Massachusetts General Hospital

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Drug overdose accounts for approximately one-fifth of all pregnancy-associated deaths (the majority involving opioids) and drug-related foster care placements for infants have quadrupled over the past decade. Pregnant and parenting women with opioid use disorder (OUD) too often experience shame and stigma; punitive responses to prenatal substance use drive pregnant women away from care, creating major obstacles to receiving life-saving medications and engaging in treatment. To address the growing number of infants affected by prenatal substance exposure, the federal reauthorization of the Child Abuse Prevention and Treatment Act (CAPTA) requires a “Plan of Safe Care” (POSC) for parent-infant dyads affected by prenatal substance use at delivery. However, state implementation efforts have been varied, and few states have fully addressed all CAPTA requirements. Current approaches to meeting the POSC requirement, which rely on a static document created at delivery, do not provide adequate support for families struggling with custody issues and substance-related stigmas. The proposed study aims to adapt and evaluate the Family Care Planning (FCP) intervention, which implements longitudinal, transdisciplinary, and family-centered teleconference meetings to bring mothers together with their clinical, community, and child welfare teams to engage in facilitated, respectful treatment planning discussions. In the R61 Phase, we will refine and standardize protocols for the FCP approach using participatory co-design principles, incorporating input from early clinical adopters, mothers, community supports, and child welfare workers (Aim 1). We will also pilot test the FCP intervention to assess feasibility, fidelity, and acceptability (Aim 2). In the R33 Phase, we will conduct a stepped-wedge cluster randomized control clinical trial using a Hybrid Type 1 Effectiveness – Implementation study design with 312 parent-infant dyads. This phase will evaluate the effectiveness of FCP, implemented longitudinally over six months in the postpartum period, to increase maternal OUD treatment engagement and rates of family preservation. Additionally, we will explore the extent to which FCP improves substance use recovery, postpartum overdose rates, maternal self-efficacy, maternal mental health, and well-child care adherence. We will also explore measures of interpersonal (participants) and interagency (clinical-child welfare) trust. Finally, we will use the RE-AIM implementation framework and mixed methods to assess the extent to which FCP implementation is associated with effectiveness outcomes (Aim 4). Findings from this study are expected to have significant implications for addressing the effects of maternal substance use in the postpartum year.

NIH Research Projects · FY 2026 · 2026-05

Project Summary MITF, particularly the melanocyte-restricted m-MITF isoform, is a key transcription factor that regulates melanocyte differentiation, survival, and pigmentation. Its expression is dynamically regulated by the MC1R receptor through the PKA signaling pathway. For decades, it was thought that CREB1 was the PKA-controlled transcription factor that drove m-MITF transcription. However, I have discovered that a non-canonical mechanism activates m-MITF independent of CREB1 and its redundant paralogs. This mechanism requires the transcriptional co-activator CRTC, which must be recruited to m-MITF promoter DNA through an unknown factor. We propose here to define this non-canonical mechanism, discover its unknown regulators, and characterize the precise molecular interactions required for m-MITF transcriptional activation. Specifically, we will 1) generate a toolkit of mutant cell lines designed to perturb select events in PKA signaling and dissect the differences between non-canonical and canonical regulation, 2) perform functional genomic screens to unveil new regulators of m- MITF using cellular proliferation and transcriptional reporter readouts, and 3) investigate physical interactions between identified regulators and the m-MITF promoter to develop a molecular model for the non-canonical mechanism. As a feature of each of these aims, we will apply our findings to genetically modified, iPSC-derived primary melanocytes and organotypic skin reconstitutions to address this mechanism's role in physiological tissue pigmentation. This work will deepen our understanding of the molecular biology of pigmentation and give insight into PKA signaling in other specialized cell types. It will lay the foundation for molecular approaches to manipulate m-MITF in a melanocyte-specific manner for the chemoprevention and treatment of numerous sun- and pigmentation-related conditions, including skin cancer and aging.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY CLN3 disease is a rare lysosomal disease affecting approximately 1 in 100,000 live born children. It is caused by recessive mutations in the CLN3 gene, which encodes a transmembrane protein that primarily localizes to the lysosome. Affected children suffer from progressive blindness, seizures, psychosis, and cognitive and motor failure, and the disease is invariably fatal. CLN3 is implicated in various cellular processes including endolysosomal trafficking and lipid metabolism, but the primary function remains incompletely resolved. Interestingly, immune system changes have been described in CLN3 patients and animal models including early neuroinflammation in brain regions that later see the first neuronal cell dropout, suggesting the neuroimmune system plays a role in the neurodegenerative disease process. In a proteomics study of CLN3- deficient microglia, we recently discovered a dramatic elevation in the levels of the Tweety homolog protein, TTYH3, which was over 10-fold elevated in microglia isolated from presymptomatic mice, and over 20-fold elevated in microglia from symptomatic mice, suggesting TTYH3 elevation is a relatively early disease event and that it progresses with disease severity. Indeed, we also identified TTYH3 elevation in a neuronal progenitor cell model of CLN3 disease, indicating TTYH3 levels increase in response to loss of CLN3 function in both neurons and microglia. In this proposal, which is responsive to the NOFO for research projects of understudied proteins linked to rare disease (NOFO PAR-25-122), we aim to develop important tools to study the TTYH3 protein in the context of CLN3 disease. We hypothesize that TTYH3 is a novel lysosomal lipid transporter, and we will test this hypothesis by studying TTYH3 subcellular localization and by establishing Ttyh3/TTYH3 knockout mouse and human induced pluripotent stem (iPS) cell-based models that will be phenotyped to evaluate lysosomal function. Finally, we will evaluate whether modulation of TTYH3 impacts CLN3 disease pathophysiology, setting the stage for future work to fully uncover TTYH3 function and whether targeting TTYH3 in CLN3 disease holds therapeutic promise.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The lack of non-invasive, real-time assessments of circadian rhythm metrics hinders the translation of circadian rhythm knowledge into clinical practice. Circadian rhythms are internal physiological processes that cycle every ~24 hours. Light is the most potent stimulus for circadian rhythm entrainment to environmental time. Misalignment of the circadian system with environmental time increases the risk of both chronic diseases (e.g., cardiovascular disease, obesity) and acute mental and physical health impairments, underscoring the need for accessible clinical assessment tools. The mechanisms underlying individual variability in circadian (mis)alignment are unclear; one potential mechanism would involve variations in how light is processed in the eye. This project will test the hypothesis that differences in multiple metrics of pupillary response to light stimuli will correlate with differences in circadian metrics – and be a potential biomarker for individual differences. Wavelength, duration, and intensity of light differentially affect the response of retinal image-forming (e.g., rods, cones) cells and non-image-forming (NIF) intrinsically photosensitive retinal ganglion cells (ipRGCs) that contain melanopsin. The NIF pathway is crucial for circadian entrainment to environmental time and impacts the pupillary light reflex, melatonin concentrations, and other physiology. Variations in the post-illumination pupillary response (PIPR), an ipRGC- linked response, have been linked to neurological conditions, including circadian rhythm sleep-wake disorders (CRSWD), suggesting that pupillary response could be used as a potential non-invasive close-to-real-time diagnostic and monitoring tool. Relationships between pupil responses during and after light stimuli and circadian timing metrics should be established. Our specific aims are to quantify (i) different metrics of pupil response during and after light stimuli of various intensities, wavelengths, and durations (ii) and their relationships with dim-light melatonin onset (DLMO, the current gold standard measurement for circadian phase) (Aim 1) and in individuals with two intrinsic circadian sleep-wake phase disorders (CSWPD) with altered sleep timing (Aim 2). An outpatient week of monitoring of sleep timing will be immediately followed by the inpatient protocol for both participant groups (Aim 1, healthy controls, leveraging a funded R01 experiment; Aim 2: Individuals with CRSWD funded with the F32 funds). The inpatient protocol will consist of multiple pupillometry sessions and an evening saliva collection for DLMO. During pupillometry, participants will be exposed to wavelengths of light designed to target the ipRGC cells (blue light) or not (red light) with a matched number of photons of different intensities and durations. This F32 award will incorporate training in the measurement and analysis of physiological measures, circadian rhythms, and photobiology, phenotyping of people with CSWPD, advanced statistical training, grant and manuscript writing, scientific communication, and lab management. Establishing a strong foundation in these areas will facilitate Dr. McCullar’s transition to an independent scientist uniquely poised to establish outpatient testing that provides non-invasive close-to-real- time assessments of circadian metrics that can be used to evaluate and monitor individuals with circadian (or other NIF- linked) pathologies, as well as tools to help facilitate the integration of circadian system monitoring into clinical practice.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Senescence and aging are associated with cytosolic DNA responses that drive chronic inflammation in the absence of infection. Chronic inflammation is associated with the infiltration of immune cells, disrupted cellular activities, an altered tissue microenvironment, and ultimately promotes many age-associated pathologies. Understanding and targeting senescence and aging-associated inflammation is a major biomedical objective. Our group has contributed to the understanding of chronic inflammation by showing that the cytosolic DNA sensing cGAS-STING pathway is involved. In senescent cells and aged mouse tissues, chromatin fragments undergo nucleus-to-cytoplasm trafficking, forming cytoplasmic chromatin fragments (CCF). CCF activate cGAS and eventually the senescence-associated secretory phenotype (SASP). These results have been independently reproduced by other groups and collectively, the CCF-cGAS-STING pathway is considered one of the central mechanisms contributing to chronic inflammation in senescence and aging. The genetic identity of CCF remains a major unaddressed question. We do not know from which chromatin regions CCF are derived and whether the formation of CCF is associated with the loss of genes, and if so, any actively transcribed genes. Unraveling the genetic identity of CCF is key to our understanding of the genetic alterations in senescence and aging as well as the origins of chronic inflammation. In this study, we propose to use cytosolic cGAS to pull down CCF followed by unbiased sequencing. Our preliminary results show that cGAS-bound CCF in senescent cells are comprised of specific chromatin regions enriched in tri-methylation of lysine 27 on histone H3 protein (H3K27me3), a heterochromatic mark associated with gene repression. Furthermore, we found that the H3K27me3 chromatin reader protein, CBX8, and not other H3K27me3 readers, is required for CCF formation. This application will examine a central hypothesis that CCF are derived from specific, rather than random, chromatin regions. We will test the specific hypothesis that the H3K27me3-CBX8 pathway mediates CCF formation, and reason that targeting CBX8 holds promise in blunting senescence and aging-associated inflammation. In Aim 1, we will test the role of the H3K27me3-CBX8 pathway in promoting CCF formation and the SASP in senescence of primary cells in vitro. In Aim 2, we will examine the role of CBX8 in promoting CCF and the SASP in vivo, employing oncogene-induced senescence in mouse liver as a model. In Aim 3, we will test this pathway in naturally aged mice, studying CBX8-mediated CCF formation and inflammaging. If the major goals are met, this study will offer novel mechanistic insights into CCF, a key event that promotes the SASP and inflammaging. The revealed chromatin mechanisms of CCF will also pave the way for future studies on the deeper biology of CCF. In addition, the study will reveal new therapeutic targets to block CCF, guiding the targeted design of therapies to address inflammaging and promote healthy aging.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Tobacco use disorder (TUD) remains highly prevalent in people with serious mental illnesses (SMI), driving a significant mortality disparity in this population. First-line pharmacotherapies for TUD combined with behavioral support significantly increase tobacco abstinence rates in adults with SMI, yet are underutilized. Community health workers (CHWs) are lay health workers trained to provide health information and services, with a strong evidence base for improving uptake of health services in underserved communities. We showed CHW support from TTS trained lay staff with provider education on TUD treatment doubled tobacco abstinence rates in those with SMI through tripling TUD treatment uptake and impacting social determinants of health. Here we seek to test the effectiveness of CHW support, delivered by existing, trained, Medicaid-funded community behavioral health staff, for smoking cessation in adults with a SMI served by a Medicaid accountable care organization (ACO). Medicaid is the single largest payor of mental health services in the US. CHW deployment within Medicaid funded care structures to date has been generally limited to special waiver programs. Widespread adoption of Medicaid ACOs provides an opportunity to test whether existing behavioral care team members, with brief training, can function as CHWs, and whether such an innovation improves TUD, cardiovascular, and mental health outcomes. To do so, 937 adults with SMI and TUD, receiving behavioral healthcare through Medicaid ACOs in a large human services agency, will be enrolled and randomly assigned to receive behavioral health team support from their Intensive Case Manager (ICM) who has received brief CHW and TTS training or continue to receive usual ICM support (Enhanced usual care, EUC). All care team clinicians will be offered education on first-line, evidence-based TUD treatment in SMI. Our aim is to determine whether CHW support integrated into behavioral health care improves tobacco abstinence and cardiovascular risk in those with SMI and TUD when delivered by ICM staff within existing Medicaid ACOs, with the hypothesis that those assigned to Integrated CHW support will have higher rates of biochemically verified 7-day point prevalence combusted tobacco abstinence at 2 years than those assigned to EUC, the primary outcome, greater reduction in cardiovascular risk estimates at 2 years, greater improvement in psychiatric symptom severity, stress, and loneliness over two years, greater engagement with care, healthcare satisfaction ratings, and reduction in emergency department visits and inpatient hospitalization days in year 2 of the intervention than those assigned to EUC. Implementation of the Integrated CHW support intervention into existing Medicaid ACO behavioral care teams will be evaluated using quantitative data and qualitative stakeholder interviews. If effective, this intervention has the potential to be widely disseminated in existing, Medicaid funded systems of care and to be transformative in overcoming adverse SDoH to improve delivery of first-line, evidence-based medical care, reducing the enormous mortality disparity faced by people with SMI.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT: Despite rising rates of opioid use disorder (OUD) among US adolescents and young adults (“youth”), most do not receive timely, evidence-based, high-quality care. There is a crucial need to establish valid and reliable measures that can be used by clinicians, health systems, and policymakers to ensure youth and families receive effective treatment. This K24 Midcareer Investigator Award in Patient-Oriented Research will provide critical support for the PI, Dr. Scott Hadland, to augment his mentorship of early-career clinician-investigators to lead clinical research on youth substance use. In parallel, the PI will expand his research program to the development of new quality measures for youth OUD treatment, and pursue training to further develop his own skills. Novel research supported by this K24 aims to (a) Identify candidate measures through semi-structured interviews with youth, family members, and clinicians; (b) Conduct a modified Delphi process with a national panel of stakeholders to assess the importance, feasibility, and usability of candidate measures; and (c) Evaluate the reliability and validity of candidate measures using national Medicaid insurance claims data and clinical data from a large regional healthcare system. In parallel, the PI will advance his expertise through training in stakeholder-engaged research, Delphi methods, and measurement science to support his own career development. Throughout the K24 award, the PI will expand his mentorship infrastructure and offer enriched, individualized support to junior investigators engaged in patient-oriented research, ultimately supporting the next generation of physician-scientists committed to improving care for youth and families. Together, these K24-supported efforts will lay a strong foundation to optimize how care for youth with OUD is measured, reported, and improved nationwide.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY AND ABSTRACT Existing AI struggles to combine multiple data types for disease prediction. This project proposes a novel deep learning method that tackles this by fusing three data sources (clinical notes, lab results, images) compared to current two-source methods. The model will learn the importance of each data type and capture complex relationships for improved diagnoses. The project focuses on analyzing data at one time point for better diagnoses, over time to understand disease progression, and across a population to identify subgroups. By achieving these goals, the project aims to significantly improve disease prediction accuracy, paving the way for personalized medicine. By achieving these goals, the project aims to significantly improve disease prediction accuracy. This paves the way for a future of personalized medicine with more effective diagnoses and targeted interventions. The project boasts several innovative techniques: A deep learning model with an attention mechanism that learns the relative importance of each data source for improved diagnoses, unlike current methods that simply combine data. A recurrent neural network (RNN) based approach specifically designed to analyze longitudinal data while fusing different modalities. This allows the model to capture the temporal relationships between data points, providing a more comprehensive understanding of disease progression. A graph deep learning technique for population-level analysis to discover potential disease subtypes. This approach represents patients as nodes in a graph, connected based on similarities in their multi-modal data. By analyzing these connections, the project aims to identify subgroups of patients with similar disease presentations, potentially leading to the development of more targeted treatment strategies. Since the applicant has a computational background, the proposed training program at Harvard, MIT and MGH will focus on multi-modal data understanding and analysis, imaging physics and psychosis during the K99 phase to develop the skills needed to transition to independence in the R00 phase. The applicant aims to become an expert in multi-modal data analysis for psychosis and push the limits of what is currently possible in biomedical research within the artificial intelligence domain, fundamentally enhancing the quality of healthcare. We believe that the proposed project is a first step in this direction and the tools developed will further pave the way for biomedical data analysis in general. This project aligns perfectly with the National Institute of Biomedical Imaging and Bioengineering's (NIBIB) mission by developing and applying cutting-edge computational tools (AI for multi- modal fusion and graph-based analysis) for analyzing biomedical data, making it a strong candidate for the K99 Award.

NIH Research Projects · FY 2026 · 2026-05

Abstract Novel multi-dimensional assessments of brain function using non-invasive electroencephalographic (EEG) signals are promising approaches for close-to-real time monitoring of the brain and other physiology. Multiple research and clinical groups have published findings using machine learning (ML) and other techniques applied to EEG signals during sleep from different healthy and clinical populations; sometimes they also correlate these results with health outcomes. Two criticisms of this work hinder the interpretation of results and the eventual application of these methods. (i) Fundamental information is missing about the night-to-night variability in EEG signals (“state”) and their dependence on modifiable behaviors (e.g., sleep loss, caffeine or other drug intake) and (ii) basic information about “normal” physiology is unknown, including the importance of “trait” (e.g., age). Such information is needed to reduce the probabilities of false positive and/or false negative conclusions at the group or individual level. In this project, we will use data already collected under highly controlled inpatient conditions in well-phenotyped individuals from multiple 2-5 week protocols conducted in the same facility with the same standardized procedures to quantify changes in the sleep EEG. The protocols include those with extended, control (i.e., 8hr)/recommended, or chronic sleep restriction durations; sleeping at night or not (e.g., such as happens with shiftwork); and/or caffeine or modafinil (stimulant) or melatonin (hypnotic) administration. During these protocols, all sleep episodes were recorded, multiple objective performance and subjective mood/alertness tests were conducted per wake episode, and a questionnaire was administered at awakening queried about self-assessed sleep quality. We will therefore be able to quantify trait vs state (including night-to-night variability) characteristics of the brain EEG in individuals and their relationships to objective and subjective metrics. Specifically, we will extend Dr. Sun’s (Co-I) work using micro- and macro-structural features of the EEG during sleep that he already applied to compute a “Brain Age Index” (BAI). The BAI correlates with the risk of disease and cognitive function. The BAI, however, was developed using single nights of sleep from a not-well phenotyped population. Our proposed work - SERIFA (Sleep EEG bRaIn Function Assessment) – will produce a Sleep Microstructure Index (SMI) with components of the EEG related to trait vs state using the data described above. The results of this project will provide information about the interpretation of results of other studies and also form the basis for additional work. Variability metrics calculated by this work will enable power calculations for future prospective clinical studies relating changes in SERIFA’s SMI to waketime exposures/interventions at individual and group levels. Data and tools (including the SERIFA software) will be made accessible on the National Sleep Research Resource, an NIH-supported website, this means that SERIFA SMI results can be available within minutes after the sleep EEG is complete for clinicians and researchers.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY / ABSTRACT Increased arterial stiffness is a risk factor for heart failure with preserved ejection fraction (HFpEF), a disease that accounts for half of all heart failure, is twice in common in females, and once established has limited therapeutic options. Identifying individuals at risk for HFpEF before its development is therefore crucial. Arterial stiffening accelerates around menopause, which may represent an optimal time for intervention. While arterial stiffness is not commonly measured, exercise systolic blood pressure (SBP) may provide an opportunity to evaluate arterial stiffness and is assessed on every clinical exercise test. An exaggerated rise in peak exercise SBP above established cut-points is common (10-15%), but its presence does not drive clinical decisions due to conflicting data on its predictive ability for cardiovascular outcomes. This reflects fact that while exaggerated rise in peak SBP may be due to higher arterial stiffness, conversely it may also be a sign of health and reflect robust augmentation in oxygen consumption (VO2) during exercise. As the implications of an exaggerated rise in peak exercise SBP are unclear, our group and others have begun to examine how indexing peak exercise SBP to VO2 may better reflect vascular health. While it is well- established that females have lower exercise SBPs, we and others have shown that indexing change in SBP (peak-rest) to change in VO2 (peak-rest) unmasks higher SBP/VO2 in females versus males. No prior work has defined whether SBP/VO2, like arterial stiffness, accelerates around menopause and is associated with changes in cardiac structure and function that predispose to HFpEF. Because exercise SBP is collected on every exercise test but is not used in management, our goal is to define whether SBP/VO2 identifies those with high vascular stiffness at risk for HFpEF. To address this goal, we will combine 1) analysis of a large cardiopulmonary exercise test (CPET) registry (FRIEND) and 2) a prospective study using novel exercise cardiac magnetic resonance (CMR) techniques. In Aim #1, we hypothesize that indexing SBP to VO2 will unmask higher values in females than in males that will further diverge with age, specifically infecting upward at peri-menopause. We will establish how indexed SBP varies based on sex & age in FRIEND (n=10,000) and, in our prospective study (n=150) we will define how SBP/VO2 is impacted by reproductive vs. chronologic age, including longitudinal follow-up in females. In Aim #2, we hypothesize that in females more so than males, higher SBP/VO2, as assessed in our prospective cohort, will be associated with increased arterial stiffness, unfavorable CMR parameters, and biomarker profiles that are known to predict incident hypertension and HFpEF. We also hypothesize that higher SBP/VO2 will be associated with adverse cardiovascular outcomes as assessed in a cohort of heart failure patients in FRIEND (n=4,000). We anticipate that this work will facilitate use of SBP / VO2 to target future interventions to improve the disproportionate impact of HFpEF on females.

NIH Research Projects · FY 2026 · 2026-05

Project Summary / Abstract Evidence from trials has established that 4 separate classes of guideline-directed medical therapies (GDMT) for heart failure with reduced ejection fraction (HFrEF) together reduce mortality by nearly two-thirds. Conversely, for heart failure with mildly reduced ejection fraction (HFmrEF), dedicated trials are infeasible due to cost and statistical power, and thus there is weaker evidence, resulting in ambiguous guidelines. A recently funded R56 has allowed us to assemble our team and start building the largest echocardiography registry in the world. Our long-term goal is to generate comparative effectiveness evidence for questions in heart failure where trials are infeasible. The overall objectives in this application are to complete the registry, test mathematical assumptions required for strong causal inference methods, and then apply the strongest methods possible to answer a key clinical question: which GDMT are associated with reduced mortality in HFmrEF? The central hypothesis is that “real-world” treatment decisions will differ at guideline-suggested thresholds of left ventricular ejection fraction (LVEF), and patients on either side of those immediate LVEF thresholds will be otherwise similar (“as good as random”), allowing the application of regression discontinuity (RD) methods to measure treatment effects. We believe these methods will demonstrate reduced mortality with GDMT. The rationale for this proposal is that (1) LVEF cutoffs in guidelines are semi-arbitrary in the sense that LVEF is a physiological continuum despite abrupt threshold guideline cutoffs, and (2) our preliminary data demonstrates expected discontinuities in treatment frequency at influential LVEF thresholds for other HF therapies (defibrillators). As such, the conditions for “as good as random” likely exist in small ranges around relevant LVEF thresholds, allowing the application of RD. Our central hypothesis will be tested with 2 specific aims. In Aim #1, we will develop and refine natural language processing tools to extract data from echocardiography reports from 11 hospitals completing the largest echocardiography registry in the world, and adjudicate both clinical information and echocardiographic images. We will validate the data extraction methods in another hospital system (New York University). We will then systematically test mathematical assumptions required for RD. In Aim #2, we will create estimates of each of the effects of each GDMT medication class on mortality in HFmrEF with RD and propensity score (PS) methods. The feasibility of PS methods does not depend on the Aim 1 analyses, so at least 1 of the 2 methods will be feasible. We therefore expect that these results will upgrade evidence from the current class 2b (“usefulness is unknown”) in heart failure guidelines for 3 of the 4 GDMT medication classes to class 2a. The proposed research is innovative because it combines strong causal inference methods to observational data with the adjudication standards of trials to answer questions trials cannot resolve. The research proposed here is significant because it will upgrade the ambiguous treatment guidelines for HFmrEF and reduce mortality for this growing population.

NIH Research Projects · FY 2026 · 2026-05

Project Summary- Abstract Adolescent and emerging adult (youth) substance use disorders present a major public health problem in the United States and result in a variety of negative consequences when left unresolved, including early mortality. Despite these harms, there is a lack of strong prevention programming, a shortage of developmentally- appropriate and accessible treatment for youth, and inadequate community supports and recovery programming. We need collaborative urgency, action, and innovation across disciplines and key stakeholders to address the current substance use crisis in our nation. This proposal seeks funding to support our annual Joint Meeting on Youth Prevention, Treatment, and Recovery (JMYPTR). JMYPTR serves as a platform for all key stakeholders including, researchers, trainees, practitioners, policymakers, and youth and their families. JMYPTR provides a forum to gather, learn, and share information about evidence-based and innovative practices and research for the prevention of substance use as well as to address questions related to enhancing treatment and recovery support services’ attractiveness and effectiveness for youth affected by substances. Through JMYPTR we seek to closely connect research, clinical interventions, and policy at the state, regional, and national levels by bringing all these key stakeholders together in one meeting. Despite the relatively recent launch of JMYPTR in 2024, there is a strong history behind the meeting as it builds on the foundation of the Joint Meeting on Adolescent Treatment Effectiveness (JMATE), which ran from 2005-2012. Our National Center on Youth Prevention, Treatment and Recovery (NCYPTR) at the Massachusetts General Hospital Recovery Research Institute, in collaboration with numerous federal, state, and national organization partners, has revamped efforts to address the public health imperative of confronting youth AOD use by hosting the annual JMYPTR. Our 2026 JMYPTR and our plans for future conference years aligns with the NIDA priorities outlined in the 2022-2026 Strategic Plan by focusing on several key aspects of research and practice. JMYPTR’s emphasis on advancing the training of the next generation of scientists as a cross-cutting NIDA priority is also at the forefront of our planning. This is represented in this R13 request for travel awards to support early career scholars, including high school students. We anticipate that the new networks and sharing of information built through this conference will help stimulate and produce a new generation of enthusiastic youth-focused substance use investigators and lead to significant and innovative research proposals in the years to come.

NIH Research Projects · FY 2026 · 2026-05

Project Summary / Abstract Developing statistical frameworks for understanding how genetic effects vary across phenotypes and over time remains a critical challenge in genomics. While advances in electronic health records and genomics have provided unprecedented data, existing models fail to capture individual-level dynamics and miss critical gene- environment interactions. In her previously published work, Dr. Urbut developed MSGene for modeling time-varying genetic effects on cardiovascular risk, demonstrating that genomic influences can vary substantially across life stages. She extended this work through Aladyn, a dynamic topic modeling framework applied to over 400,000 individuals in the UK Biobank, which established the computational feasibility of large-scale Bayesian inference across heterogeneous disease types. Building on these successes, her preliminary work for the current project with a novel survival-based framework has identified 20 unique disease signatures, capturing previously unrecognized patterns of disease progression and enabling both genomic discovery and individualized prediction. These results demonstrate the feasibility of Bayesian hierarchical models for understanding diverse phenotypes across the life course. First, Dr. Urbut proposes to develop and validate a novel Bayesian multivariate model integrating time-varying genetic and clinical factors across over 300 diagnostic phenotypes. This model has the dual objective of both identification of latent signatures for genomic discovery and producing calibrated estimates for prediction. Second, she will investigate how genetic factors influence disease trajectory timing through a novel "genetic warping" framework. Third, she will leverage identified disease trajectories to optimize therapeutic strategies by analyzing treatment response variability across patient subgroups. This work will take place in the Division of Cardiology at Massachusetts General Hospital. Dr. Urbut will perform this research under the mentorship of Dr. Pradeep Natarajan, Director of Preventive Cardiology and Associate Professor of Medicine, and Professor Giovanni Parmigiani, an expert in Bayesian methodology at the Harvard T.H. Chan School of Public Health and Dana Farber Cancer Institute. Dr. Urbut's goal is to become an independent investigator developing novel statistical methods to understand complex disease evolution and improve therapeutic targeting. She aims to use this K08 research as a foundation for future R01 applications in computational approaches to precision medicine.

NIH Research Projects · FY 2026 · 2026-05

This proposal requests NIH funding for the procurement of a VisualSonics Vevo F2 LAZR X20 Multi-Modal Imaging system. The Vevo F2 LAZR X20 is a highly versatile imaging system specifically designed for non- invasive pre-clinical small animal research. This newer generation ultrasound/photoacoustic imager will replace the old generation Vevo 2100 LAZR system that has been phased out by Fujifilm VisualSonics. The new equipment will enable high resolution longitudinal investigation of anatomical and functional changes associated with disease progression and enable monitoring of therapeutic responses in a non-invasive manner. The instrument will support 8 major users, 5 minor users and 4 early-career investigators at the Massachusetts General Hospital’s Wellman Center for Photomedicine (Dermatology and Pathology), Neurosurgery, Cardiovascular Research Center (Medicine), and Athinoula A. Martinos Center for Biomedical Imaging. The diverse research applications of these researchers are focused on using imaging technology to understand the pathophysiology of an array of high impact diseases such as cancer, cardiovascular disease, abnormal brain function, neurological pathologies/injury, and antibiotic-resistant infections. Collectively, these scientists have experience using the most sophisticated optical imaging technologies currently available to biomedical research, each of which has its own intrinsic strengths and weaknesses. An internal advisory committee formed will ensure smooth operations, training, maintenance, compliance and resolve user time conflicts. A strong institutional and departmental support will ensure maintenance, support for core staff and other technical staff and a provision for training new research staff. There is no accessible photoacoustic system available to us where animals can be easily transported for any of the above applications. There are just two existing US/PAI systems in the Boston area – Vevo 3100 LAZR- X. However, the sales of this model has been discontinued by the vendor with official support ending in 2027, further limiting their ability to sustain or expand access for new users. This will be the first Vevo F2 LAZR X20 system in Boston. A few unique features of the new Vevo F2 LAZR X20 system are listed below: • An increased wavelength range (660-1320 nm) with increased laser power enabling photoacoustic imaging for treatment planning and monitoring at a depth not obtainable with other optical imaging technologies • Capability to customize configuration (waveforms and pulse sequences) for acoustic engineering • Real-time display of co-registered physiological and anatomical information of target tissues • Capability to perform 4D and whole-body imaging • Measure tissue oxygenation and hemodynamics • Monitoring physiological and anatomical changes in high resolution

NIH Research Projects · FY 2026 · 2026-05

Abstract Pathogenic missense variants in the ACTA2 gene at arginine 179 (most commonly replacement by histidine) cause a severe Ultra-Rare syndrome termed Multisystem smooth muscle dysfunction syndrome (MSMDS) characterized by systemic smooth muscle cell (SMC) dysfunction causing hypotension, aortic aneurysms and devastating cerebrovascular disease that leads to neurodegeneration and death in the first 3 decades of life. The recurrent nature of the mutation and the severity of the disorder make MSMDS a candidate for genomic editing approaches. In this proposal we present proof of concept data in animal models of a novel gene therapeutic approach to treat MSMDS involving a novel CRISPR/Cas9-directed Adenine Base Editor (ABE) to correct the most common mutation (ACTA2 c.536G>A, p.R179H). The ABE is delivered to the vasculature by a novel AAV vascular-targeting capsid named AAV-PR. We noted complete rescue of multiple clinical phenotypes in a mouse model of MSMDS accompanied by efficient levels of correction of the mutation. In this proposal we propose IND-enabling studies including: GLP and GMP drug product (DP) production, completion of POC studies, murine and NHP toxicity studies, as well as clinical and regulatory development activities. We provide a comprehensive plan to enable an IND application for a novel genomic editing gene therapeutic by the end of the proposal period.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY In this K23 proposal I detail a 5-year training plan that will launch my career as an independent investigator focused on developing and testing effective mind-body interventions to bolster pain coping and reduce pain catastrophizing among patients with chronic pain in the ED and other acute care settings. I propose an innovative and clinically meaningful research and training plan that is tied to my career development goals. Background: Chronic pain (i.e., pain that persists for >3 months) is highly prevalent, engenders a significant economic burden, and is challenging to treat. Chronic musculoskeletal pain (CMP) is among the most common reasons individuals seek medical care, and is a primary reason for Emergency Department (ED) visits. EDs are not well-suited to address the complex needs of patients with CMP, and current treatment approaches for CMP in the ED fail to address factors that motivate patients to seek emergency care for their pain. Interventions addressing the cognitive (e.g., catastrophizing), emotional (e.g., worry), and behavioral (e.g., repeated ED usage) aspects of CMP may be vital to reducing the burden of CMP in the ED. Specific aims: The goals of the current proposal are to develop, refine, and establish the feasibility of a novel mind-body intervention, Toolkit for Optimal Pain Management in the ED (TOPMED), aimed at decreasing pain catastrophizing and pain anxiety among patients with CMP who seek care in the ED. My aims are three-fold: 1) Adapt established Toolkit for Optimal Recovery mind-body skills to address CMP in the ED using qualitative interviews with patients with CMP seeking pain care in the ED (N=~20) and individual interviews with ED medical stakeholders (N=20); 2) refine TOPMED through an open pilot (N=10) with exit interviews (for feedback) and pre-post assessments (for initial feasibility and acceptability); 3) test TOPMED for feasibility and acceptability (N=50) through a pilot randomized clinical trial (RCT) of TOPMED compared to a minimally enhanced usual care control. Training: My research aims are supported by three training goals: 1) advanced qualitative methods for mind-body intervention development; 2) mixed methods approaches and intervention and protocol refinement (integrating exit interview qualitative data with pre-post assessment quantitative data); 3) conduct of RCTs within the ED. My multidisciplinary mentorship team is led by Dr. Ana-Maria Vranceanu, a clinical health psychologist and expert in developing and refining mind-body interventions for pain, and Drs. Jeffery Dusek and Christine Sieberg, clinical psychologists and experts in integrative health clinical trials and pain measurement and outcomes research, respectively. My training goals are supported by 1) committed, multidisciplinary mentors, 2) a rich institutional environment at Massachusetts General Hospital and Harvard Medical School (MGH/HMS), and 3) targeted coursework, seminars and workshops, scientific meetings, and experiential learning. My proposal is in line with the NCCIH priority of “Whole Person Health” approaches. Impact: I am a T32 postdoctoral fellow at MGH/HMS. The research and training activities proposed for this K23 will support my transition to an independent investigator role. The results of the proposed project will inform a future multisite feasibility R01 trial. TOPMED has the potential to be a feasible and effective solution to the management of chronic pain patients in ED settings, with important implications for patients, providers, and the larger healthcare system.

NIH Research Projects · FY 2026 · 2026-04

Efficient clearance of amyloid-β (Aβ) peptides is crucial for maintaining cognitive health and preventing Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) dynamics are vital for removing Aβ from the brain's interstitial spaces. Understanding how CSF flow and exchange influence Aβ clearance is essential for elucidating AD mechanisms and developing effective therapies. The emerging glymphatic theory suggests that the protein exchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) at the perivascular spaces (PVS) could play a critical role in Aβ clearance. However, accurately measuring CSF flow and Aβ dynamics in these small, intricate spaces, particularly in the deeper brain regions, has been a significant hurdle due to the limitations of current imaging technologies. This proposal aims to address that gap by developing advanced high-resolution MRI methods to noninvasively track CSF flow and soluble Aβ diffusion through the PVS. These tools will provide direct evidence of CSF-mediated Aβ clearance in healthy brains and reveal its disruption during AD pathogenesis. We hypothesize that Aβ plaque deposition at the PVS, a critical site for glymphatic clearance, impairs protein exchange between ISF and CSF and leads to reduced CSF Aβ42 levels. If validated, targeting CSF-mediated Aβ42 clearance via the PVS may offer a promising therapeutic strategy to enhance Aβ removal and prevent plaque formation in early-stage AD. We will test three specific aims: Aim 1. Develop and optimize novel MR mapping schemes to detect CSF flow dynamics through PVS and ventricles. This aim focuses on enhancing the resolution and accuracy of PVS mapping and developing rapid, high signal-to-noise ratio (SNR) sampling methods to measure CSF flow in the PVS and ventricles. Aim 2: Identify soluble Aβ42 dynamics in the CSF with MRI and two-photon microscopic (2PM) imaging. This aim will characterize Aβ42 distribution dynamics in the CSF of normal brains using the novel MRI method. The cortical surface distribution of Aβ42 will be validated with 2PM imaging in the same mice. Aim 3: Characterize the impaired Aβ42 diffusion through the blocked PVS by plaques in the 5xFAD AD mouse model. This aim will provide direct evidence that amyloid plaque–induced PVS blockage alters CSF Aβ42 dynamics in AD mice. Eventually, the newly developed MR methods will enable detection of CSF flow through the PVS in both normal and AD mouse brains. By integrating MRI with multiphoton deep-brain imaging, we will identify plaque accumulation near the PVS as a key driver of impaired perivascular Aβ clearance, opening a novel therapeutic avenue to restore Aβ dynamics and PVS function in AD.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: GPAT2 REGULATES MINERAL METABOLISM IN KIDNEY DISEASE Mineral disorder is a common complication of chronic kidney disease and is characterized by increased vascular mineralization and impaired skeletal mineralization—a phenomenon known as the mineralization paradox. This imbalance contributes to cardiovascular and skeletal disease and is a major driver of mortality in patients with chronic kidney disease. Despite its high clinical burden, there are currently no effective therapies to prevent or reverse mineral disorder or to reduce the associated cardiovascular risk. We recently uncovered a novel kidney-driven mechanism in which glycerol-3-phosphate, released from injured renal tissue, stimulates the production of fibroblast growth factor 23 (FGF23). FGF23 is a phosphate-regulating hormone that is also implicated in cardiac hypertrophy and adverse outcomes in chronic kidney disease. This signaling pathway requires glycerol-3-phosphate acyltransferase 2 (GPAT2), a lipid-handling enzyme involved in triglyceride synthesis that determines whether free fatty acids are stored or used for energy metabolism. We hypothesize that reducing GPAT2 activity will shift lipid metabolism, increasing the availability of free fatty acids and decreasing lysophosphatidic acid—a precursor in triglyceride synthesis and a direct stimulator of FGF23. As a result, we expect lower circulating FGF23 levels, reduced cardiovascular stress, and improved phosphate balance, even in the setting of reduced kidney function. Our preliminary data show that patients with advanced chronic kidney disease exhibit elevated GPAT2 expression and decreased free fatty acids. In a mouse model with targeted deletion of Gpat2 in bone-forming cells, we observed increased fatty acid metabolism, reduced FGF23 levels, and surprisingly, a reduction in serum phosphate—suggesting improved phosphate incorporation despite impaired renal clearance. In Aim 1, we will determine whether modulation of GPAT2 can dissociate the harmful effects of elevated FGF23 from the risk of phosphate accumulation by enhancing phosphate utilization in peripheral tissues. We will evaluate systemic mineral metabolism, vascular and cardiac morphology, and the impact of lipid remodeling in both constitutive and inducible Gpat2-deficient mice. We will also investigate the cellular mechanisms by which GPAT2 influences fatty acid metabolism and phosphate handling. In Aim 2, we will test whether either genetic deletion of Gpat2 or pharmacologic inhibition of GPAT activity can prevent or reverse mineral disorder in mouse models of chronic kidney disease. Outcomes will include improvements in vascular calcification, phosphate levels, and cardiac remodeling. If successful, this project will define a kidney-lipid signaling axis as a modifiable driver of phosphate imbalance and cardiovascular disease and may lead to new therapeutic strategies for improving outcomes in patients with chronic kidney disease.

NIH Research Projects · FY 2026 · 2026-04

Abstract Familial dysautonomia (FD) is a neurodegenerative inherited disease caused by a splicing mutation in the Elongator acetyltransferase complex subunit 1 gene (ELP1) that results in variable skipping of exon 20, leading to a premature termination codon. This, in turn, leads to a drastic reduction of ELP1 protein, primarily in the central and peripheral nervous system. All FD patients possess at least one copy of the c.2204+6T>C mutation, with 99.5% of patients being homozygous for this mutation. Individuals with FD have a complex multisystemic neurological phenotype that includes diminished pain and temperature perception, decreased or absent myotatic reflexes, blood pressure instability, proprioceptive ataxia, and progressive retinal degeneration. Currently, no treatments are available to halt the continuous neuronal loss characteristic of this devastating disorder. In this proposal, we aim to develop a novel gene-editing strategy for FD and generate critical in vivo proof-of- concept data to evaluate the in vivo efficacy and synergy of a combinatorial therapy. This approach combines a small molecule splicing modulator compound (SMC), which rescues ELP1 mis-splicing, with a genome editing strategy that permanently corrects the FD mutation. Our goal is to assess the effectiveness of these combined treatments to significantly attenuate systemic disease manifestations in a humanized mouse model of FD, overcoming the limitations of currently explored single therapeutic options. Combining the two strategies leverages the rapid, systemic action of SMCs and the durable, long-term correction from gene editing. Additionally, a combinatorial strategy has the potential to reduce compound dosing, minimize toxicity, and synergistically enhance ELP1 splicing correction. In Aim 1, we will customize and optimize a base editing strategy to permanently correct the mutation in ELP1 causing FD. This innovative approach will overcome a major barrier in the field and holds promise for advancing base editing technology for other human genetic disorders. In Aim 2, we will perform an in-depth evaluation of off-target effects for both genome editing and SMC strategies. These experiments are crucial for providing a comprehensive analysis of the specificity of our approaches and for ensuring the successful translation of our combinational strategy to the clinic. In Aim 3, we will assess the therapeutic effectiveness of our combinatorial approach in rescuing disease manifestations in a humanized mouse model of FD. The significance of this proposal lies in developing a novel combinatorial approach to address the complex and multisystemic disease manifestations characteristic of FD. More importantly, this R01 proposal aligns with our long-term goals of leading a translational research program toward a durable therapeutic strategy to correct the ELP1 splicing defect in FD patients.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Polygenic risk scores (PRS) are becoming increasingly accessible through direct-to-consumer (DTC) platforms and clinical practice. While PRS have the potential to enhance health monitoring and motivate preventive behaviors, misinterpretation of probabilistic risk estimates may also induce distress, reinforce genetic determinism, and lead to misguided health-related decisions. Present research indicates that patients and the public frequently misunderstand PRS results, often overestimating genetic influence and failing to contextualize probabilistic risk. Additionally, despite the rapid expansion of PRS use, standardized guidelines for communicating their meaning, limitations, and predictive accuracy remain lacking. This mixed-methods research program aims to systematically examine PRS comprehension, identify psychological predictors of genetic determinism, and develop evidence-based educational interventions to enhance genetic risk communication and comprehension. Aim 1 will assess how individuals understand genetic and statistical concepts underlying PRS through the development and evaluation of infographics designed to improve comprehension. Additionally, this aim will investigate how genetic causal attributions and genetic beliefs shape PRS interpretations, psychosocial responses, and health decisions. Aim 2 will experimentally evaluate how different PRS result formats (percentile rank vs. percentage change) and the inclusion of predictive accuracy metrics influence risk perception, emotional reactions, and subsequent health behaviors. Aim 3 will build upon these findings by experimentally testing PRS infographics integrated with a comprehension assessment and targeted corrective feedback to enhance public understanding and informed health decision-making. Overall, this research will identify key comprehension barriers, determine effective communication strategies, and establish best practices for responsibly reporting PRS results in both clinical and DTC settings. Findings will provide critical insights for healthcare providers, policymakers, and genomic companies to optimize PRS integration into precision medicine, empowering individuals to make informed, personalized health choices. This research will further serve as the foundation for a future R01-funded longitudinal randomized controlled trial (RCT) evaluating the long-term effectiveness of PRS communication strategies on psychosocial and behavioral health outcomes. By improving PRS comprehension, this work will help bridge the gap between scientific advancements in genomics and their ethical, effective application in public health.

NIH Research Projects · FY 2026 · 2026-04

During recent years, neuromodulation techniques such as transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS), as well as alternative methods using optical and ultrasonic modulations, have become an important means to study how complex neural circuits interact in the brain, to manipulate human cognition and to treat brain disorders. MRI can now be performed either concurrently with or pre and post these neuromodulation techniques to visualize their effects on the human brain, to understand the neurophysiological mechanism and to improve their efficacy. This topic aligns with the goals of the NIH BRAIN Initiative and public interest in brain-computer interfaces. The proposed endorsed ISMRM workshop will be the second of its kind on this relevant topic, after the celebration of the very successful one in October 2022 at the NIH, also supported by the NIH R13 mechanism. The workshop will be organized partially by the governing committee of the ISMRM Study Group (SG: MRI of Neuromodulation) as part of their goals and activities of the study group. The goal is to bring together a wide variety of scientists and clinicians as well as industry partners who are interested in developing and applying advanced MRI techniques to visualize, understand and quantify neuromodulation effects on the human brain. The proposed 2.5 days’ workshop will take place in April 2026 (from 7th-9th), at the Vienna University, in the heart of Vienna, Austria. The program will be designed for both senior investigators and junior scientists. The organizing committee will also emphasize attendance by students and trainee members of ISMRM and engage the international research community and will work with industry partners to secure funding to provide travel support for trainees. The meeting will include invited talks, discussions and sessions for power-pitch poster presentations followed by an hour of digital poster sessions for more in-depth discussions. The workshop’s schedule will integrate presentations with ample discussion periods covering advances in various MRI techniques for neuromodulation (electromagnetic field mapping, functional connectivity, advancement in hardware, arterial spin labeled perfusion and permeability, temperature and acoustic radiation force imaging etc), pre-clinical animal models and cellular-level mechanisms of neuromodulation, and safety issues related to MRI with neuromodulation devices. Existing and emerging clinical applications for MRI in neuromodulation and biomarker development will be discussed between academic and industry partners. A consensus paper will be drafted to summarize the discussions.

NIH Research Projects · FY 2026 · 2026-04

Cholera is a severe dehydrating illness of humans. It is endemic in over 50 countries and causes 3 to 5 million cases a year, resulting in approximately 100,000 deaths. Currently available cholera vaccines are poorly immunogenic in children under the age of 5 years, and often do not induce robust long-term memory responses in immunologically naïve populations. Antibodies targeting O-specific polysaccharide (OSP) are associated with protection against cholera. We here propose to extend our highly productive ongoing R37 international program that is defining OSP-specific immune responses in humans with cholera, including how OSP-specific antibodies protect. Such knowledge would be high impact and would directly inform cholera control efforts, including advancement of next generation cholera vaccines. In Aim #1, we will continue to define mechanisms of protection against V. cholerae afforded by OSP-specific responses using human isogenic OSP-specific monoclonal antibodies and human enteroid models. In Aim #2, we will define single cell and population responses at the mucosal surface in mucosal tissue samples obtained through endoscopic biopsy of cholera patients using single-nuclei sequencing (snRNA-seq) with T cell receptor (TCR) and B cell receptor (BCR) sequencing. In Aim #3, we will (a) define the OSP-specific response in intestinal tissue and luminal contents of patients recovering from cholera in Bangladesh, (b) deeply interrogate peripheral blood antigen-specific and functional immune responses using a system serology- based approach, and correlate these responses to responses directly assessed at the mucosal surface [in (3a)], and (c) assess the validity of whether such peripheral markers predict protection against cholera in our ongoing household contact study in Bangladesh. This extension builds upon our fully-approved and ongoing human, animal and bench-top studies, protocols and samplings, including at the International Centre for Diarrhoeal Disease Research-Bangladesh (icddr.b); no new additions are proposed. RELEVANCE (See instructions): Currently available oral cholera vaccines have a number of shortcomings. Developing improved vaccines or vaccination strategies is hampered by the reality that we do not currently understand the mechanism of immune protection against cholera although it is known that a primary component of that immunity targets O-specific polysaccharide (OSP) of V. cholerae. We here propose an investigative approach to define and evaluate OSP-specific responses during cholera.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Functional dyspepsia (FD) is common, affecting 12% of adults in the United States with high morbidity (e.g., work absenteeism, malnutrition) and healthcare costs. FD symptoms most commonly include early satiation and epigastric pain, worsened by meal ingestion in the absence of clear structural etiology. Precision medicine is lacking due to the complex pathophysiology thought to underlie gut-brain axis dysfunction in FD. Identification of maintenance mechanisms is necessary to determine which existing and new treatments work for whom and why. Gut interoception—how the gut and brain communicate to sense (i.e., attend to), interpret, and integrate gut signals at both conscious and unconscious levels—may be a useful model for understanding dynamic body-to-brain (‘bottom up’) and brain-to-body (‘top down’) processing in FD. This proposal uses multi- disciplinary methods (i.e., functional magnetic resonance imaging: fMRI, resting state functional connectivity, gut connectivity, self-report). We will examine three dimensions of interoceptive processing: gastric attention, interpretation of gastric signals, and gut-brain signal integration. We will contrast gut interoception in adults with FD (n=50) to healthy controls (n=50) and a clinically relevant comparator (anorexia nervosa; n=50) to test our central hypothesis: FD is linked to neural hyper-attention to gastric signals, neural fear-based interpretation of gastric signals, and poor bi-directional gut-brain integration. First, we hypothesize FD will exhibit fasting and pre-meal neural hyper-attention to gastric cues in primary interoceptive regions (insula, anterior cingulate cortex) of the Salience Network (involved in interoception and cognitive/emotional integration). We expect hyperactivation to correlate with a trait-level gut interoceptive awareness. Second, we hypothesize that FD will show pre-and post-meal resting state hyperconnectivity in the primary hub of interoception—the mid insula— and the amygdala (primary limbic region of the Salience Network) alongside hypoconnectivity with the orbital frontal cortex (a primary food-reward region of the Salience Network). Finally, we expect FD to show greater connectivity than controls and AN between the nucleus tractus solitarius (key brain stem region involved in processing interoceptive signals) and the Salience Network, which we expect will correlate with slower gastric motility. Conceptualizing FD pathophysiology within an interoceptive framework has strong potential to advance precision medicine for FD by identifying neural mechanistic targets—hyper-attention (e.g., attention re-training), dysregulated interpretation (e.g., behavioral exposure therapy), and altered integration (e.g., vagal nerve stimulation).

NIH Research Projects · FY 2026 · 2026-04

Coronary artery disease (CAD) is a leading cause of death worldwide. Familial hypercholesterolemia (FH) is an extreme form of inherited hypercholesterolemia and an important risk factor for CAD. FH is caused by pathogenic variants in known cholesterol-related genes, and carriers are exposed to severe hypercholesterolemia and often develop CAD at an early age. Early intervention reduces the progression of atherosclerosis and prolongs CAD-free survival; therefore, early diagnosis and treatment are essential in the management of FH. Current guidelines recommend genetic screening and genotype-based risk stratification for individuals with severe hypercholesterolemia, as well as specific therapies. However, current genetic diagnostic criteria are limited to previously described genes and variants. Recent investigations, including our own, suggest that the diagnostic yield of genetic testing for FH is low (<2% of individuals with severe hypercholesterolemia). Furthermore, only ~2% appear to have a comparably strong polygenic contribution, despite evidence of a substantial genetic influence on FH. Based on these findings, Dr. Koyama hypothesizes that undiscovered FH alleles exist and may be important for diagnosis, surveillance, and treatment. To improve the genetic diagnostic yield for FH and capture currently undiagnosed carriers, Dr. Koyama proposes to develop updated diagnostic criteria for FH using population-scale genome sequencing cohorts and a comprehensive variant-interpretation framework. In this proposal, Dr. Koyama will (1) extend rare-variant analyses to noncoding variants that are not covered by current diagnostic criteria using whole-genome sequencing data, and (2) integrate commonand rare-variant risk-stratification models to more comprehensively describe genetic risk for hyperlipidemia. This project builds on Dr. Koyama's clinical and research experience and will allow him to further develop expertise in cardiovascular genetic research. He will benefit from the rich scientific resources and collaborations at MGB Personalized Medicine and will lead this clinically meaningful project independently.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Catatonia is a potentially fatal, often curable, and highly underdiagnosed neuropsychiatric disorder characterized by motor phenomena, changes in affect, and cognitive-behavioral disturbances. Once identified, catatonia can be rapidly and effectively treated, but in present clinical practice most cases of catatonia are not appropriately diagnosed. Thus, there is a critical unmet need to develop biomarkers to detect catatonia and to longitudinally monitor its treatment. This K23 Mentored Patient-Oriented Research Career Development Award will use detailed clinical phenotyping and machine learning analysis to transform clinical electroencephalography (EEG) recordings into valid, reliable, and accurate digital biomarkers for the detection and monitoring of catatonia. This will involve Aims of 1) developing a physiologic grading scale for catatonia using EEG recordings and contemporaneous clinical exam in the largest ever (N=1,400) prospective cohort of patients hospitalized with altered mental status; and 2) monitoring longitudinal EEG and clinical changes in patients with catatonia as they receive gold-standard treatment with benzodiazepines during the “lorazepam challenge test.” This research plan will be accompanied by a rigorous 5-year career development plan to advance the Principal Investigator, James Luccarelli, MD, DPhil, as a clinician-scientist with expertise in 1) prospective clinical research; 2) responsible conduct of research; 3); neurophysiology; 4) data science; and 5) scientific leadership and communication. This career development plan will build directly on Dr. Luccarelli’s clinical expertise in catatonia treatment for patients of all ages as a child, adolescent, and adult psychiatrist and his existing strengths in computational analysis and retrospective clinical research. On this foundation, training will be guided by a stellar team of mentors. Primary mentorship will be provided by Brandon Westover, MD, PhD, a neurologist and world leader in applying machine learning to human neurophysiology, along with co-mentor Timothy Wilens, MD, a child, adolescent, and adult psychiatrist and expert in prospective clinical research in psychiatric populations. Critical additional mentorship will be provided by cross-disciplinary team of scientific advisors: Paul Croarkin, DO (child psychiatry at the Mayo Clinic); Hang Lee, PhD (biostatistics); Sahar Zafar, MBBS (neurology); and Thomas McCoy, MD (bioethics). By leveraging the deep expertise of these world-class mentors and the unparalleled institutional environments of the Massachusetts General Hospital and Harvard Medical School, this K23 Award will support an innovative program of career development and patient-oriented research. This will provide Dr. Luccarelli with the skills necessary to become an independent investigator leveraging a clinically actionable biomarker for the enhanced clinical detection and monitoring of catatonia that will set the stage for future EEG-guided clinical trials of new treatments.