high-impact contributions and interdisciplinary collaborations. Through this comprehensive training plan and carefully selected mentorship team, I will be ideally positioned to be an independent investigator with a unique expertise in the brain-immune interface.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Hepatitis C virus (HCV) infection poses a formidable global health challenge, impacting an estimated 58 million individuals worldwide, with 1.5 million new infections emerging annually. If left untreated, HCV can progress to severe conditions such as cirrhosis and hepatocellular carcinoma. Despite recent strides in cost-effective HCV treatments, swift and early detection of active cases remains a key hurdle, especially in resource-limited settings. Alarmingly, only 21% of HCV-infected individuals receive a diagnosis globally, underscoring the urgent need for improved screening strategies. Of particular concern are American Indians and Alaska Natives (AI/AN), who bear a disproportionate burden of HCV infection. They experience a rate of 2.9 cases per 100,000, compared to 0.5 cases per 100,000 in African Americans and 1.2 cases per 100,000 in non-Hispanic Whites, with higher mortality rates. Achieving the World Health Organization's (WHO) HCV elimination targets, aiming for an 80% reduction in new infections and a 65% reduction in HCV-related mortality by 2030, requires substantial improvements in screening efforts. The existing two-step HCV testing protocol, involving initial antibody testing followed by confirmatory RNA testing, proves costly and time-consuming, leading to attrition in HCV management. An alternative approach lies in cost-effective, rapid, sensitive, and specific Point-of-Care (POC) HCV antigen (Ag) testing, offering potential for streamlined screening and diagnosis in a single step. However, commercially available and FDA-approved devices for POC HCV antigen testing are currently lacking. Existing assays are laboratory-based, relatively costly, and lack the necessary sensitivity and specificity, particularly for samples with low viral loads (<1000 IU/mL). To bridge this gap, there is an imperative for the expeditious development of an affordable, rapid, sensitive, and specific POC HCV Ag diagnostic assay. Here, we propose to develop POC LUCAS (LUminescence CAscade-based Sensor), an ultrasensitive bioluminescence assay designed for HCV Ag detection using a fingerprick volume of whole blood. POC LUCAS HCV Ag aims for complete automation, delivering rapid results in under 30 minutes with high sensitivity (Limit of Detection ranging from 200 IU/mL to 1000 IU/mL). This system utilizes a minimal fingerprick volume (<100 µL) of whole blood, applied to an affordable (material cost <$2), disposable, and easily mass-producible microfluidic-based cartridge. In summary, POC LUCAS HCV Ag assay stands as a promising solution to enhance access to HCV care, especially for populations disproportionately affected, providing a comprehensive and accessible approach to diagnosis in resource-limited settings and populations experiencing HCV-related health disparities.