Brigham And Women'S Hospital

NIH Research Projects · FY 2025 · 2025-07

Project Summary Antibiotic-induced delayed-type drug hypersensitivity reactions (dtDHR) are a major yet underappreciated public health problem, occurring commonly in skin-limited form, morbilliform drug eruption (MDE), and causing significant morbidity and mortality in severe systemic forms, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Antibiotic- induced dtDHR are significantly understudied. Consequently, understanding of immunopathogenesis has been limited, and subsequent to that, so too clinical care. The bulk of translational research in the field focuses on effector immune cell populations, most commonly T cells, as well as the role of Human Leukocyte Antigen (HLA) in pathogenesis. This narrow focus along with clinical knowledge gaps and research barriers have markedly hampered progress. Herein, we propose the potentially transformative hypothesis that some other “X-factor” is critical in driving antibiotic-induced dtDHR onset, phenotype and/or severity. We propose three possible “X-factors”: immune dysregulation via aberrant regulatory T cell response, concurrent active infection, and host microbiome. Any or all of which, if true, have potential to completely shift the paradigm of disease pathogenesis. Each factor is individually hypothesized and tested in a Specific Aim. Each Specific Aim harnesses innovative translational approaches across humans and mice to explore then directly test through highly mechanistic experimentation each hypothesis. There are two overarching experimental approaches common to all three aims. First, we perform a prospective longitudinal translational study of antibiotic-induced dtDHR patients along with matched antibiotic-tolerant controls, in which biologic samples along with comprehensive and unbiased clinical data are collected. This overcomes several knowledge gaps in the field and markedly strengthens the robustness and clinical applicability of our translational findings. Second, we exploit our own recent advances with novel mouse models and research tools to overcome prior research barriers and bolster our human experimentation. Importantly, to achieve its goals, this grant builds on ample preliminary data and the highly complementary expertise of its investigators to ensure feasibility and scientific rigor. This study’s findings have potential to profoundly impact fundamental understanding of not only antibiotic-induced dtDHR but more broadly allergy and immunology in health and disease, while also to directly transform clinical care in both the short- and long-term.

NIH Research Projects · FY 2026 · 2025-07

Ectopic calcification in the intimal and medial layers of blood vessels associate with increased risk of cardiovascular morbidity and mortality. Calcification in the medial layer is a hallmark of aging and occurs ubiquitously throughout the vascular tree. Medial calcification is present in >30% of individuals over 60, and causes systemic arterial stiffening leading to heart failure, and in severe disease, critical limb ischemia requiring amputation. This pathology is distinct from intimal calcification localized to atherosclerotic plaques. These vascular calcification subtypes have different risk factors and microenvironments: notably, medial calcification lacks the local inflammatory stimuli typically associated with intimal calcification. Compared to intimal atherosclerotic calcification, medial calcification is relatively understudied leaving gaps in knowledge regarding the mechanisms specifically governing medial calcification. Despite the prevalence, no intervention strategies currently exist to prevent or treat this condition. To address this gap in knowledge, we will systematically compare the mechanisms involved in these two subtypes of calcification using spatially resolved and histology-informed unbiased technologies. The deposition of calcium-phosphate crystal in the vascular wall is regulated by the release of specialized cell-derived extracellular vesicles (EVs). Using proteomics, we identified phosphate-regulating enzymes enriched in EVs derived from arteries with calcification. Abnormalities in phosphate regulation are central to aging and our preliminary findings in whole artery tissue suggest proteomic differences between intimal and calcific lesions may have phosphate metabolism as a distinguishing feature. This preliminary data provides a premise for the central hypothesis that medial and intimal calcification have distinct disease drivers, and medial calcification is distinctly regulated by EV phosphate-mediated mechanisms. In Aim 1, Dr. Turner will use spatial and EV multi-omics to map profiles of disease progression in both medial and intimal calcification lesions compared to non-calcified arterial tissue controls. In Aim 2, she will functionally assess EVs and predicted phosphate modulating disease drivers from each subtype. These studies will be the first interrogation of calcification sub-type resolved disease mechanism. In Aim 3, Dr. Turner will use the -omics and nanoparticle expertise she gained in Aim 1 and Aim 2 to interrogate the proteomic composition of circulating calciprotein particles as a novel biomarker of phosphate status and medial calcification. These findings will provide insight into interventional strategies to mitigate the contribution of phosphate in aging-related medial calcification and push forward the development of tools to identify populations that could benefit from phosphate-targeting interventions. These studies will be conducted under the mentorship of Dr. Elena Aikawa, a pioneer of EV-mediated cardiovascular calcification using systems biology, as well as a committee of professional and scientific advisors committed to Dr. Turner’s success and transition to independence.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT OVERALL COMPONENT Alzheimer’s disease manifests along a spectrum of levels of neuropathology, age of onsets and rates of cognitive decline. Genetic studies support a heterogeneous etiology, with around 70 associated loci, implicating several biological processes that mediate risk for AD. Studies are just beginning to emerge that attempt to provide frameworks for subtyping AD based upon biomarker data, genetic data and/or -omics profiles from the postmortem brain. Despite this, the majority of experimental systems for testing new therapeutics are not designed to capture the genetically complex drivers of AD. In turn, past clinical trials may have suffered from an inability to predict individual responsiveness based upon the drivers of disease in AD subtypes. A one-size-fits- all approach to clinical trials and clinical care is unlikely to be successful across all cases (i.e. anti-amyloid immunotherapy may work well in a subset of cases but not in others). Successful establishment of the proposed PRECISION-AD Center, which will establish a toolkit of 2D and 3D microphysiological systems (MPS) that capture human genetic diversity underlying risk and resilience to AD and report on the function of biological domains relevant to AD, is an important first step in identifying convergent and divergent mechanisms of AD and testing person-specific responsiveness to therapeutic interventions. Here, we will leverage a set of iPSC lines that we recently developed from over 100 participants in the Religious Order Study (ROS) and Memory and Aging Project (MAP) that span ethnically diverse populations and include deeply phenotyped and genome sequenced individuals. Our ability to analyze matched brain and plasma from the same individuals provides a valuable opportunity for cross-platform validation of key molecular findings. Under this award, we have four overarching goals: 1) To generate an atlas of molecular signatures of 2D and 3D MPS experimental systems across 100 ethnically diverse genetic backgrounds that are matched with multi-omic data from brain tissue and plasma from the same individuals; 2) To develop preclinical efficacy assays for testing of six interventional strategies for AD that target different biological domains and to identify biomarkers of responsiveness to each intervention; 3) To establish rigorous, automated pipelines for scaling preclinical assays of efficacy to enable testing of interventional strategies across diverse genetic backgrounds, and 4) To establish robust pipelines for open-access sharing and distribution of MPS models, methods, and data to ensure facile distribution to scientists from the academic and biopharma communities. To accomplish these goals, we have assembled a multidisciplinary team with deep experience in Alzheimer’s biology, stem cell modeling, drug discovery, screening, lipidomics, proteomics, computational biology, and open resource sharing platforms. Together, we aim to develop 2D and 3D models as scalable platforms for the use as precision medicine research tools to investigate the complex biology of AD and to accelerate drug discovery and preclinical drug development.

NIH Research Projects · FY 2026 · 2025-07

Project Summary Neutropenia-related pneumonias account for 40% of infections at sites other than the bloodstream and are typically treated with broad-spectrum antibiotics and G-CSF therapy. However, not all patients respond to these treatments. The long-term goal of this project is to explore an alternative strategy for treating and preventing neutropenia-related pneumonia by increasing the lifespan of neutrophils in the lungs of neutropenic patients. Since neutropenia-related pneumonia primarily results from an insufficient number of neutrophils in the infected lungs to eliminate invading pathogens, prolonging neutrophil survival will increase the neutrophil count in the infected lungs, thereby enhancing host defense against invading pathogens. Here, it is proposed that prolonged neutrophil survival can be achieved by targeting Gasdermin D (GSDMD), a pore-forming cell death executor. The premise of this study is supported by preliminary data on the role of GSDMD in mediating bacteria-induced neutrophil death. The hypothesis is that inhibiting GSDMD will prevent bacteria-induced neutrophil death and elevate neutrophil-mediated host defense, thus representing a viable therapeutic strategy for the treatment of neutropenia-related bacterial pneumonia. To further advance the understanding of the role and regulation of GSDMD in neutropenia-related bacterial pneumonia and explore its therapeutic potential, three specific aims will be investigated. (1) GSDMD activation depends on the cleavage of the full-length protein and the generation of the GSDMD N-terminal fragment (GSDMD-NT). Aim 1 will uncover the underlying mechanism responsible for GSDMD cleavage and activation in neutropenia-related bacterial pneumonia. (2) Preliminary data show that GSDMD mediates bacteria-induced neutrophil death in vitro, but it has never been investigated whether Gsdmd-deficiency in neutrophils can intrinsically lead to their prolonged survival in vivo in neutropenia-related bacterial pneumonia. Aim 2 will elucidate the role of GSDMD in regulating neutrophil lifespan in the lungs of bacteria-infected neutropenic mice. (3) Aim 3 will explore GSDMD inhibition as a therapeutic strategy for treating neutropenia-related bacterial pneumonia. It will determine whether neutrophil specific Gsdmd disruption or pharmacological inhibition of GSDMD can enhance host defense and mitigate lung damage. Additionally, the effect of GSDMD inhibition on bacteria-induced death of human neutrophils will be investigated both in vitro and in vivo using NSG mice. Together, results from this study will confirm GSDMD-mediated neutrophil death in the lungs as a key regulatory mechanism in host defense and as a novel therapeutic target for the treatment of neutropenia-related bacterial pneumonia. Furthermore, a better understanding of the underlying mechanisms responsible for the cleavage and subsequent activation of GSDMD in bacteria-infected lungs will aid in designing strategies to achieve specific inhibition of GSDMD activation and GSDMD-elicited cell death in neutrophils.

NIH Research Projects · FY 2025 · 2025-06

Project Summary Single-cell transcriptomics have revolutionized biomedical research over the last decade and are now widely used in both industry and academia. Today there are >100 million cells profiled and available in the public domain, and many of these datasets were generated through Common Fund projects such as HuBMAP, GTEx, BRAIN, and SCORCH. These and other projects aim to serve as reference datasets that can be re-used for comparisons with other datasets, and such resources are often referred to as cell atlases. Therefore, the ability to integrate cell atlases with each other and with external datasets is crucial to ensure their utility. However, combining datasets can be challenging due to the presence of batch effects—experimental artifacts resulting from variability in sample processing. If not accounted for, batch effects can be mistaken for biological signals. In recent years, several computational methods to identify and correct batch effects have been developed. Nonetheless, challenges remain, particularly in scaling up to millions of cells from thousands of batches. Additionally, users need to download large volumes of data, which can be costly and time-consuming. One of the most popular methods for batch correction is Harmony, which we published in 2019. Harmony is transparent, intuitive, fast, and accurate, as demonstrated by independent benchmarks. Briefly, Harmony first uses principal component analysis to project cells into a latent space. It then iteratively performs k-means clustering and ridge regression to identify robust clusters that are not confounded by artifacts. Here, we propose two aims to add new functionality to Harmony to eliminate some of the remaining bottlenecks. In many use cases, a researcher will want to integrate their own data with a subset of an atlas, such as datasets containing the same tissue type. To speed up this process, we will leverage our pre-calculated global integration to allow for fast comparisons. This will be achieved by building a tree structure where nodes represent cell types at various levels of granularity. New cells are then projected into the same latent space, and by traversing the tree, we can quickly identify which existing cell types they most closely resemble. With cell atlases containing millions of cells, downloading and storing the data can become an issue. One way to overcome this challenge is to perform computations where the data resides, rather than transferring the data first. As previously mentioned, Harmony relies on three classic algorithms (PCA, k-means, and sparse regression), all of which can be executed in a distributed manner. In this context, we assume different parts of the data will reside on distinct servers, and Distributed Harmony will require only summary statistics to be transferred between servers. We envision that the proposed methods can be deployed in collaboration with organizations maintaining cell atlases. Additionally, the distributed algorithms and infrastructure we develop will be valuable for many other applications in computational genomics, e.g. population genetics and microbiome research.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Astrocytes are abundant cells of the central nervous system (CNS), with important roles in neurologic diseases such as multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE). Although mechanisms driving astrocyte pathogenic activities and subsets have been identified, less is known about the mechanisms that suppress them. In preliminary studies aimed to define astrocyte-intrinsic regulatory mechanisms we made the following observations: 1) A genome-wide CRISPR/Cas9 screen identified Clec16a, which has been linked to MS in genetic studies1,2, as a suppressor of NF-kB- and NLRP3 inflammasome-driven pathogenic astrocyte responses; 2) Genetic and pharmacologic studies established that mitophagy driven by CLEC16A expressed in astrocytes (CLEC16AAST) limits the accumulation of mitochondrial products that activate NF-kB and the NLRP3 inflammasome; 3) CLEC16AAST inactivation results in the worsening EAE and the expansion of pathogenic ACLY+ p300+ astrocytes that display increased NF-kB activation and IL-1b production; 4) CLEC16AAST inactivation boosts microglial pro-inflammatory responses in EAE; 5) A CNS-penetrant NLRP3 inhibitor abrogates the worsening of EAE induced by CLEC16AAST inactivation; and 6) CLEC16A and mitophagy are decreased in astrocytes in MS, while NLRP3 activation is upregulated. These are important findings because most MS-associated genes have so far been linked to the control of immune cells, but not astrocytes. In addition, mitophagy deficits in neurons, but not astrocytes, were previously linked to neurologic disorders. Finally, little is known about the role of the NLRP3 inflammasome in the control of astrocyte responses and subsets. Based on these findings, we hypothesize that CLEC16AAST limits NF-kB- and NLRP3 inflammasome-driven pathogenic astrocyte responses in CNS inflammation. Thus, we propose to study the regulation of astrocyte responses by this novel CLEC16A-NF-kB-NLRP3 inflammasome signaling axis. Specifically, we propose to: 1) Establish the effects of CLEC16AAST on pathologic astrocyte responses in EAE and MS; 2) Perform transcriptomic and epigenetic studies to define subsets of astrocytes and other cells controlled directly and indirectly by CLEC16AAST and the mechanisms involved; 3) Use genetic barcoding and cell-specific gene perturbation approaches to identify the effects of CLEC16AAST on astrocyte interactions with other cells and the mechanisms of cell-cell communication involved; 4) Map the CNS location of cell subsets and interactions controlled by CLEC16AST using in situ transcriptomics, immunofluorescence and single-cell RNA-seq datasets; and 5) Use CNS-penetrant NLRP3 inhibitors in combination with CLEC16AAST deficient mice and astrocyte-specific in vivo CRISPR/Cas9- driven gene perturbations to define the role of the NLRP3 inflammasome in the control of astrocyte responses and subsets, and its potential for the therapeutic management of astrocyte-driven CNS pathology. In summary, this project investigates the role of a novel CLEC16AAST-NF-kB-NLRP3 inflammasome signaling axis in the control of astrocyte pathogenic activities and subsets, and its potential as a therapeutic target for MS.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract Asthma is one of the most common chronic respiratory diseases worldwide. Microbial dysbiosis in the gut and lungs has increasingly been associated with the incidence and severity of asthma, indicating the potential of the microbiome to be a determinant factor in asthma pathogenesis. However, as the most likely connection between the gut and lungs, the role of the blood microbiome in the “gut–lung axis” is still unclear for asthma pathogenesis due to the lack of cost-effective and high-throughput sequencing methods. Indeed, it is either impossible, or prohibitively expensive, for conventional sequencing methods to handle microbial DNA samples that are in trace amounts, heavily degraded, or dominated by host DNA, e.g., in human blood. We hypothesize that the presence of microorganisms in the blood is related to the risk of asthma occurrence, and these microbial blood biomarkers can be captured by a reduced metagenomic sequencing method for diagnosis or even early detection of asthma with the help of a deep learning framework. In this application, a strain-resolved computational pipeline for the reduced metagenomic sequencing will be developed to profile the blood microbiome in the “Vitamin D Antenatal Asthma Reduction Trial” --- an ongoing randomized, double- blind, placebo-controlled clinical trial of 881 pregnant women with both questionnaires and maternal, cord, and child blood samples available. Meanwhile, a deep-learning framework will be developed to optimize the accuracy of diagnosis and prediction models for asthma using blood microbiome data. Finally, with the aid of the new computational pipeline and deep-learning framework, the role of the blood microbiome in the gut– lung axis and asthma pathogenesis will be investigated. Dr. Sun’s trainings in molecular biology, bioinformatics and metagenomics have prepared him well for this proposed research. However, understanding the molecular basis connecting asthma through the analysis of blood microbiome data is a challenging task that requires further training in specific areas. Dr. Sun will leverage the excellent intellectual environment of Harvard Medical School (HMS) and its teaching hospital Brigham and Women’s Hospital (BWH). He will have access to extensive computational resources at BWH and HMS. Through formal coursework and workshops, and with the help of a strong mentoring team and a world-class advisory committee with complementary expertise, Dr. Sun will immerse himself in a training program focusing on advanced programming, statistical modeling, deep learning, respiratory pathophysiology, and clinical translation. Dr. Sun will meet with his two mentors and advisory committee members on a regular or needed basis to present his progress and get prompt feedback and advice. Altogether, Dr. Sun’s training and research plan will enable him to expand his current skill set to include the ability to address the challenges of low microbial biomass sequencing in blood sample, deep learning in microbiome study and identifying the role of blood microbes in asthma pathogenesis, and ultimately contribute to the precision medicine of lung diseases.

NIH Research Projects · FY 2026 · 2025-06

ABSTRACT KNDy neurons in the arcuate nucleus (ARC) control GnRH pulsatility through the interplay of neurokinin B (NKB) and dynorphin, creating kisspeptin pulses that directly stimulate GnRH neurons. Disruptions in this system can lead to various reproductive disorders, from hypothalamic amenorrhea to polycystic ovary syndrome (PCOS). Our recent work has shown that peripherally restricted kappa opioid receptor agonists (PRKAs) can activate dynorphin's receptor (KOR) in the mediobasal hypothalamus, decreasing LH release and restoring reproductive markers in a PCOS mouse model. Intriguingly, this effect persists even without KOR in Kiss1 neurons, suggesting an upstream target. We aim to identify and characterize the neuronal population that is peripherally accessible, responsive to dynorphin, and capable of modifying KNDy neuron activity. Tuberoinfundibular dopaminergic (TIDA) neurons emerge as prime candidates, exhibiting oscillatory patterns similar to KNDy neurons and correlating with prolactin and LH pulses. Moreover, our preliminary data has identified that KNDy neurons are uniquely enriched with dopamine receptor 2 (Drd2) in the ARC, and dopamine levels are reduced in PCOS models. Our overarching hypothesis posits that TIDA and KNDy neurons form a major oscillatory network controlling GnRH release, with decreased dopamine tone in PCOS leading to KNDy neuron hyperactivation, reversible by PRKAs. We will investigate this through three aims: 1) examining KNDy activity in normal and PCOS-like conditions and their PRKA response, 2) characterizing dopamine's role in KNDy neuron activity, and 3) elucidating TIDA neurons' role in KNDy neuron control under various conditions. This project promises to unveil novel mechanisms in reproductive neuroendocrinology and may lead to innovative PCOS treatments.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT Asthma is a leading cause of morbidity in the US and worldwide, affecting almost 10% of the US population. Individuals with severe asthma, who are uncontrolled on conventional therapy, account for a disproportionate share of asthma-related morbidity and mortality. For these patients, the advent of multiple monoclonal antibodies “biologics” has provided additional therapeutic options to improve outcomes in this potentially fatal disease. While these biologics have helped to improved outcomes in many patients with asthma, there is considerable uncertainty on the optimal choice of biologic in patients who meet criteria for two or more biologics, a common occurrence. There are no head-to-head trials of these therapies and results of indirect treatment comparisons have been limited or conflicting. Moreover, indirect comparisons are fraught with multiple limitations, including that the populations recruited into different trials for the therapies being compared may differ in ways which may influence the outcome(s) of interest. Consequently, current asthma guidelines have limited evidence-based guidance on how to approach biologic initiation in patients who are eligible for multiple biologics. To optimize the value of these expensive biologics, data on their comparative effectiveness are solely needed. In the absence of randomized trials, observational data can be used to generate evidence on the comparative effectiveness of these biologics using ‘real-world’ data. However, to mitigate biases in non-experimental research and to ensure sound conclusions are drawn from the data, we need to leverage subject matter expertise with advanced and innovative causal inference and pharmacoepidemiology techniques. This proposal leverages the PI and study team’s clinical expertise in asthma and monoclonal antibody research with expertise in causal inference and epidemiologic study design to emulate hypothetical randomized and adaptive trials in answering questions on the comparative effectiveness of the respiratory biologics approved for asthma. We will compare the monoclonal antibodies in pairwise comparisons and simultaneously. In addition, we will identify the dynamic treatment-switching strategy which maximizes outcomes in patients with severe asthma. This research is poised to fill important gaps in the evidence-base of respiratory biologics in asthma potentially leading to improvements in the care of individuals with severe asthma. Additionally, it will provide a framework that can be applied to other therapies and conditions.

NIH Research Projects · FY 2025 · 2025-06

Project Summary/Abstract: A key unmet need in the treatment of rheumatoid arthritis (RA) is to understand the cellular mechanism underlying treatment failure. Recent studies have implicated joint fibroblast activation and fibrosis in treatment- resistance RA, yet the mechanism underlying synovial fibrogenesis in RA remains poorly understood. We now have data that indicates Notch signaling controls a fibrogenic program through regulation of transforming growth factor beta (TGF-β) signaling. Single-cell and spatial transcriptomic profiling of RA synovia revealed expansion of fibrogenic programs around Notch-activated stroma. The immediate goal of this project is to define the origin of synovial fibrogenesis and its impact on joint inflammation and treatment response in RA. The long-term goal of the project is to define targeting fibroblasts as a novel adjuvant therapy in RA. In pursuit of these findings, we propose 3 complementary aims to define the role of Notch-driven fibrogenesis in treatment failure in RA. Aim 1. Define a Notch-driven fibrogenic transcriptional program in synovial fibroblasts. This aim seeks to elucidate the molecular sequence of the fibrogenic program in synovial fibroblasts. Our goal is to demonstrate the molecular mechanism by which Notch signaling regulates TGF-β signaling in synovial fibroblasts. We will employ genetic perturbation via CRISPR/cas9 and transcriptomics to define the role of TGFB1 and TGFB3 in the Notch-mediated fibrogenic program. Next, we will apply high-resolution transcript mapping to define the spatial regulation of the fibrogenic program. Aim 2. Determine the consequence of a Notch-driven fibrogenic program on treatment outcomes. We hypothesize that a Notch-mediated fibrogenic program is associated with a poor treatment outcome in RA. We will apply spatial transcriptomics to pre- and post-treatment synovial biopsies to characterize baseline fibroblast phenotypes and evaluate for correlation between longitudinal shifts in fibroblast phenotypes and treatment response. We will validate our findings using an independent cohort of treatment- naive RA biopsies. We hypothesize fibrogenic fibroblasts predict treatment failure. Aim 3. Define the effect of Notch levels on inflammatory and fibrotic niche formation. The focus of this aim is to gain insights into how differing levels of Notch signaling lead to distinct stromal environments and their impact on inflammatory phenotypes in RA. We hypothesize a low stromal Notch level facilitates lymphocyte aggregation while a high stromal Notch level induces fibrinogenesis (Fig. 1). We will test this hypothesis by utilizing two synovial organoid systems we developed: 1) a cellular reconstitution, micromass- based organoids, and 2) RA patient-derived organoids.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Difficulty with inhibitory control, which contributes to impulsive behavior, is a core feature of bipolar disorder (BD) and persists across mood states. Response inhibition (RI), an aspect of behavioral inhibition, is classified as a subconstruct under the domain of cognitive systems within the Research Domain Criteria (RDoC) framework. Although impaired RI has been observed in BD, there is still a limited understanding of this aspect of inhibitory control, and it has not been translated into treatment options in the clinic to date. Elucidating the role of impaired RI and its underlying neurobiology in BD is critical for identifying novel targets for interventions to reduce impulsivity and related risky behaviors. The proposed study will focus on understanding the behavioral, neural and inflammatory measures of RI in BD and employ an interdisciplinary approach to 1) characterize RI using self-report and performance based measures (Training goal 1); 2) characterize the neural circuitry underlying RI by measuring a) brain activation patterns, while performing the Parametric Go/No-Go Test (PGNG), and b) resting-state functional connectivity of cognitive control network (Training goal 2); 3) examine the association of peripheral inflammation (i.e., CRP, IL- 6, TNF-α) with behavioral and circuit-based processes that underlie RI (Training goal 3), and 4) examine the association of central inflammation (extracellular free water [FW]) with both peripheral inflammation and RI (Training goal 3). We will enroll 100 affectively stable BD patients and 50 demographically matched controls. Subjects will complete the Stop Signal Test (SST) and the PGNG outside the scanner. Inflammatory markers in blood and FW levels in the brain will be quantified. Fifty BD patients and 50 controls will undergo resting-state and task-based functional magnetic resonance imaging (fMRI), and diffusion-weighted MRI (DWI-FW). This Mentored Research Scientist Development Plan aims to assist the candidate in achieving the following goals: 1. To receive specialized training in neurocognitive testing, with a focus on inhibitory control, and gain experience in clinical symptomatology and research considerations in patients with BD, 2. To gain theoretical and applied knowledge in the collection and interpretation of brain-based measures, with a specific focus on the cognitive control network, 3. To expand knowledge in psychoneuroimmunology within the context of mental health research by integrating peripheral inflammation and a proxy measure of neuroinflammation. Training activities aligned with the proposed project will include formal coursework, hands-on training, directed readings, workshops, grant writing, and research activities. This project and related training activities will primarily take place at Brigham and Women's Hospital, Harvard Medical School. This proposed research study and training plan will prepare the candidate to become an independent scientist establishing a research program that integrates biological, behavioral and cognitive measures to identify biobehavioral mechanisms that inform intervention development, reduce disease burden and promote the quality of life of patients with mood disorders.

NIH Research Projects · FY 2026 · 2025-05

Abstract In chronic autoimmune conditions, lymphocytes are continuously recruited to the inflamed site to sustain the pathologic inflammatory response. T cells that migrate to inflamed tissues such as the synovium in rheumatoid arthritis often express chemokines receptors that detect chemokines produced in response to acute inflammatory mediators such as TNF or IL-1, including CLL2, CCL3, CCL4, CCL5, and CXCL16. Receptors for these chemokines, including CCR2, CCR5, and CXCR6, and highly enriched on T cells from joints of RA patients as compared to T cells in blood or secondary lymphoid organs. Despite the widespread expression of these receptors on T cells in inflamed sites, little is known about the extrinsic signals or transcription factors that induce their expression. Expression of CCR2, CCR5, and CXCR6 are not directly linked to a specific T cell effector subset, such as Th1 or Th17 cells; thus, we hypothesize that a distinct set of factors regulate expression of this migratory program independent of differentiated T cell effector subsets. Here we will use arrayed CRISPR screens and cytokine stimulation screens to identify transcription factors and cytokines that promote expression of CCR2, CCR5, CXCR6 and related chemokine receptors. We will use a combination of epigenetic analyses to identify common and distinct regulation patterns controlling the genes that encode these receptors. We will use spatial transcriptomics and human synovial organoids to dissect the interactions within RA synovium that may sustain expression of these receptors within an inflamed tissue. We expect that this project will reveal dominant pathways that control coordinated expression of receptors required for T cell migration to inflamed sites and will nominate new strategies to interfere with pathologic T cell migration therapeutically in ways that are more robust that targeting individual receptor-ligand interactions.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Glioblastoma (GBM) is the most lethal primary brain tumor with standard-of-care therapies providing only partial palliation. One of the cornerstones of clinical care for GBM patients is surgical tumor debulking and subsequent chemo- and radiotherapeutic treatment. Oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit antitumor effect via oncolysis and production of neoantigens are among the recently approved promising therapies for cancer patients. Although phase I and Ib oHSV clinical trials in GBM patients have shown signs of anti-tumor activity, clinical response rates have been sub-optimal primarily due incomplete understanding of the immune evasion and oHSV delivery issues in the tumor resection cavity post-surgery. Considering the critical and very limited timeline from diagnosis to primary surgical intervention in GBM patients, allogeneic “off-the-shelf” engineered stem cells offer a promising therapeutic strategy to target residual GBM cells post-surgery. We have previously demonstrated that MSC armed with different oHSV variants (MSC-oHSV) home to tumors and synthetic extracellular matrix (sECM) encapsulated MSC-oHSV have a significantly better therapeutic efficacy than the purified oHSV in GBM. These results although promising, have raised fundamental questions on how to develop MSC based therapeutic approaches that specifically kill tumor cells and simultaneously activate immune effector functions against GBMs. To enhance the therapeutic efficacy of MSC-oHSV, we have created oHSV resistant CRISPR/Cas9 nectin-1 (utilized by oHSV as a mode of entry into the cell) knockout MSC (MSC-N1KO) thus allowing us to co-deliver immunomodulators in combination with MSC-oHSV. Utilizing MSC-N1KO engineered immunomodulator screening, we have identified interleukin (IL)-12, which is known to activate both innate and adaptive immunity, to enhance the therapeutic efficacy of MSC-oHSV. Based on these findings, MSC-N1KO will be engineered to express regulatable IL-12 and the therapeutic efficacy of co-delivered MSC-oHSV and MSC-N1KO- IL12 will be tested in immune-phenotyped nodular and semi-invasive syngeneic GBM models of resection that we have recently developed and characterized. Given that oHSV/IL12 mediated therapies upregulate programmed death ligand (PD-L)1, MSC-N1KO-IL12 will be further engineered to express next generation of anti-PD-1 antibodies (nanobodies; Nb) and the therapeutic efficacy and fate of encapsulated MSC-oHSV and MSC-N1KO-IL12/Nb-PD1 will be assessed in syngeneic GBM models of resection. We hypothesize that surgical resection-elicited recruitment of immune effector cells at the residual tumor site will synergize with MSC-delivered oHSV, IL-12 and Nb-PD-1, resulting in increased therapeutic benefit. To ease clinical translation, engineered human MSC will be developed and tested in invasive and nodular patient derived GBM resection models in humanized mice. The integration of the kill switch in MSC will ensure safety in our approach and the incorporation of 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 MSC based therapies for GBM and are likely to define a new treatment paradigm for patients with other cancers.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT - Metabolic determinants of Mtb virulence, vulnerability and variation Mycobacterium tuberculosis (Mtb) has emerged as the world's most deadly pathogen based in large part on the highly unusual biological and chemical properties of its cell envelope. Comprised of a distinctive hydrophobic outer mycolate membrane, anchored to an underlying complex of polysaccharide and peptidoglycan polymers, the Mtb envelope serves as both the primary interface with, and barrier to, the human host. In human tuberculosis (TB) disease the Mtb envelope mediates a years-long standoff, and serves as the barrier to all anti-mycobacterial drugs. Yet, knowledge of its native composition, variation and regulation of drug entry remains fragmentary. This team of applicants has created new genetic and metabolomic tools to comprehensively dissect and analyze the metabolite and lipid components of the Mtb envelope on an organism-wide basis across a large set of clinical isolates. Moreover, this TBRU proposes to provide the first descriptions of cell envelope variation among isolates from human patients and identify key determinants of its virulence and barrier to drug action that could inform the development of better diagnostics and therapeutics. Structures of new molecules will first be determined using synthetic chemistry and mass spectrometry. The genes encoding these metabolites will then be identified and functionally validated using new genome-scale CRISPR interference technologies, assays for penetration into the cell envelope, and genetically defined mouse models of in vivo growth. Using mass spectrometry, we will solve the structures of up to 250 surface barrier lipids and more than 41 gene-lipid pairs that dominate in cell envelope variation among patients. Patient-derived Mtb strains will be obtained from clinical samples collected at our field sites in Masiphumelele, South Africa, where we will implement clinically relevant technology for detection of live Mtb in exhaled (non- coughed) human bioaerosols. Studies of barrier function place special emphasis on rifampicin as a model compound due to its clinical importance as a frontline drug and role as a defining element of drug resistant TB. The ability to analyze patient urine and serum has further resulted in the discovery of new biomarkers of disease activity and response to drug therapy, motivating linked translational efforts to advance the development of non-sputum based, real time point-of-care diagnostic tests. This highly interactive group of scientists thus seeks to provide better drugs and diagnostic tests, as well as a deep and durable scientific foundation for understanding of the Mtb envelope, especially the particular genes and molecules that control active remodeling, drug action and human host response.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Approximately one in three deaths results from hemorrhage (bleeding) or thrombosis (blood clots). ABO blood type is a major risk factor for hemorrhage or thrombosis. Type O individuals are at higher risk for bleeding than those with non-O blood types. Conversely, non-O individuals are at higher risk of thrombosis. The reason that blood type O is associated with a higher risk of bleeding and lower risk of thrombosis is incompletely understood. Several recent publications have suggested that differences in platelet function contribute to the increased bleeding risk in type O vs non-O individuals. Despite the clinical importance of ABO type as a risk factor for thrombosis and hemorrhage, the mechanism by which platelet ABO(H) blood group antigens impact hemostasis and thrombosis remains uncharacterized. Our central hypothesis is that ABO(H) antigens on functionally relevant platelet membrane glycoproteins impacts their binding to ligands. I will test this hypothesis via the following aims: AIM 1. Define the impact of ABO(H) glycans on platelet binding to Von Willebrand Factor (VWF). Our working hypothesis is that GPIb⍺ that is decorated with A or B antigen containing O-glycans will exhibit enhanced binding to VWF compared with type O(H) GPIb⍺. We will use enzyme-linked immunosorbent assays (ELISA) and surface plasmon resonance to quantify the binding kinetics of VWF to platelets of blood types O, A, B, and AB. AIM 2. Identify ABO(H) antigen carrying glycoproteins on platelets using a click chemistry enrichment strategy and mass spectrometry proteomics. Our working hypothesis is that there are dozens of functionally relevant platelet glycoproteins that carry the ABO(H) blood group antigens. We will use an innovative click chemistry strategy to selectively enrich H antigen carrying glycoproteins from platelet lysates, and identify these proteins using mass spectrometry proteomics. We will validate these hits using western blot, glycomics, and glycoproteomics. The successful completion of this project will provide mechanistic insight into how platelet ABO blood type affects binding to VWF and a comprehensive inventory of the glycoproteins and glycans on the platelet surface that carry ABO(H) antigens. This will provide unprecedented insight into platelet-intrinsic mechanisms underlying the well-known epidemiologic association between ABO blood type and risk of bleeding and clotting. This work will fill a critical knowledge gap in our understanding of why ABO blood type is associated with risk of bleeding and clotting, and provide a molecular framework that will facilitate future development of diagnostic tests and therapies to better predict, prevent, and manage thromboembolic disease and hemorrhage.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY/ABSTRACT Standard first-line therapy for drug-susceptible tuberculosis (DS-TB) is highly effective but complicated by long treatment duration and rifamycin drug-drug interactions, particularly with antiretroviral therapy (ART) in high HIV- TB burden countries. A well-tolerated and efficacious rifamycin-free regimen that can shorten TB treatment duration is critically needed to achieve World Health Organization (WHO) targets towards ending TB. Our group pioneered the use of an artificial-intelligence-enabled parabolic response surface (PRS) platform allowing rapid identification of the most effective drug-dose combinations by testing only a small fraction of the total drug-dose efficacy response surface. This approach determined that drug combinations including bedaquiline (BDQ), clofazimine (CFZ), and pyrazinamide (PZA) at optimal dose ratios were more effective than standard DS-TB treatment, achieving relapse-free cure in mouse models within 3-4 weeks. Adding delamanid (DLM) as a 4th drug was equivalent in potency, achieving 100% relapse-free cure in only 3 weeks. This is substantially shorter than time to relapse-free cure in mouse studies supporting other TB treatment shortening trials. Bactericidal and sterilizing ability confirmed in other experiments, and favorable intra-lesional pharmacokinetics (PK), provides additional justification for evaluation of the BDQ-CFZ-PZA-DLM (BCZD) combination for treatment shortening. This 8-week rifamycin-free ultrashort regimen fulfills key requirements of the WHO target regimen profile for DS- TB: lower potential for drug-drug interactions, established tolerability and safety, constituent agents registered and accessible, and optimized dosing based on clinical data. We hypothesize that BCZD will demonstrate superior microbiologic efficacy relative to standard therapy during the first 8 weeks of treatment for patients with DS-TB. To test this, we shall conduct a Phase IIc, open-label, randomized controlled trial to investigate the efficacy and safety of an 8-week regimen of BCZD, paving the way for a definitive treatment-shortening trial and potentially shifting clinical practice. Our trial, called PRESCIENT, will randomize 156 adults with smear-positive DS-TB, with and without HIV, to receive BCZD for 8 weeks versus standard therapy for 26 weeks (1:1 ratio). The primary objective is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks; the Phase IIc design also enables evaluation of clinical endpoints through extended post-treatment follow up to 56 weeks (Aim 1a - efficacy). Secondary objectives include rigorous assessment of safety and tolerability (Aim 1b - safety), and drug susceptibility testing and whole genome sequencing to determine frequency of treatment- emergent resistance to BCZD (Aim 1c - resistance). We shall also explore the effect of experimental drug exposure, derived from population PK models, on time to culture positivity as a measure of mycobacterial burden and treatment response, and on corrected QT interval (Aim 2 - PK/PD). PRESCIENT will be conducted at established clinical research sites in Haiti and South Africa which have access to large populations of patients with DS-TB and have the necessary expertise and infrastructure to successfully implement this project.

NIH Research Projects · FY 2026 · 2025-05

Asthma is a disease of the respiratory tract that results in reversible narrowing of airways, leading to symptoms ranging from wheezing and dyspnea to death. The US Centers for Disease Control estimate that over 26 million Americans live with asthma. Incidence of asthma is more prevalent in boys in childhood, but is more prevalent in women in adulthood, and there are wide disparities in asthma incidence by race/ethnicity, socioeconomic status, and exposures to environmental factors. A growing body of evidence has suggested that individual environmental exposures (e.g. air pollution) are associated with asthma incidence, however, other environmental factors are understudied. Furthermore, most studies have only examined the health effects associated with one environmental exposure at a time, or only in one stage of the life course (e.g. prenatal). In reality, individuals are exposed to multiple exposures simultaneously. However, without rigorous approaches to estimate the health effects associated with multiple exposures across decades, the environment-related health burden will likely be underestimated. Using the vast resources of the nationwide prospective Nurses’ Health Studies (NHS, NHSII, NHS3), Health Professionals’ Follow-Up Study (HPFS) and the Growing Up Today Studies (GUTS), we are in a unique position to study the complex associations of multiple long-term environmental exposures on incidence of asthma. GUTS participants can be followed from the prenatal period through young adulthood, while all other cohorts can be followed throughout adulthood. Using the addresses of each participant during follow-up, we are able to append information on multiple chemical stressors (air pollution, traffic), physical stressors (temperature, humidity, ultraviolet radiation), features of the built and natural environment (greenness, blue space, walkability) to more than 300,000 participants for decades. Plasma metabolomics in adulthood are available for over 20,000 participants. These data will be used to explore biological pathways that may underlie the associations with the environmental exposures. We will assess the following specific aims: (1) Determine how multiple long-term environmental exposures are associated with incident asthma; (2) Identify demographic (e.g., age, sex, race/ethnicity), behavioral, and social environmental characteristics that modify the associations of multiple environmental exposures with incident asthma; (3) Explore how features of the plasma metabolome may mediate the impact of the multiple environmental exposures in adulthood on incidence of asthma. Our findings will provide valuable information on the role of modifiable exposures on risk of asthma, how multiple exposures interact, and factors that impact resiliency.

NIH Research Projects · FY 2025 · 2025-05

Alzheimer’s disease (AD) manifests along a spectrum of neuropathological presentation, ages of onset and rates of cognitive decline. Genetic studies support a heterogeneous etiology, with over 70 associated loci, implicating several biological processes that mediate risk for AD. Vascular pathologies commonly occur in AD and have a strong influence on cognitive function. For example, moderate to severe cerebral amyloid angiopathy co-occurs in 47% of individuals with a diagnosis of Alzheimer’s dementia. In addition, several genes and pathways implicated in AD are expressed in cells of the blood-brain-barrier. Despite this, the majority of experimental systems for elucidating disease mechanisms and for testing new therapeutics are neither designed to capture the genetically complex drivers of AD nor do they recapitulate the complex intercellular interactions between peripheral blood mononuclear cells, endothelial cells, pericytes, astrocytes, microglia and neurons that occur at the neurovascular unit. Here, we will leverage a set of iPSC lines that we recently developed from over 100 participants in the Religious Order Study (ROS) and Memory and Aging Project (MAP) that span ethnically diverse populations and include deeply phenotyped and genome sequenced individuals to develop and optimize an improved all-human cellular system for studying AD and ADRDs. Over the past four years, we used an “Organ-on-Chip” 3D microfluidic device to develop an all-human iPSC-derived “Brain-Chip” that incorporates cells of the neurovascular unit including endothelial cells, pericytes, astrocytes, neurons, and microglia. Here, we have four overarching goals towards improving this system for the study of ADRDs: 1) To define the delivery conditions for the introduction of patient blood cells (PBMCs) and plasma into the Brain-Chip system, 2) To determine the physiological consequences of introduction of AD-relevant stressors on the integrity and molecular profiles of cells of the blood-brain barrier, 3) To establish an experimental model of cerebral amyloid angiopathy in the Brain-Chip system, and 4) To establish an experimental and analytic pipeline for quantifying responses to therapeutic interventions following delivery through the “blood” chamber in the Brain-Chip. Successful execution of this study will provide a platform for the scientific community which enables 1) the study of known and unknown genetic risk factors for dementia and 2) safety and efficacy testing of therapeutic interventions across diverse genetic backgrounds.

NIH Research Projects · FY 2025 · 2025-05

Project Summary COPD remains one of the leading causes of morbidity and mortality in the western hemisphere. Pulmonary hypertension (PH) remains one of the key complications of smoking related lung disease, the presence of which leads to increased morbidity and mortality. Treatments for pulmonary arterial hypertension (PAH; Group 1 PH) have led to significant improvements in life expectancy and quality of life but have not had success in PH associated with COPD. We believe that part of the reason for this is that pulmonary hypertension in COPD arises from a complex set of mechanisms with only a partial pathophysiologic overlap with PAH. Additionally, patients with COPD are at significant risk for postcapillary pulmonary hypertension due to elevated left-sided pressures, which complicate treatment with pulmonary vasodilators used in PAH. CT imaging is increasingly obtained in smokers and is now often part of a lung-cancer screening of smokers. Features of pulmonary vascular remodeling have been previously described in pulmonary hypertension. In this proposal we seek to better understand the changes in the pulmonary vasculature and their relationship to changes in the lung parenchyma using a comprehensive, advance set of features from CT imaging in patients with group 1 (PAH) and those with COPD. To accomplish this, we use PVDOMICS cohort, a NIH funded multicenter dataset of patients with pulmonary hypertension, the MGB cohort, a dataset spanning the Massachusetts General Hospital/Brigham and Women’s Hospital and affiliated hospitals (MGB) and COPDGene, a data set of 10,000+ smokers. We additionally another NIH funded cohort, CARDIA, which is a longitudinal study in a general population to establish normative values in the overall population. All these data sets have already collected accompanying CT scans. In the first Aim we use data with accurate hemodynamic diagnosis of PH to find CT features that predict the presence of PH. In the second Aim, we find CT features that are predictive of significant precapillary remodeling and that are shared with group 1 PH, for which treatments targeting precapillary PH work well. In Aim 3, we use the baseline and follow-up CT scans from COPDGene, to study how these CT markers evolve over time in relationship to the patient’s health. This study leverages data from PVDOMICS, COPDGene and CARDIA, three highly curated NIH funded datasets, as well as clinical data from two large hospitals with advanced lung programs. The study team has 15+ years of experience in analyzing CT imaging of the lung incorporated into the Chest Imaging Platform, an NIH funded software package. The PI has developed specific expertise in both COPD and pulmonary hypertension which is his main clinical focus. The completion of this study will lead to insights in using CT scans for the noninvasive diagnosis and screening of pulmonary hypertension in nonsmokers and smokers, as well as a better understanding of the mechanism and clinical impact of PH in smokers.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY Breast cancer cases and deaths are rising rapidly in low- and middle-income countries (LMIC), including in sub-Saharan Africa, where most women with breast cancer are diagnosed with advanced-stage disease. Largely because of late-stage presentations, breast cancer survival in sub-Saharan Africa is poor. To address these global breast cancer inequities, the World Health Organization has emphasized the need for expanded access to breast cancer diagnostics in LMIC, and particularly calls for decentralizing diagnostic testing to primary- and secondary-level health facilities while maintaining care quality. Diagnostic breast ultrasound (U/S) is an evidence-based intervention that is essential in evaluation of palpable breast abnormalities, including for determining which lesions require biopsy. However, diagnostic breast U/S is typically only provided by radiologists, of whom there is a profound shortage in sub-Saharan Africa; further, radiologists are typically based at urban referral hospitals. This impedes access for low-income rural patients in particular, limiting quality, equity, timeliness and efficiency of breast evaluation and contributing to diagnostic inefficiencies and delays. To address this issue, Rwanda’s chief health implementation agency (Rwanda Biomedical Centre) has called for decentralized provision of breast U/S at district hospitals through task-shifting to non-radiologist clinicians. Supportive supervision is regarded as essential for successful task-shifting. However, scalable strategies for clinical supervision of non-radiologist clinicians to ensure sustained provision of high-quality decentralized breast ultrasound have not been investigated. Our preliminary work training a small group of non-radiologist clinicians in Rwanda suggests that virtual support through electronically shared images and asynchronous feedback is feasible and potentially beneficial after intensive training. However, supervision with real-time teleultrasound technology could be more effective in facilitating sustained ultrasound provision and quality in a broader population of district hospital clinicians receiving shortened in-person training. The objective of this research project is to compare 2 implementation strategies (teleultrasound supervision and asynchronous virtual feedback) to facilitate decentralized breast ultrasound at Rwandan district hospitals. In Aim 1 we will conduct a hybrid Type 2 implementation-effectiveness trial to compare the strategies’ impact on penetration of guideline-concordant diagnostic breast ultrasound (implementation effectiveness). In Aim 2 we will compare the strategies’ impact on trainee-performed breast U/S image quality (clinical effectiveness). In Aim 3 we will estimate the implementation strategies’ costs and cost-effectiveness in facilitating high-quality breast U/S, as well as exploring downstream cost offsets associated with decentralized breast U/S. This project will be embedded in Rwanda’s national Women’s Cancer Early Detection Program at government- funded health facilities. It will directly inform breast cancer diagnosis pathways in Rwanda and shape the workforce and credentialing processes for breast U/S. In addition, this project will contribute to global understanding of feasible, contextually appropriate and effective strategies to increase access to breast cancer diagnostic services through task-shifting in LMIC– a topic of major global interest in light of rapidly rising breast cancer incidence and mortality in LMIC. This project aligns with the National Cancer Institute’s special interest in implementation research related to cancer control in low- and middle-income countries and its commitment to pursuing equity in global cancer control.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY-ABSTRACT Nephrolithiasis, or kidney stone disease, affects over 10% of the U.S. adult population, leading to significant healthcare burdens. As the primary treatment, urologic endoscopy via ureteroscopy (URS) varies considerably in outcomes and complication rates among surgeons, revealing a critical opportunity for surgical care quality measurement and improvement. This project proposes the development and validation of an Artificial Intelligence (AI) Surgical Coach system designed to enhance surgical performance and patient outcomes during URS procedures. Utilizing machine learning (ML) algorithms to analyze video data and neuroergonomic metrics from the operating room (OR), we aim to create a model predictive of surgical efficiency and clinical outcomes. Specifically, this project will: A) Model real-life intraoperative URS performance through surgical videos unobtrusively captured in the OR, expecting that ML models will be predictive of surgical efficiency and patient outcomes. B) Conduct high-fidelity simulations to establish the construct validity of our ML models across various levels of surgical expertise. C) Develop and evaluate the usability of an explainable AI (xAI) interface within the AI Surgical Coach, providing automated personalized feedback for surgeons' skills enhancement. D) Evaluate the effectiveness of the AI Surgical Coach through a randomized controlled trial (RCT), measuring the impact on surgeons’ URS skills improvement and sustainment. Our multidisciplinary team brings together expertise from surgery, medical education, human factors, and computer science to execute this innovative research. The anticipated outcomes include an AI-powered surgical coaching system that objectively assesses and provides actionable feedback, improving surgical performance and patient care in urologic endoscopy. The project will set the stage for a future multicenter R01 clinical trial and align with the National Institute of Biomedical Imaging and Bioengineering (NIBIB) - Division of Discovery Science and Technology (DDST) program's interest in AI-based virtual coaching for performance improvement in medical procedures.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY / ABSTRACT Inherited cardiac arrhythmias are a significant and devastating cause of sudden cardiac death (SCD) both in the US and globally. One prominent example is Brugada syndrome (BrS), which is a significant cause of SCD in young patients, typically with structurally normal hearts. The first BrS-associated gene, SCN5A, which encodes the cardiac sodium channel NaV1.5, was reported in 1998 and since then several other ion channel genes and their interactors have been implicated. Despite these advances, only ~30% of BrS cases have a known variant in one of these genes, leaving the remaining ~70% genetically undiagnosed. Recently, our collaboration conducted the largest BrS genome-wide association study (GWAS) to date, which identified 9 novel genetic loci. At one locus, MAPRE2, which encodes the microtubule plus end-binding protein 2 (EB2), emerged as one of the top candidates based on bioinformatic analyses. My preliminary data using both a mapre2 null (KO) and N- terminus truncated mutant (ΔN-EB2) support the role of MAPRE2 as a novel gene contributing to BrS. Specifically, mapre2 loss-of-function leads to decreased NaV function both in the embryonic and adult ventricular myocytes, a hallmark of BrS, as well as general sarcomeric disarray and microtubule network disorganization. Furthermore, MAPRE2 may interact genetically with HEY2, a well-known cardiovascular developmental gene which has been strongly implicated in BrS. Finally, RNA-sequencing implicates the Wnt pathway in mapre2 loss- of-function and treatment with SB216763, a GSK3β inhibitor and activator of Wnt, rescues ECG abnormalities in adult mapre2 mutant fish. These and other evidence led me to hypothesize that MAPRE2 loss-of-function leads to trafficking and subcellular localization defects of NaV1.5 and associated proteins, and more generally disrupts the microtubule network and cytoskeleton, contributing to cardiac arrhythmogenesis. During the K99 phase, I will explore MAPRE2 as a novel gene contributing to BrS and define its pathogenesis, paying special attention to its unique 43 aa N-terminus which is absent in the other family members (EB1 and EB3). During the R00 phase, I will study HEY2’s gene-gene interaction with MAPRE2 and SCN5A in the context of BrS and NaV1.5 dysfunction. I will also define more broadly the role of EB2 and microtubule network in cardiac Wnt signaling and arrhythmogenesis including carrying out a phenotypic chemical screen using zebrafish embryos based on in vivo Wnt/β-catenin activity, explore GSK3β inhibition as a novel therapeutic avenue for BrS and related arrhythmias, and study genetic interaction between MAPRE2 with an established arrhythmogenic cardiomyopathy mutant. Together, this proposal will allow me to fulfill my short-term goal of gaining skills and expertise in cardiac genetics and zebrafish research, as well as build novel tools and genetic models during the K99 phase. This will enable me to pursue my long-term objective during the R00 phase and beyond: to define a paradigm shift in our understanding of inherited cardiac arrhythmias and discover novel therapeutics useful in treating BrS and related NaV arrhythmias.

NIH Research Projects · FY 2026 · 2025-04

Kaposi's sarcoma (KS) herpesvirus (KSHV) is the etiologic agent of KS and primary effusion lymphoma (PEL), and is tightly linked with multicentric Castleman's disease (MCD). These tumors are most common in immune suppressed individuals, especially those with AIDS. There are no specific therapies for KSHV malignancies. KS is a leading AIDS malignancy, and is epidemic in sub-Saharan Africa. KS often involves the oral cavity and can disseminate to visceral organs. Saliva is the KSHV vehicle of transmission. For unknown reasons, and in contrast to other herpesviruses, which are ubiquitous, KSHV epidemiology mirrors that of P. falciparum malaria and certain helminth infections. Accordingly, seroprevalence is high in sub-Saharan Africa (~80%) and much lower in western nations (~5%) that lack similar endemic infections. KSHV seroprevalence is also elevated (30-60%) in men who have sex with men. Latency is the hallmark of KSHV and gammaherpesvirus infection during which only several of its ~100 genes are expressed. KSHV latently infects cells, including tumor cells, and viral genomes persist as extrachromosomal, circularized, multi-copy, episomes. KSHV establishes lifelong infection, and persists in latently infected B cells. Paradoxically, however, in vitro infection of B cells is inefficient, and cells are short lived, suggesting absence of necessary factor(s). MCD infected cells exhibit B cell plasmablast characteristics, and PEL cells those of plasma cells, suggesting these diseases derive from aberrant development at different stages of B cell infection. B cells may differentiate to plasmablasts and long-lived plasma cells by proceeding through a germinal center reaction, in which they undergo somatic hypermutation, thus producing high affinity antibody. Alternatively, B cells may progress through an extra-follicular pathway to generate plasma cells. In this case, somatic hypermutation is typically absent, with low affinity antibody produced. MCD and KSHV (alone, without coinfecting EBV) PEL cells lack somatic hypermutation suggesting development from an extra-follicular pathway. We recently found KSHV infects mononuclear phagocytes (monocytes, macrophages) with high efficiency, and that these cells drive latently infected B cell differentiation to plasmablasts and then long lived plasma cells, thereby promoting long term KSHV B cell latency. Monocytes are elevated in malaria and in the helminth infections KSHV is associated with, suggesting increased phagocyte abundance in those parasitic diseases may underlie KSHV’s geographic disparity. These findings therefore demonstrate a key role for mononuclear phagocytes in B cell latency, providing a new paradigm for KSHV B cell latency establishment. Here, we use rigorous, detailed, in depth approaches to investigate the interactions occurring between KSHV, mononuclear phagocytes, and B cells that lead to long term KSHV B cell latency.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY South Africa bears the brunt of the global HIV epidemic, with over one-fifth of the 37 million people living with HIV within its borders. While we have seen tremendous success with the scale-up of effective treatment to over 20 million people, we are at a pivotal moment in the global HIV response, and South Africa lies at the center of the effort to reach the UN Sustainable Development Goal of ending HIV as a public health threat by 2030. A critical challenge in the care continuum in South Africa is the number of people living with HIV who are not virally suppressed. In 2022, over 30% were not on ART or had a detectable viral load. Individuals with gaps in care represent a substantial proportion of those who are not virally suppressed, and those who manage to return to care continue to face challenges. In the Western Cape Province, only 29% of those with prior gaps were virally suppressed one year after restarting treatment. Drivers of engagement behavior are heterogeneous, and include individual, social, and system factors that interact dynamically over years of treatment. Differentiated Service Delivery (DSD) models of person-centered care have been shown to effectively address these barriers to care, however, to date, DSD models have been offered only to people with HIV considered ‘stable’ (i.e., retained in care and virally suppressed). Thus, those at high risk of poor outcomes are ineligible for DSD models. In response, our team intends to work with the City of Cape Town and provide the critical data needed to impact policy guidelines. We designed CARES–Club-based Adherence support for Reinforcing Engagement and Sustaining Viral Suppression for South Africans with Gaps in HIV Care–to test a scalable, evidence-based DSD model (CARES-DSD) to address individual, social, and structural barriers to long-term engagement among people with HIV who have experienced an ART interruption or unsuppressed VL (PWH-Gaps). CARES-DSD is a six-month adherence club model of care that offers flexible services with multi-month dispensing of medication de-linked from clinic processes and support from lay counselors and peers, which has been proven to sustain retention and viral suppression in the Western Cape. We propose a Hybrid Type 1 trial to evaluate the effectiveness of CARES-DSD on viral suppression among PWH-Gaps at 24 months post-enrollment, as compared to an enhanced standard-of-care (an optimized guidelines-based approach). We will recruit 300 participants from our current study (SUSTAIN, R01MH125703, MPI: Orrell/Sabin), through which we have identified persistent engagement gaps in 43% of the participants despite adherence counseling, to test this model of care. We will then assess the mechanisms of intervention impact using mixed methods, guided by the Capability, Opportunity, and Motivation model of Behavior (COM-B), and determine the implementation outcomes using Proctor’s model. Ultimately, our goal is to provide an effective and efficient model of care to ensure people living with HIV achieve optimal health and well-being, and South Africa reaches the 2030 goals.

NIH Research Projects · FY 2026 · 2025-03

ABSTRACT Minimally invasive surgery (MIS) is favored for its benefits, such as reduced pain, shorter recovery times, and minimized scarring, with 7.5 million laparoscopies performed worldwide in 2015. Procedures like lung cancer surgery, tubal ligation, cholecystectomy, gastric bypass, myomectomy, and prostatectomy are predominantly conducted using MIS, a trend expected to grow by up to 15% in the next 5–10 years. However, adapting surgical tools for the confined environments of MIS remains challenging. Traditional retractors and stabilizers often cause tissue damage and can detach during procedures, and their bulkiness limits their effectiveness. Effective hemostasis in gastrointestinal (GI) surgeries using endoscopic methods is a critical unmet need, as current methods like mechanical clips, thermal coagulation, and injection therapies face challenges with precision, potential tissue damage, and risk of rebleeding. Tissue adhesives that can adhere to wet tissues in confined environments could provide effective wound closure and tissue retraction. Currently available tissue adhesives, such as fibrin sealants (e.g., Tisseel™), cyanoacrylate-based glues (e.g., Histoacryl™, Dermabond™, Omnex™), and protein/peptide-based glues (e.g., BioGlue™, TissuGlu™), have limitations such as limited adhesion strength, inability to reposition, and toxicity, making them less suitable for MIS. An ideal tissue adhesive for MIS should be easy to apply, rapidly adhere to wet tissue, repositionable, avoid reactive chemistry or ionizing radiation, withstand multiple extension/compression cycles, and be biocompatible and resorbable. This proposal aims to develop a novel PSB system for MIS. Pressure-sensitive adhesives (PSAs) form instant, reversible attachments through viscoelastic properties and have potential applications in MIS by enabling easy repositioning and removal of surgical equipment, minimizing tissue damage, and enhancing surgical adaptability. Despite their potential, available medical PSAs do not attach to wet internal organs because water on the wet tissues blocks the direct contact of the viscoelastic PSAs to the tissue. Our preliminary studies on a PSB based on poly(glycerol sebacate) (PGS) combined with poly(ethylene glycol) (PEG) show that it can adhere instantly to wet tissues like the heart and lungs, even in the presence of blood or body fluid. The PSB can be integrated with medical devices without specific surface chemistry limitations. Reversible adhesion provides atraumatic detachment and reattachment, reducing tissue damage and assisting surgeons with adaptable positioning during procedures. Aim 1. Fabricate PSB with tunable viscoelastic properties and adhesive properties to different types of tissues. Aim 2. Explore the PBS's performance for minimally invasive applications. Aim 3. Evaluate the feasibility of PSB for translational MIS scenarios – hemostatic adhesive and tissue stabilization during endoscopic procedures.