Massachusetts General Hospital

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract This K23 proposal focuses on using continuous glucose monitoring (CGM) technology to optimize glycemic monitoring and management in people with type 2 diabetes and chronic kidney disease (CKD), fostering the career development of Mengyao Tang, MD, MPH, as an independent clinical researcher bridging diabetes and CKD research. Approximately 40% of individuals with type 2 diabetes develop CKD, a devastating complication that markedly amplifies risks for kidney failure, cardiovascular events, and premature death. Glycemic control is a cornerstone of diabetes management in CKD, yet the standard method of glycemic monitoring, HbA1c, is less accurate in CKD patients, and glycemic management is further complicated by heightened risk of hypoglycemia. CGM has revolutionized diabetes care, yet it remains under-studied and under- utilized in the CKD population. For the first time in CKD patients, Aim 1 will test the associations between CGM-based metrics (time in range and CGM-detected hypoglycemia) and long-term clinical outcomes (CKD progression, cardiovascular events, and mortality) in a large cohort. Furthermore, older adults with type 2 diabetes and CKD, who represent the largest CKD subpopulation, face unique multi-level barriers that may undermine the short-term benefits of CGM. Therefore, Aims 2 and 3 will use an implementation science framework to refine and pilot- test a supported CGM intervention to examine feasibility and short-term efficacy in this high-risk group. Dr. Tang is a board-certified nephrologist at Massachusetts General Hospital (MGH). Her career goal is to become a leading physician-scientist who implements patient-centered technology and treatments to improve clinical outcomes and quality of life for people with diabetes and CKD. Dr. Tang has assembled a multi-disciplinary mentoring and advisory team led by experts in endocrinology, nephrology, implementation science, biostatistics, and psychology. During her K23 grant period, Dr. Tang will acquire essential clinical investigation skills through a detailed career development plan, including formal coursework, attendance at conferences and seminars, and hands-on experience in CGM data analysis and clinical use, implementation science, and mixed methods research. Dr. Tang will thrive in the rich environment at MGH, which is deeply committed to her success as a junior faculty member. In summary, this K23 project will lay the groundwork for a hybrid effectiveness-implementation trial of using CGM (vs. HbA1c alone) to optimize diabetes management in older adults with type 2 diabetes and CKD. The project will also foster cross-disciplinary collaborations and provide a robust training and research niche for Dr. Tang, facilitating her development into a successful, independent clinical researcher.

NIH Research Projects · FY 2026 · 2026-04

Glioblastoma (GBM) is an aggressive brain tumor that recurs in treatment-refractory form within months of initial standard-of-care (SOC) treatment. Extensive study of primary (pre-treatment) GBM has revealed numerous characteristics that impede treatment, including marked intratumoral genetic, transcriptional, and spatial heterogeneity; rapid infiltration throughout the brain parenchyma; a uniquely compromised immune microenvironment; and immunosuppression beyond the central nervous system. However, the mechanisms by which these factors enable disease progression are not understood, and the critical disease entity -- recurrent GBM -- is comparatively understudied. The central hypothesis of this study is that identifying the unique characteristics of recurrent GBM and the mechanisms driving its evolution from primary GBM will reveal new therapeutic targets. Our overall objective is to identify transcriptional, genetic, neuronal, and immunological factors that influence GBM formation, progression, and treatment response, with an emphasis on therapeutically targetable ligand-receptor interactions. We utilize unique human tissue repositories, novel experimental designs, and spatially-resolved single-cell approaches with the rationale that reversible interactions between tumor cells and diverse nonmalignant cells drive tumor formation, progression, and drug resistance. We pursue our objective through three Specific Aims: (1) Identify unique molecular, cellular, and spatial features of recurrent human GBM; (2) Identify mechanisms underlying distal pathological effects of GBM, including distant brain infiltration and systemic immunosuppression, in whole-brain and whole-body autopsy settings; and (3) Elucidate the dynamic reconfiguration of the GBM ecosystem during tumor formation and treatment response using mouse models, single-cell lineage tracing, and spatial transcriptomics. In Aim 1, we will integrate spatial transcriptomics (ST) with novel long-read single-nucleus RNA-sequencing (snRNA-seq) and exome sequencing to identify cell states, single-cell clonal architecture, multicellular niches, and heterotypic ligand-receptor interactions specific to recurrent GBM. In Aim 2, we will leverage unique resources at MGH that enable the analysis of diverse brain regions and peripheral immune organs in post-mortem GBM patients. We will combine snRNA-seq, ST, and single-cell T-cell receptor sequencing to study brain invasion and immunosuppression within the brain and peripheral immune system. In Aim 3, we will perform time-resolved single-cell RNA-seq (scRNA-seq) and ST in a mouse model of GBM to map the temporal and spatial co-evolution of tumor and immune cells during tumor development and response to SOC. Critically, we will integrate single-cell lineage tracing with scRNA-seq and ST to distinguish among possible mechanisms by which treatment reconfigures the tumor ecosystem. This study addresses innovative questions using unique resources, novel study designs, and new combinations of genomic and computational approaches. The work is significant because it will enable the discovery of therapeutic vulnerabilities associated with GBM development, progression, and recurrence.

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

Background: Depression is a serious mental disorder, with treatment selection largely relying on trial and error, often prolonging patients' suffering. The increased availability of electronic health records (EHRs) and advancements in AI offer new opportunities to address this clinical challenge. However, current EHR-based approaches have shortcomings: a. they underutilize information in unstructured data that could be important for outcome prediction and confounding adjustments; b. they lack accuracy in cohort definition and treatment response assessments; c. they omit genomic information, which is known to affect treatment response; and d. they are not aware of uncertainties arising from the fitness of assumptions required to produce reliable predictions, potentially providing misleading estimates. In addition, genetic tests currently available are limited to select genetic variations, failing to utilize information from the full genome. Research: We propose to address these limitations by crafting advanced AI models for predicting differential antidepressant treatment responses, leveraging the latest developments in natural language processing (NLP), predictive modeling, causal inference, and the inclusion of both EHR and genomic data. Aim 1 will involve developing a large language model-based, human-in-the-loop active learning framework to identify an incident-user cohort started on antidepressants for depression, assess treatment responses, and extract key depression-related information from clinical notes. Aim 2 will develop uncertainty-aware, EHR-based prediction models for differential antidepressant responses, accounting for cases where a patient-antidepressant pairing falls outside the training data and for residual confounding. Aim 3 will combine EHR and three classes of genomic predictors for response prediction: genome-wide and pathway-specific polygenic risk scores, and variations associated with cytochrome P450 enzymes. This effort will enhance our understanding of integrating EHR and genomic data to predict personalized treatment responses, paving the way for future comprehensive systems. Candidate's Career Development, Goals, and Environment: The research objectives and the candidate's career development will be facilitated by the abundant resources at Massachusetts General Hospital and Harvard Medical School, as well as formal training and mentorship in (G1) advanced clinical NLP, (G2) integration and analysis of large-scale EHR and genomic data, (G3) ‘causal machine learning’ and its uncertainty assessments, and (G4) grantsmanship, leadership, effective collaborations, and research management. The mentorship team comprises Mentor Dr. Jordan Smoller, a leader in precision psychiatry and clinical predictive analytics; Co-Mentor Dr. Tianxi Cai, an authority in bioinformatics and healthcare predictive modeling; and Consultants Dr. Timothy Miller, an expert in NLP and AI, Dr. Issa Dahabreh, a specialist in causal inference, and Dr. Tian Ge, a renowned statistician and geneticist. This award will equip the candidate with the advanced skillset to become an independent researcher in precision psychiatry.

NIH Research Projects · FY 2026 · 2026-04

As people living with HIV (PWH) reach older age, determining their risk for mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRDs) is emerging as a major public health priority. Because HIV is relatively rare in the United States, particularly in the elderly, data in this area have largely been limited to young populations and lacked large samples with brain imaging and biomarkers to determine disease phenotypes. Moreover, social and clinical health predictors of MCI/ADRD differ meaningfully in PWH, so risk factors and their impact on households cannot be extrapolated from other populations. To respond to these gaps, we will leverage a team of experts in HIV epidemiology, diagnosis and phenotyping of MCI/ADRDs with fluid and imaging biomarkers, and machine learning (ML), and a large and well-established cohort of older people with HIV. Preliminary data generated by our team include neuropsychological screening of 300 older virologic suppressed PWH in Uganda (mean age >60), and 300 demographically similar people without HIV, showing that >30% of PWH have characteristics of MCI and that brain MRI and ML techniques add critical phenotyping data to standard batteries. Four specific aims are proposed: Aim 1: Determine the prevalence and classification of MCI/ADRDs (1A) and compare trajectories of cognitive performance (1B) between older PWH and similar people without HIV. Comprehensive neuropsychological assessments will be completed in older adults with and without HIV in the cohort (n=600) annually during years 1-4. MCI/ADRDs will be identified using multi-disciplinary case consensus criteria to provide diagnoses and underlying etiologies. Aim 2: Identify pathophysiologic contributors to MCI/ADRDs in older adults through deep phenotyping with novel plasma biomarkers and neuroimaging. Assessments will include Aβ42/Aβ40, p-tau217, GFAP, and NfL biomarkers and brain MRIs to characterize phenotypes. Aim 3: Estimate the psychosocial and economic impacts of MCI/ADRDs on adult household members. We will conduct in-depth interviews (n~40, Aim 3A) to learn about lived experiences of caregivers, and quantitative surveys (Aim 3B) to all adult household members of the cohort (n~1800) on employment and resource use, caregiving burden, quality of life, stigma, social participation, loneliness, and mental health. We will compare participants by the presence vs absence of MCI/ADRDs in the household. Aim 4: Discover and validate novel, multilevel mechanistic models of MCI/ADRDs among older PWH by employing ML methods with the full array of data collected in Aims 1-3. We will determine which combinations of highly dimensional features reliably classify individuals according to MCI/ADRDs profiles. Completing these aims will advance our understanding of MCI/ADRDs epidemiology among older PWH. In doing so, it will lay the foundation for diagnostic and intervention efforts to address research priorities for PWH in the United States and beyond.

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 · 2026-03

Project Summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder long associated with functional connectivity abnormalities that are widespread throughout the brain. Despite countless studies on the topic, no single unifying model of functional connectivity abnormalities in ASD has emerged to date. Enthusiasm for studying functional connectivity differences in ASD has subsided in light of evidence of alterations that are more heterogeneous than some of the earlier hypotheses suggested, and because the links of these alterations to neural mechanisms of ASD have been challenging to map. Yet, one related theme that has garnered support has been that functional connectivity in ASD is increased in the bottom-up (or "feedforward") direction and decreased in the top-down (or "feedback) direction. Here, we propose to test a hypothesis that the functional characteristics of ASD are rooted in a fundamental imbalance between feedforward and feedback influences. This hypothesis stems from our preliminary data and prior studies, and it is motivated by many aspects of the ASD phenotype: These include increased perceived salience of sensory stimuli and evidence of reduced top-down control in ASD, which manifest across a range of atypical behaviors characteristic of the disorder. Thus far, mapping feedforward and feedback inputs non-invasively in the human brain has been methodologically challenging. Here we propose a multimodal neuroimaging approach, which combines (a) effective connectivity measures using millisecond temporal resolution magnetoencephalography (MEG) with (b) highly novel submillimeter-resolution layer- specific 7T functional MRI. We will use these advanced techniques to characterize feedforward and feedback flow of information along the auditory cortical hierarchy, in 90 ASD and 60 neurotypical (NT) adults, ages 21- 35, with average or above average IQ. Using our multimodal research design, which is firmly rooted in laminar neurophysiological recordings in non- human primates, we will pursue the following Specific Aims: (1) Test the hypothesis that feedforward inputs are abnormally increased in ASD relative to NT individuals; (2) Test the hypothesis that feedback inputs are abnormally decreased in ASD relative to NT individuals; (3) Test the hypothesis that the extent to which feedforward and feedback inputs in the ASD group are indeed different, is predictive of ASD severity and the extent of auditory processing deficits, assessed behaviorally. We expect that the results of this study will lead to a substantially more detailed, comprehensive, and mechanistically motivated framework for the wide range of functional connectivity abnormalities observed in ASD.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) affects one in eight Americans over 65 and is among the leading causes of death in the United States. Despite its prevalence, the accurate clinical diagnosis of AD remains challenging due to non-specific clinical tests and symptom overlap with other types of dementia. Except at top medical centers, the resulting misdiagnosis rates in excess of 15% relative to “gold-standard” neuropathologic analysis at autopsy negatively impact the efficacy of care, patient outcomes, and clinical trial efficiency. Although there are biomarkers that correlate with the neuropathology of AD, many are either invasive or largely inaccessible in routine clinical practice, such as PET imaging. One in-vivo marker that could be largely accessible is morphological metrics derived from non-invasive T1-weighted structural brain magnetic resonance imaging (MRI). These scans are already routinely acquired for individuals presenting with age-related cognitive decline, but integration barriers hamper the clinical accessibility of derived metrics. The fundamental goal of this project is to enable hospitals with limited access to AD biomarkers to achieve the diagnostic accuracy of top-performing institutions. We aim to improve the sensitivity and accessibility of structural MRI metrics by improving longitudinal, within-subject approaches that drive the morphometric analysis of MRI scans using a subject-specific reference image—a template—constructed from time points after rigid registration correcting for differential head positioning. We will build upon recent image-synthesis techniques and cutting- edge deep learning to develop anatomy-aware registration tools that generalize to medical imaging data across different MRI scanners and hospitals, without retraining or preprocessing. First, we will incorporate randomized, synthetic atrophy of AD-specific structures, ventricular expansion, and MRI distortions into a generative model. We will use this model to develop a deep neural network for rigid brain regis- tration that is robust to localized change and irrelevant intensity variations common in clinical imaging. Second, we will develop a deformable registration network that differentiates session-specific MRI distortions from disease effects. We will leverage AD-aware registration networks to construct individualized deformable templates across time to enhance the sensitivity of longitudinal morphometry, making it compatible with the clinical workflow. The project will result in deep-learning tools for longitudinal brain registration and template construction that are fast, accurate, and easy to use without machine-learning expertise or high-end computational resources. They will increase the power to detect disease effects with fewer subjects and dramatically reduced runtimes.

NIH Research Projects · FY 2026 · 2026-03

SUMMARY Developmental gene expression is tightly regulated by the dynamic interplay of H3K4 methylation (H3K4me) and H3K27 methylation (H3K27me) associated with active and repressed genes, respectively. However, our understanding of the individual and combinatorial roles these histone modifications play in adult physiological contexts remains incomplete. To overcome these limitations, we have recently generated histone mutant transgenic tools to uncover a previously unappreciated role for H3K4me in adult hematopoiesis. Adult mice globally depleted for all forms of H3K4me via expression of an inducible histone H3 lysine-4-to-methionine (H3K4M) mutant allele succumbed to a severe loss of all major mature blood cell types. Unexpectedly however, H3K4M-expressing hematopoietic stem cells (HSCs) and most committed progenitors were present at normal numbers and persisted upon transplantation into recipient mice, suggesting that H3K4me is dispensable for the maintenance and early commitment of HSCs and progenitors but essential for the terminal maturation of progenitors. Mechanistically, we showed that H3K4me opposes the deposition of repressive H3K27me at differentiation-associated genes bivalently marked by H3K4me3 and H3K27me3 in HSCs or progenitors. Indeed, by concomitantly suppressing H3K27me in H3K4me-depleted mice with an H3K27M transgene, we could rescue the acute lethality, hematopoietic failure and gene dysregulation. Thus, our results reveal that H3K4me guides hematopoiesis by opposing repressive H3K27me at fate-instructive bivalent genes, providing the first evidence for the functional interaction between these crucial chromatin marks in mammalian tissue homeostasis. These preliminary data raise fundamental questions with clinical relevance that will be addressed in 3 complementary aims. In Aim 1, we will further define the consequences of H3K4me loss on the function of HSCs and progenitors using self-renewal and differentiation assays. Additionally, we will assess whether any observed defects are reversible upon restoration of H3K4me. In Aim 2, we will identify epigenetic regulators that mediate the H3K4M- dependent arrest and the H3K27M-dependent rescue by purifying proteins associated with H3K4M and H3K27M; measuring changes to all major histone modifications; and testing select candidates for their ability to phenocopy the effects of H3K4M and H3K27M. In Aim 3, we will dissect the molecular basis by which H3K4me/H3K27me safeguard hematopoiesis with a focus on fate-instructive cytokine receptors and transcription factors dysregulated in H3K4M mice but normalized in H3K4M/H3K27M mice. Moreover, we will investigate the contribution of other epigenetic marks to the H3K4M phenotype using DNA methylation inhibitors and a novel histone mutant library. Collectively, this proposal will leverage novel tools to probe the direct, physiological impact of two antagonizing chromatin marks on hematopoiesis. As arrested differentiation and disrupted H3K4me/H3K27me have been implicated in diverse hematological conditions, our results will elucidate the underlying mechanisms and may pave the way for novel therapeutic interventions.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT The ongoing overdose crisis in the United States is exacerbated by an increasingly unpredictable illicit drug supply, including the emergence of novel substances and high-potency drug combinations. Such rapid and evolving shifts in the drug supply make it increasingly difficult for public health responses, such as resource allocation for overdose prevention and harm reduction programs. Therefore, the ability to detect change points in the drug supply, whether involving single substances or co-occurring combinations, is crucial for mitigating overdose risks. Given the complex spatial and temporal dynamics of drug supply shifts and overdose trends, advanced machine learning methods are necessary for granular analysis. We will leverage the highly restricted National Forensic Laboratory Information System (NFLIS-Drug) data, which provides detailed drug composition reports from law enforcement seizures, to track trends in the prevalence of illicit substances. We will further integrate this data with county-level overdose mortality data from the Centers for Disease Control and Prevention (CDC), allowing for a systematic assessment of how changes in drug supply influence overdose fatalities across both time and geography. Our study has two specific aims. Aim 1 is to identify spatiotemporal change points in the prevalence of key substances from 2013 to 2026, including fentanyl, heroin, stimulants, xylazine, and novel synthetic benzodiazepines, as well as their combinations. We will apply correlated anomaly detection models, such as Gaussian Process Subset Scanning and spatial-temporal outlier detection methods, and benchmark them against alternative machine learning approaches to ensure the robust and accurate detection of significant shifts in the drug supply. Aim 2 aims to evaluate the impact of these change points on overdose trends. Using spatiotemporal deep learning methods, specifically Convolutional Long Short-Term Memory networks, we will integrate change points from NFLIS-Drug data with county-level CDC overdose mortality data. This approach will account for temporal and spatial dependencies, time lags, and various county-level characteristics, enabling us to assess how shifts in the illicit drug supply influence fatal overdoses. Understanding drug supply dynamics is critical for optimizing resource allocation and informing policy decisions. By identifying regions and periods with significant changes in the drug supply, public health agencies can allocate resources more effectively to areas with heightened overdose risks. Furthermore, determining which substances and their combinations drive overdose surges and how early these shifts occur will provide insights into the optimal timing of public health responses. By leveraging our unique access to granular data and applying cutting-edge data science techniques, this research aims to advance the utility of NFLIS-Drug data, improve the timeliness and effectiveness of overdose prevention strategies, and inform policy and resource allocation to address emerging overdose crises.

NIH Research Projects · FY 2026 · 2026-03

Suffolk County, an Ending the HIV Epidemic (EHE) priority area in Massachusetts, has seen a dramatic increase in bacterial sexually transmitted infections (STIs). Although diagnosis of bacterial STIs is an indication to consider HIV pre-exposure prophylaxis (PrEP), uptake of PrEP remains inconsistent across patient populations, often not reaching those at greatest risk for HIV acquisition. To address the rising rate of STIs, the Massachusetts Department of Public Health (MDPH) is implementing a provider-initiated electronic partner notification (ePN) platform for STIs, through which index patients can anonymously alert their sexual partners about STI exposure and link them to care resources. The goals of this platform, which, to our knowledge, is the first state-sponsored, statewide ePN intervention in the US, include not only an increase in the number of people tested and treated for STIs, but also the promotion of HIV testing and PrEP. ePN has the potential to overcome barriers to STI/HIV services by increasing awareness and linking notified individuals to accessible, low-cost care. How best to design and implement ePN to promote integrated STI/HIV services that serve populations at increased risk for STIs and HIV in community settings is unknown. In collaboration with MDPH and three high-volume sexual health clinics in Suffolk County, we propose to leverage this statewide "natural experiment" through the following three specific aims: 1) To evaluate the impact of ePN implementation on number of partners notified and engaged in care statewide when: 1a) used by field epidemiologists as an adjunct for assisted partner notification services for people diagnosed with syphilis; and 1b) initiated by clinicians at STI clinics for people diagnosed with gonorrhea and chlamydia; 2) To identify determinants of ePN implementation for STIs via qualitative interviews with index patients, partners, field epidemiologists, and clinicians and use the ADAPT implementation process to develop enhancements that incorporate HIV services; and 3) To implement and evaluate the impact of ePN platform enhancements on PrEP uptake and HIV care re-engagement at three selected high-volume MDPH-funded STI clinics deploying ePN and statewide, including an assessment of reach into different patient populations. We hypothesize that ePN will increase the number of partners notified and engaged in sexual health care and that enhancements to ePN will increase PrEP uptake and HIV care re-engagement among notified individuals, thereby helping to address both the STI and HIV epidemics. This proposal is directly responsive to the NIH HIV/AIDS research priorities to improve uptake of multi-level HIV prevention interventions, develop prevention strategies for HIV-relevant coinfections, and address high HIV incidence populations. It is also responsive to the NIH Director's strategic priority to use implementation science to advance EHE efforts in the US. This work will shift the paradigm of HIV and STI care by reimagining partner notification for the digital age and expanding its reach to enable more effective linkage to HIV services.

NIH Research Projects · FY 2026 · 2026-03

Abstract This R01 resubmission is a 4-year methodology grant (PAR-25-332). The overarching goal is to assess the utility of 64Cu-fibrin-binding-probe-8 Positron Emission Tomography (or FBP8 PET) for the in vivo detection and quantification of pathological fibrin in brain, within a multi-biomarker framework. We will study Harvard Aging Brain Study 2 (HABS-2) participants who underwent amyloid (Aβ) and tau PET, Magnetic Resonance Imaging (MRI), APOE genotyping, and cognitive testing. This includes individuals with (+) and without (-) evidence of Aβ and/or tau load or cognitive impairment (MCI/AD). As reviewed by Badimon (2023), fibrinogen is a soluble plasma protein that is converted to an insoluble fibrin clot by the serine protease thrombin. After fibrinogen cleavage by thrombin, fibrin forms a mesh-like network that traps blood cells and other components to form a clot, preventing further bleeding and facilitating tissue repair. Vascular damage in AD allows for plasma protein extravasation into brain and there is literature evidence of fibrin and fibrinogen in AD brain, co-localizing with Aβ. Fibrin deposition has been reported to increase in AD brain, compared to healthy controls, and to correlate with the degree of Aβ pathology. There is also evidence that Lecanemab (FDA-approved anti-amyloid AD therapeutic) targets Aβ and overlaps with the fibrinogen binding site. Our preliminary data suggest an age-related increase in 64Cu-FBP8 PET uptake in healthy brain. We will evaluate the in vivo pharmacokinetics of FBP8 in cognitively unimpaired young and older control and MCI/AD HABS-2 participants using standard compartmental modeling approaches and identify a simplified method for routine quantification of fibrin load in brain (Aim 1). We hypothesize that a quantitative kinetic modeling approach will emerge as a reference standard that provides robust measures of fibrin load in the brain. To achieve this, we will evaluate model performance and in vivo parameters that include FBP8 metabolism in plasma and extent that FBP8 fibrin load measures depend on BBB leakage and/or blood flow (by measuring DCE MRI KTRANS and 15O-water PET K1-WATER respectively). Finally, we will evaluate how age, Aβ load, and tau load relate to FBP8 PET fibrin load (Aim 2). We hypothesize that there will be a significant relationship between FBP8 fibrin load and age, with an interaction between Aβ and/or tau PET load and age. The availability of a well characterized PET fibrin brain imaging agent that is feasible to apply in older adults and patients with AD could enable new possibilities for the study of in vivo relationships between BBB dysfunction, fibrinogenesis and fibrinolysis, and impact of these factors with AD therapeutic efficacy. This includes those who may be vulnerable to edema and/or microhemorrhages that result from Aβ- related imaging abnormalities (ARIAs), a major side effect of anti-amyloid therapies.

NIH Research Projects · FY 2026 · 2026-03

Project Summary / Abstract The conference, “Planning for Prevention of Parkinson's Disease and Related Synucleinopathies: A trial design forum”, the 4th in this now biennial series, will be held May 22 to 24, 2026, with future conferences planned for 2028 and 2030. The long-term objectives of this R13 program are to foster the education, training, and research of investigators in the emerging translational and clinical neuroscience theme of preventative therapeutics for Parkinson’s disease (PD) and related synucleinopathies like dementia with Lewy bodies (DLB); and to improve the design of the first prevention trials by fostering exchange of early experiences and emerging visions. These objectives will be achieved through five specific aims (SAs). SA #1 is to educate and update attendees on the critical design elements for prevention trials via interactive symposium sessions and workshops. SA #2 is to engage and educate early career investigators (ECIs) through travel fellowships and an additional curriculum with networking and mentorship opportunities, with direct support from this project. SA #3 is to foster partnerships within the growing community of stakeholders in synucleinopathy prevention, including individuals who are at high risk based on genetic and prodromal features and thus most likely to benefit from effective preventative therapy. SA #4 is to facilitate pre-competitive knowledge exchange and collaboration among researchers developing the first prevention efforts by inviting sharing and comparing of their early protocols and designs. SA #5 is to ensure enduring and wide access to the knowledge gained through the open-access publication of meeting findings and consensus in peer-reviewed neuroscience journals. Thuse the conference series will engage, educate, and motivate a wide collaborative community of prevention stakeholders to accelerate development of rigorously designed early trials for PD prevention, thereby enhancing prospects for their success.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY There are an estimated 3.7 million people who inject drugs (PWID) in the US. They are at high risk for morbidity and mortality from drug overdoses, acute bacterial infections, and complications of chronic viral infections such as HIV and hepatitis C. The syndemic of substance use disorder (SUD) and infections leads to poor health outcomes and high healthcare costs. Bridge clinics are rapid-access, transitional models of SUD care which provide timely initiation of medications for opioid use disorder (MOUD) and treatment for other SUDs. Compared to the traditional model of referral to separate sites for outpatient SUD and infectious disease (ID) care, bridge clinics provide an opportunity to integrate both SUD and ID care and improve outcomes. This project seeks to determine the clinical impact and cost-effectiveness of integrating ID care into bridge clinics to reduce drug overdose and injection-related infections. To achieve this goal, I have two Specific Aims proposed over a 4-year period: 1) to build a longitudinal database of clinical outcomes and healthcare utilization among PWID who receive care in bridge clinics or in standard outpatient care within the largest healthcare system in Massachusetts, and 2) to expand a novel simulation model of injection drug use and assess the cost- effectiveness of bridge clinics compared to standard outpatient SUD care and of integrating ID care into bridge clinics compared to the traditional separate SUD and ID care sites. I am an infectious disease physician and an early-stage clinician-investigator committed to using the methods of decision science to improve care and outcomes for PWID. I seek to leverage my clinical experience in providing care within a bridge clinic and my research experience in simulation modeling and cost-effectiveness analysis to conduct novel research that informs relevant clinical and health policy questions regarding the syndemic of drug use and related infections. To achieve my proposed research aims, I require additional training in 1) database development and observational cohort analysis (skills I will need to derive novel model inputs), and 2) advanced modeling techniques and methods in cost-effectiveness analysis to address model uncertainty. I will accomplish these research and training aims through rigorous methodologic coursework, seminars, and scientific meetings, with support from an accomplished multidisciplinary mentorship team with expertise in simulation modeling and cost-effectiveness analysis (Dr. Andrea Ciaranello), addiction care and policy (Dr. Sarah Wakeman), and database development and observational cohort analysis (Dr. Virginia Triant). The research aims and complementary training plan will set a foundation for becoming an independent investigator advancing methods in decision science and clinical epidemiology at the intersection of drug use and infectious diseases, and for improving access to care and healthcare outcomes for the millions of people who use drugs in the US.

NIH Research Projects · FY 2026 · 2026-03

In 2023, more than 100,000 people died of an opioid overdose in the United States, and 2.5 million adults in the U.S. have an opioid use disorder (OUD). Paradoxically, people’s access to opioids often happens in the context of medical procedures and are prescribed by clinicians. Opioids are effective in treating moderate to severe pain and are often prescribed following surgical procedures such as back surgery. Iatrogenic harms associated with opioid use for medical purposes (e.g., OUD) pose an ethical and medical conundrum: How to properly balance the risks associated with opioid use with the potential medical benefits in terms of pain management and improved clinical outcomes? To help inform this decision, companies have developed genetic tests that use polygenic risk scores (PRS) to estimate a person’s genetic risk for developing an OUD. The FDA recently approved one such test, and tests for other substance use disorders (SUD) are in development.  A tool that can accurately estimate a person’s genetic risk for OUD, could help prevent opioid prescription, use, and save lives. However, the use of genetic tests to identify people at increased risk of OUD or any SUD is itself, ethically challenging. How reliable are these tests perceived to be, in which circumstances should they be ordered, how much genetic risk for OUD is too much to deny opioids to a patient in pain, how should OUD risk information be managed in the medical record, who could have access to OUD risk results, and how could this information be misused? Furthermore, OUD, other SUDs, and pain are stigmatized which may influence clinician and patient decision-making regarding ordering genetic tests for OUD and integrating results. Little empirical research has examined the ethical and clinical implications of these novel tests in medicine. The proposed study examines key stakeholders’ (e.g., patients scheduled for surgery, patients with history of OUD, surgeons, pain management specialists, medical geneticists, legal experts) views, concerns, expectations, decision-making factors, and proposals for the responsible use of OUD genetic tests. The long-term goal of this research is to promote patient well-being and advance genomic science by generating data and analysis to inform the responsible use of genetic tests for SUDs in medicine. The objective of this study is to empirically examine stakeholders’ views, concerns, expectations, and decision-making factors on whether and how to responsibly integrate genomic risk estimates for OUD in surgical care. In Aims 1 and 2, we will conduct semi-structured interviews with patients scheduled for surgery, patients with history of OUD, surgeons, pain management specialists, medical geneticists and other relevant clinicians to examine their views, concerns, expectations, decision-making factors, and proposals for the responsible use of PRS for OUD. In Aim 2, we will also experimentally examine which factors drive clinician decision-making regarding whether to order OUD genetic tests. Finally, in Aim 3, we will conduct a modified Delphi panel with stakeholders to identify the most pressing challenges and potential solutions for the responsible use of OUD genetic tests in medicine.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Developing effective interventions for postoperative delirium (POD), one of the most common surgical complications in older adults urgently requires a better understanding of modifiable risk factors and underlying mechanisms. Sleep health has emerged as a key public health initiative for optimizing health outcomes in older patients. There is evidence that alterations in the ~24-hour sleep/wake cycle, regulated by our underlying circadian rhythms, worsen after surgical insult to coincide with POD. Sleep and circadian rhythm disturbances are not only more common in older patients and Alzheimer’s disease (AD) and Related Dementias (ADRD) but also track preclinical AD pathology (e.g., tauopathy) and cognitive decline, major delirium sequelae. Our recent work showed that poor sleep traits and 24-hour rest/activity rhythm disturbances were associated with POD risk and predicted ADRD progression. However, these findings have not been rigorously tested in a dedicated surgical cohort with longitudinal sleep/circadian rhythm tracking. Our central hypothesis is that perioperative sleep/circadian disruption promotes POD vulnerability and long-term cognitive decline via AD pathology burden. To address this, we propose SLEEP-POD2, a multisite longitudinal cohort involving 400 older non-cardiac surgery patients (>65 years) from Boston and Baltimore with their representative populations. Leveraging our established perioperative sleep/geriatric research infrastructure (including retention strategies and psychological expertise for delirium sequelae from our first pilot SLEEP-POD study), this proposal will comprehensively assess repeated sleep/circadian measures (ambulatory 7-day actigraphy, electronic sleep diary, & 3-day EEG headband), preclinical AD pathology (via plasma amyloid, tau, neurodegeneration, ATN), and cognition (NIH Toolbox Cognition Battery) at baseline, 1-, 3-month, and 1-year post-surgery. This will establish sleep/circadian health as a potential target for POD prevention and novel insights into neurocognitive recovery after surgery. Guided by strong preliminary data, we propose the following Specific Aims: 1) Determine the effect of preoperative sleep/circadian disruption on POD risk, cognitive decline, and morbidity outcomes, 2) Examine the longitudinal relationship between sleep/circadian disruption and AD pathology, and its relevance to cognitive decline, and Ancillary 3) Establish a biophysiological repository for novel insights into POD, cognitive decline, and AD/ADRDs. Significance: This proposal addresses a key gap in understanding sleep and circadian health in older persons undergoing major surgery. It builds on prior work to provide direct clinical evidence to guide perioperative sleep interventions in older patients that may benefit the most. Innovation: Few studies have leveraged this comprehensive, multidisciplinary approach tailored to older patients to understand sleep before and after surgery. Impact: Successful completion will accrue clinical data to establish potential sleep or life rhythm targets that optimize POD prevention and aid cognitive recovery in older surgical patients.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Establishing a reliable method to achieve allograft tolerance remains an ultimate goal in organ transplantation. We previously reported long-term immunosuppression (I.S.)-free renal allograft survival in humans after induction of only transient hematopoietic chimerism through donor bone marrow transplantation. However, a major limitation of this approach has been its inapplicability to deceased donor transplantation, as the required conditioning regimen must be initiated 5 days before combined kidney and bone marrow transplantation (CKBMT). To expand the application of our approach, it is now imperative to 1) expand the clinical applicability to deceased donor recipients and 2) improve our understanding of mechanisms whereby I.S.-free renal allograft acceptance via induction of transient mixed chimerism is achieved. Current strategies for kidneys preservation include static cold storage and hypothermic machine perfusion7, which limit preservation to a maximum of one day. Longer preservation times are associated with severe ischemia reperfusion injury (IRI) which promote acute rejection, adversely affects long- term graft survival allograft, and importantly inhibits transplant tolerance induction. To reduce IRI, our team previously targeted the integrin CD11b/CD18 (CD11b mAb), which is highly expressed on the surface of innate immune cells. These findings prompted preliminary studies, demonstrating in NHP that CD11b mAb improves hematopoietic chimerism and graft survival. In parallel, advancements in technology, and the development of sophisticated warm perfusion platforms at 22 to 34°C enabled our group and others to mitigate IRI and sustain ex-vivo perfused human kidneys in a metabolically active state for up to 5 days. Therefore, in this R21 proposal, we will 1) Explore an alternative strategy by preserving kidneys with normothermic machine perfusion (NMP) for 5 days, allowing sufficient time to complete a standard non-toxic conditioning regimen prior to CKBMT, 2) In addition to NMP we will inhibit innate immune responses with CD11b mAb, which might promote tolerance induction by mitigating IRI, and 3) Elucidate the molecular mechanisms by which NMP ± CD11b mAb affects mixed chimerism and immune tolerance. We anticipate that mitigation of IRI using NMP and CD11b mAb will allow the safe preservation of kidney grafts for 5 days, enabling the induction of mixed chimerism and achieve allograft tolerance. This will, for the first time, make tolerance induction strategies available to recipients of deceased donor allografts using clinically available technologies. This is a design-driven project with the goal of demonstrating success in a clinically relevant NHP model to justify human clinical trials / R01 application.

NIH Research Projects · FY 2026 · 2026-02

Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is one of the leading causes of dementia. In addition to memory deficits, Alzheimer’s patients exhibit sleep impairments. Aberrant neuronal circuit activity contributes to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients. Multiple lines of evidence suggest that disruptions in slow oscillations facilitate Alzheimer’s progression and might contribute to dementia. Thus, aberrant slow wave activity is not simply symptomatic but can be targeted with therapies. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to rescue cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies are being developed for a number of neurological disorders and could be applicable to Alzheimer’s disease. Alzheimer’s disease is characterized by circuit hyperexcitation at early prodromal stages due to deficits in inhibition, thus disrupting slow brain rhythms, including slow oscillations. Thus, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. We show that isolation of embryonic mouse MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis restores slow wave activity in young mice. We will test the degree to which cell therapy slows neuropathophysiology and rescues sleep as well as memory impairments. Furthermore, to increase translational impact of this work, we will transplant human iPSC-derived interneuron progenitors and determine their role on circuit function and Alzheimer’s progression in a mouse model of amyloidosis. We will implement leading-edge methodology including imaging with voltage-sensors and high-resolution multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will evaluate the efficacy of stem cell therapy using mouse and human progenitors for the treatment of Alzheimer’s disease in a mouse model of amyloidosis. This work will provide strong bases for translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Fibrillar alpha-synuclein (αSyn) aggregates accumulate in dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple systems atrophy (MSA), with distinct topological spread in association with the progression of each disease. While DLB and PD fibrils are structurally similar, MSA fibrils are distinct. PET molecular imaging of amyloid plaques and tau tangles has revolutionized diagnosis, understanding, and clinical trials in Alzheimer’s disease (AD), and PET imaging of αSyn pathologic changes in life has similar potential for these αSyn-associated ADRD that can arise in isolation as well as in association with AD co-pathology. We previously identified SY08 as a molecule that selectively binds αSyn fibrils outside of the ThioT binding site and does not bind αSyn monomer, amyloid-42, or tau fibrils. SY08 binds Lewy body disease brain tissue homogenates with high affinity and with high selectivity over AD tissue, with no significant off target binding to more than 50 CNS targets. Brain [11C]SY08 retention was increased in rodent PD αSyn models. In non-human primates, [11C]SY08 PET imaging showed rapid CNS entry across brain regions; plasma radioactivity analysis showed rapid clearance from blood with limited brain uptake of radiometabolites. In the first-in-human [11C]SY08 PET study (NCT06098612), we detected increased brainstem and cortical binding in PD and DLB, yet limited binding in MSA participants, compared to aged-matched healthy control (HC) participants. Building on these results, the overall goals of this proposal are to 1) evaluate whether fibrillar αSyn burden measured with [11C]SY08 differentiates DLB, PD, and MSA from each other and from HC and AD, and 2) to relate regional [11C]SY08 binding to the expected topology of αSyn pathologic changes and clinical features. As an exploratory aim, we will evaluate if [11C]SY08 binding is increased in isolated REM sleep behavioral disorder (iRBD), a prodromal synucleinopathy state. We hypothesize that [11C]SY08 PET imaging will distinguish DLB, PD, and MSA from HC and from AD participants; that binding in DLB and PD will be higher than in MSA; and that the pattern of [11C]SY08 retention will reflect the distinct topographies of αSyn pathology and the clinical features of each synucleinopathy, without impact of co-morbid amyloid- when present. We also hypothesize that brainstem [11C]SY08 retention will be elevated in iRBD. To accomplish these objectives, we will acquire neurologic exams, detailed cognitive testing, simultaneous [11C]SY08 PET-MRI, and biomarkers of brain amyloid deposition in PD, DLB, and MSA participants with evidence of αSyn pathology on skin biopsy, AD, HC, and participants with isolated RBD. Together, these efforts will establish the potential for developing [11C]SY08 PET as an imaging marker of αSyn pathology in PD, DLB, MSA, and iRBD.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY We aim to test the efficacy of a multi-site resilience intervention for emotional distress in caregivers of patients with severe acute brain injury (SABI) “The Coma Family Program (COMA-F).” Background: Roughly 258 for every 100,000 Americans are admitted to an intensive care unit (ICU) for SABI that causes coma, many of whom survive but remain functionally dependent. Up to 50% of caregivers of such patients experience chronic emotional distress, which drives poor quality of life, caregiver burden, and adverse health events. To address this need we developed COMA-F to promote resilience in SABI caregivers. Innovation: COMA-F fills the increasingly high demand for psychosocial services for SABI caregivers. This population is historically excluded from clinical trials and is without evidence-based psychosocial treatment options. COMA-F begins early to prevent development of chronic distress; specifically, caregivers learn coping skills in vivo to manage stressors related to both acute and long-term caregiving. COMA-F is fully remote (over video call) to increase access and reach, and is low burden (six, 30–45-minute weekly sessions) to account for caregivers’ feelings of overwhelm and competing time demands. COMA-F is innovative and necessary, as the alternative caregiver treatment routinely provided is nothing. Intervention characteristics: We developed COMA-F following the NIH Stage Model. Specifically, we took an efficacious stage 2 intervention (Recovering Together – program among cognitively-intact patients admitted to the Neuro-ICU and their caregivers) and returned to Stage 1 for tailoring for SABI caregivers (we maintained 2 of 3 core mechanisms: mindfulness and coping). We then interviewed 30 SABI caregivers from 14 different Neuro-ICUs, refined content based on their feedback, then conducted a successful multi-site open pilot trial (exceeded feasibility and acceptability benchmarks). COMA-F builds caregivers’ mindfulness and adaptive coping skills to enable them to approach and manage distress, rather than avoid it. Skills are transdiagnostic (address emotional distress broadly) and are rooted in experiential avoidance theory and theories of resilience as a process. Specific aims: We will recruit N=150 SABI caregivers from 3 geographically diverse intensive care units (Massachusetts General Hospital/Harvard Medical School [MGH/HMS], University of North Carolina School of Medicine [UNC], and University of Maryland School of Medicine [UMB]) to 1) determine the efficacy of COMA-F vs health education control in improving emotional distress, 2) evaluate whether effects of COMA-F are maintained through 3-months, 3) determine the degree to which COMA-F-dependent improvements in emotional distress are mediated by improvements in treatment mechanisms (mindfulness, coping) and modified by demographic and clinical variables. Team: Our team is led by Dr. Alexander Presciutti, clinical health psychologist at MGH/HMS, Dr. David Hwang, chief of the Neuro-ICU at UNC, and Dr. Melissa Motta neurointensivist at UMB, all experts in supporting families of SABI patients. We are supported by the robust recruitment infrastructure we built during our multi- site open pilot. Our proposal aligns with the NIA’s Strategic Direction Goal C-6 of “promoting positive caregiving outcomes and supports.” Impact: Our project can drastically improve emotional distress in SABI caregivers a population in high need of evidence-based psychosocial treatments and whose alternative is nothing.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Immigrant workers are integral to American society, contributing to its cultural intactness and economic growth. While much attention has been given to understanding and addressing the health needs of these workers, the equally important challenge of caring for their aging parents has been comparatively overlooked. These aging parents, referred to in this proposal as the “zeroth generation” immigrants, represent a unique demographic whose lives in the US are deeply intertwined with those of their adult children—the first generation. The zeroth generation faces profound challenges, including cultural adjustments, language barriers, social isolation, loss of independent access to resources, and the absence of familiar support systems. These challenges are especially pronounced among zeroth-generation older Chinese immigrants, making their experience even more difficult than that of their adult children. Emerging research underscores the critical role of sleep and circadian function in healthy aging. Studies suggest that immigrant workers are susceptible to sleep disorders and circadian disruptions, likely due to heightened migration stress and acculturation difficulties. Furthermore, immigrants who arrive in adulthood often show poorer cognitive performance compared to those who immigrate earlier in life, with earlier generations displaying more pronounced deficits than their offspring, especially among those with low levels of acculturation. These sleep, circadian, and cognitive challenges may be even more severe in the aging zeroth generation. To address this knowledge gap, we have assembled a multidisciplinary team with expertise in sleep science, circadian rhythms, gerontology, immigrant health, and population health research, uniquely positioning us to conduct this study. The proposed project will establish a cohort of 100 older Chinese immigrants, aged 65 and above, who have joined their adult children in the US, with equal representation of men and women. Participants will undergo comprehensive assessments, including immigrant history, acculturative stress, and cognitive performance evaluations. Sleep and circadian rhythms will be measured using actigraphy, complemented by sleep diaries and validated questionnaires. This two-year pilot project has two specific aims: Aim 1 will investigate whether acculturative stress is associated with poorer sleep and circadian health, defined by worse subjective sleep quality, shorter sleep duration (subjective and objective), greater daytime sleepiness, and more disrupted rest-activity rhythms. Aim 2 will examine whether higher levels of acculturative stress are linked to worse cognitive performance, and whether sleep and circadian health moderates this relationship. This study will provide crucial insights into the cognitive aging of a vulnerable population, guiding future public health interventions and initiatives aimed at supporting aging immigrant populations.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Temporomandibular joint (TMJ) osteoarthritis (OA) is characterized by chronic inflammation, resulting in cartilage degradation and subchondral bone erosion, leading to jaw pain and a compromised quality of life. With no effective treatment currently available, there is a pressing need for new clinical approaches to the problem. Our innovative approach, which could potentially prevent the progression of TMJ-OA to more advanced stages, has the potential to reduce the need for complex and costly surgical procedures. Photocrosslinking tissue proteins (i.e., collagen) is a straightforward and clinically advantageous procedure. It involves applying an aqueous Rose Bengal (RB) solution to the tissue and exposure to green light. Protein crosslinking has been investigated for wound closure, anastomosis, nerve repair, and enhanced wound healing in many tissues. It has also been shown to reduce inflammatory responses in treated tissues, hence the term photochemical tissue passivation (PTP). Published data from our group shows that the network formed by extracellular protein crosslinking prevents inflammatory markers from infiltrating the treatment site. We also showed in rodent knee and shoulder models of fibrosis and post-traumatic arthritis that PTP reduces inflammation in the joint capsule. PTP was initially applied in other tissues by Dr. Redmond’s group. Only after collaborations with Dr. Guastaldi the leap was made to TMJ and this proposal. Dr. Redmond is a pioneer of photocrosslinking therapeutics, and Dr. Guastaldi has extensive experience with animal models, TMJ disease, and regeneration. We believe this innovative approach is only possible due to this partnership's unique combination of expertise. In addition, utilizing state-of-the-art optical diagnostic imaging techniques via Dr. Redmond’s and Dr. Guastaldi’s collaborators at the Wellman Center for Photomedicine (MGH) is another powerful and innovative step in assessing TMJ disease progression and therapeutic efficacy. Polarization- sensitive optical coherence tomography (PS-OCT) is an optical technique that has recently demonstrated the ability to measure cartilage fiber structure and orientation. Dr. Vakoc is a leader in the field of PS-OCT, and his lab is well-equipped to conduct rapid volumetric PS-OCT imaging. We propose to apply to the TMJ for the first time. The overall goal is to explore the potential of PTP to reduce inflammation and prevent the progression of TMJ-OA. A well-established rat model of TMJ-OA will be used to achieve this goal. We hypothesize that PTP of the TMJ capsule offers a promising, minimally invasive approach to halting TMJ-OA progression by reducing inflammation within the TMJ. The following specific aims will address the hypothesis: SA1) To assess the effect of PTP on the whole TMJ structure. PS-OCT imaging, micro-CT, histology, and pain assessment will assess the impact of PTP on the whole TMJ structure. SA2) To assess the efficacy of PTP to reduce TMJ-OA-related inflammation. Whole TMJ specimens tissues will undergo quantitative (Q-PCR) and qualitative (IHC staining) assessment for the presence of inflammatory markers.

NIH Research Projects · FY 2026 · 2026-02

Project Abstract Allergic diseases result from dysregulated Type-2 immune responses to environmental allergens, with sensory neurons playing a key role in both allergen detection and immune activation. Sensory neurons, specifically TRPV1+ peptidergic (PEP) neurons, detect protease allergens, triggering itch and releasing Substance P, which activates dendritic cells to initiate Type-2 immunity. Recent findings reveal a bidirectional neuroimmune circuit involving sensory neurons and a subset of epidermal  T cells, termed GD3s, which produce IL-3. GD3s reside near free nerve endings, where their IL-3 primes Il3ra-expressing PEP1 neurons to enhance allergen detection and promote allergic immunity. Our long-term goal is to elucidate the mechanisms that regulate GD3 maintenance and function in both model organisms and humans. Type-2 immunity depends on feedback loops between sensory and immune cells that amplify allergic inflammation. Our central hypothesis is that sensory neurons not only respond to IL-3, but also sustain murine GD3s and their human counterparts – epidermal  T cells – through ligand-receptor interactions. Supporting this, we find that PEP1 neurons express Ccl8 and Bdnf, while GD3s express the corresponding receptors Ccr8 and Ntrk2, respectively. GD3s depend on Ccr8 for localization and proliferate in response to BDNF, suggesting that neurons actively regulate GD3 positioning and function. Furthermore, we find that human epidermal  T cells share common transcriptional signatures with murine GD3s, suggesting that epidermal  T cells may serve as the human correlate of GD3s. To test our central hypothesis, we will integrate cellular immunology, neurobiology, and molecular biology approaches across three specific aims: (1) Evaluate the chemokine-mediated pathways driving cutaneous GD3 localization, (2) Determine the neuronal factors driving GD3 function, and (3) Identify the human equivalent of GD3 cells. These studies will establish a fundamental understanding of the neuroimmune interactions that drive allergic immune activation, laying the foundation for therapeutic strategies to prevent allergic sensitization, treat chronic itch, and target chronic allergic inflammatory disorders.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY More than one million children who are HIV-exposed but uninfected (HEU) are born to pregnant people with HIV (PPHIV) every year. HEU children have poorer early-life outcomes than their HIV-unexposed peers, including an increased risk of adverse neurodevelopmental outcomes. The pathophysiology of HEU neurodevelopmental outcomes is poorly understood. Mounting evidence suggests that altered placental gene expression may play a key mechanistic role, but the mechanisms have not been fully elucidated. A better understanding of the mechanisms of adverse developmental outcomes in HEU children is essential to improve the care of PPHIV and their offspring. Our overarching goal is to determine the effects of maternal HIV infection and specific antiretrovirals (ARVs) on placental and neural development, identify shared mechanisms of abnormal vascularity affecting both placenta and fetal brain, and how these perturbations impact HEU child neurodevelopment. Leveraging our ongoing multi-country birth cohort and linked placental biobank, we will perform spatial transcriptomics analysis, immunostaining, flow cytometry, and leverage a mouse model of pregnancy to determine which gene expression changes occur in the setting of maternal HIV and ARVs that might be linked to adverse neurodevelopmental outcomes. Innovation: Distinct advantages of our proposed research include 1) novel focus on the placenta-brain axis and the placenta as a source of adverse child health outcomes, 2) large multi-site cohort across HIV-affected regions of Africa and use of formalin-fixed samples, and 3) innovative methods to identify intervenable mechanisms. Investigators: Our interdisciplinary mPI team with expertise in HIV and birth cohorts (Bebell), placental immunology in HIV (Gray) and mouse models of ARVs (Serghides) paired with expertise in spatial transcriptomics (Arora), computational analysis (Shu), maternal and child health (Ngonzi, Kumbakumba) and perinatal pathology (Roberts, Mtshali) is well-poised to complete this work. Approach: We will leverage biobanked placental samples from mother-child dyads enrolled in mPI Bebell's (K23AI138856/ R01HD11232) and mPI Gray's (R01HD102050) birth cohorts, mPI Serghides' established mouse model of ARVs and HIV in pregnancy, and mPI Gray's established HIV immunology laboratory to elucidate mechanisms of HIV and ARV exposure on the placenta and neurodevelopment through via these Specific Aims: 1) investigate the impact of HIV and specific ARVs on placental spatial proteomic and transcriptomic expression differences, 2) compare quantitative and functional β-catenin, LEF-1 and FXIIIA1 expression between PPHIV and HU controls, and 3) assess endothelial network development in placenta and brain tissue during pregnancy and early life in HIV- and ARV-exposed mice. Identifying mechanisms HIV- and ARV-related placental abnormalities and adverse HEU child neurodevelopment and growth has great potential to improve child health outcomes by optimizing ARV selection in pregnancy and identifying and intervening early for children at risk of adverse growth and neurodevelopmental outcomes.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The recent approval of the Respiratory Syncytial Virus (RSV) vaccine for administration in pregnancy presents a novel opportunity to define immune responses of the maternal-fetal dyad, and how that response crosses the placenta and mammary tissue. Recent work indicates that timing of maternal RSV vaccination alters placental antibody transfer to the fetus. To maximize infant protection after maternal RSV vaccination, key gaps in knowledge include: 1. The extent to which maternal vaccination elicits direct fetal antigen-agnostic and antigen- specific cellular responses to augment infant protection from RSV and other infections. 2. How gestational age at vaccination alters maternal antibody response, subsequent placental and breastmilk antibody transfer, and persistence of immunity in the infant. The proposed studies will test the central hypothesis that timing of maternal vaccination, antibody Fc-receptor binding properties, glycosylation profiles, neutralizing antibody levels and non-neutralizing antibody functions are all key determinants of placental and breastmilk antibody transfer to the neonate. These antibody features will work in concert with fetal innate and adaptive immune responses to maternal vaccination, driving protection of the infant through 6 months of age. In a cohort of 400 pregnant women and their infants, this study will examine fetal cellular responses to maternal RSV vaccination, both RSV-agnostic and RSV-specific, by evaluating fetal immune cells isolated from placental villi and cord blood (Aim 1). It will comprehensively profile placentally- and breastmilk-transferred antibodies after RSV vaccination in pregnancy, evaluating IgG subclass, Fc-receptor binding, glycosylation profile, and neutralizing capacity of antibodies using in vivo and in vitro assays (Aim 2). It will then evaluate how antibody properties and timing of maternal vaccination impact the durability of antibody-mediated and cellular immunity in infant blood and breastmilk, through 6 months of age (Aim 3). Machine learning approaches will be used to estimate the magnitude and specific features of protective immune responses induced by maternal vaccination, not only for RSV, but also for influenza, Tdap, and COVID-19. These methods will generate a comprehensive model of durable infant protection from maternal vaccination spanning multiple pathogens. Defining these immune principles across the maternal-fetal dyad will generate key biological insights necessary to optimize neonatal and infant protection.