Massachusetts General Hospital

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract Nutrients and oxygen are sensed within our muscle to control muscle growth. Disruption of either signal is sufficient to promote muscle atrophy and is driven by a common transcriptional program via the Forkhead box O (FoxO) and Hypoxia Inducible Factor (HIF) transcription factors, which sense nutrient starvation and oxygen, respectively, to control cellular homeostasis. While the critical transcription factors that sense the absence of these signals have been identified, the downstream mechanisms that initiate muscle loss when nutrients or oxygen are limiting are complex and still only partly understood. Muscle atrophy occurs when protein degradation rates exceed protein synthesis. Autophagy is an intracellular degradation pathway that is activated in skeletal muscle under starvation or hypoxia. How, mechanistically, these signals activate autophagy remains unclear. Here, we identify C10orf10/Depp1, a protein of unknown function, as a direct transcriptional target of FoxO and HIF controlled by nutrient starvation or hypoxia in skeletal muscle. Upon expression, C10orf10/Depp1 localizes to the mitochondria and is necessary and sufficient to induce skeletal muscle autophagy and atrophy in vivo. We hypothesize C10orf10/Depp1 is a key mediator of muscle homeostasis that when activated promotes muscle atrophy. To investigate this hypothesis, we will interrogate 3 specific aims. In Aim 1, we will define the role of C10orf10/Depp1 in skeletal muscle using novel C10orf10/Depp1 mouse models. In Aim 2, we will define the role of C10orf10/Depp1 at the mitochondria in vitro and in vivo. In Aim 3, we will test the role of C10orf10/Depp1 in mouse models of FoxO and HIF-mediated muscle atrophy. The proposed studies will be conducted using ex vivo models of human skeletal muscle cells and genetically modified mouse models to define a novel muscle atrophy pathway that is controlled by multiple upstream atrophy signals. Our ultimate goal is to develop clinical relevant strategies to reduce muscle loss across multiple disease scenarios.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Breast cancer is the second leading cause of cancer-related death for women in the US. Three imaging modalities are used for breast cancer screening – mammography is the standard routine imaging modality, while ultrasound and MRI are reserved for supplemental imaging. Mammography has reduced breast cancer-specific mortality in randomized controlled trials; however, there remains controversy regarding its high false-positive outcomes, use of ionizing radiation, and low sensitivity/specificity to dense breasts. MRI has high specificity and sensitivity in detecting earlier stage breast cancer, leading to better prognosis and improved estimated 10-year survival. However, it is only used as a supplemental breast screening modality – currently reserved for high-risk women due to cost, IV contrast requirements, and limited throughput of 1.5 T and 3 T scanners. We propose using low-field MRI to improve the nationwide accessibility of breast cancer screening. While ultra-low (<0.01 T) and low field (~0.01 T to 0.1 T) MRI has been explored for some time, recent advances in low-cost hardware, novel image encoding, and deep learning-based reconstruction create new opportunities for broader impact and clinical translation. We build on this progress and propose a unique combination of innovations in RF coil design, pulse sequence design, and AI-based image reconstruction. In this regime, the unique MRI physics translates into distinct image contrast mechanisms that rely on the MR parameters T1 and T1rho. Published work demonstrates that quantitative ex vivo T1/T1rho measurements could clearly differentiate between tumor, fibroglandular tissues and fat at low magnetic field strengths, but little has been explored in vivo. We hypothesize that T1/T1rho can be a sensitive marker to identify cancerous tissues and recognize a unique opportunity to screen for breast cancer with ULF MRI. We will use our ULF MRI scanners at Martinos Center and NIST as test- bed systems to demonstrate that we can quantitatively distinguish cancerous tissue from healthy breast tissues. We will prototype high performance flexible bilateral RF coils specifically for low field, develop and implement a compressed-sensing based T1rho-sensitive magnetic resonance fingerprinting (MRF) pulse sequence and validate its diagnostic performance in breast cancer patients. Our AI-based image reconstruction pipeline, DRONE, will be used on the T1rho-MRF data to generate quantitative T1, T2 and T1rho maps of fat, fibroglandular and tumor tissues. While mammography is a mature and entrenched modality, our proposed approach provides a radiation-free, pain-free, and portable alternative that can serve populations currently excluded from screening. If successful, this innovative methodology will be ready for further evaluation on a larger population and commercialization as a future point-of-care low field breast scanner. Regardless of breast density, all persons would benefit from this new ULF screening method, especially high-risk persons for whom radiation-based methods are contraindicated, persons with implants who cannot undergo the breast compression, persons with implanted metal, and finally, those 29.5 million women who opt-out of mammography.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Suicide is a leading cause of death among adolescents, and rates of suicide in this age group have nearly doubled over the past two decades. However, our ability to predict and prevent suicidal thoughts and behaviors (STB) is limited, in part due to an emphasis on static, distal risk factors. Emerging research suggests that irregularities in sleep and circadian rhythms—systems which undergo marked change during adolescence— may be promising short-term predictors of suicide risk. However, prior studies have largely relied on retrospective self-report measures, long follow-up intervals, and have often overlooked the contribution of the circadian system, which collectively limits insight into the mechanisms underlying these dynamic processes that may increase suicide risk. This K23 project aims to address these gaps by leveraging intensive longitudinal methods, including actigraphy and collecting a biological indicator of endogenous circadian rhythms in a clinically acute adolescent sample. The proposed study will recruit 100 adolescents hospitalized for STB. During hospitalization, participants will continuously wear wrist actigraphs to measure objective sleep metrics (e.g., total sleep time, sleep onset latency) and provide continuous urine samples to estimate endogenous circadian timing using 6-sulfatoxymelatonin (aMT6s), a reliable indicator of circadian timing. Participants will also complete ecological momentary assessments (EMA) of suicidal ideation throughout their inpatient stay. STB will be reassessed at 1 and 3 months post-discharge, a period of heightened suicide risk. Three aims guide the project: (1) to test whether night-to-night variations in sleep predict next-day SI during hospitalization and STB after discharge; (2) to evaluate whether later circadian timing is associated with higher SI during hospitalization, increased risk for STB post-discharge, and shifts in the timing of SI toward later hours; and (3) to examine whether greater circadian misalignment—i.e., discrepancies between sleep behaviors and the biological clock—predicts increased STB both during hospitalization and after discharge. The proposed training plan complements the Candidate's research plan and will provide the Candidate with rigorous training in actigraphy, biological measurement of circadian rhythms, and advanced longitudinal data analysis. A team of leading scholars will provide expert mentorship in the assessment of adolescent suicide, sleep and circadian biology, and, intensive longitudinal methods, and biostatistics. The project is embedded in a rich, interdisciplinary research environment at Massachusetts General Hospital. By identifying modifiable, objective markers of short-term suicide risk, this research has the potential to advance predictive models and inform clinical interventions, particularly chronotherapeutic approaches. The proposed study will promote the Candidate's long-term goal of establishing an independent program of research focused on leveraging sleep and circadian science to improve youth mental health and reduce STB.

NIH Research Projects · FY 2026 · 2026-06

Abstract The ability of tumor cells to adapt and survive endogenous and environmental stress is essential for tumor initiation and development. Glioblastoma (GBM) is the most malignant brain tumor, with high mortality and resistance to therapy. Within the heterogeneous GBM tumors, a highly tumorigenic subpopulation of Glioma Stem Cells (GSCs) drives tumor growth and promotes recurrence. GSCs can survive and proliferate in a relatively hostile tumor microenvironment, which triggers adaptive stress response mechanisms to restore protein homeostasis and promote tumor cell survival under abnormal conditions. Most forms of stress converge on one signaling pathway termed the integrated stress response (ISR), which signals through phosphorylating eIF2α (p-eIF2α; eukaryotic translation initiation factor 2α). Activation of the ISR causes a temporary shutdown of global protein translation and selective translation of cytoprotective transcripts. However, under prolonged stress, p-eIF2α promotes apoptosis. p-eIF2α halts protein synthesis by inhibiting eIF2B, which plays a key role in regulating mRNA translation and balancing the pro- and anti-survival effects of p-eIF2α. Our studies revealed a direct link between ISR signaling and response to several GBM therapeutics. Our central hypothesis is that the interplay between p-eIF2α and eIF2B determines therapeutic sensitivity and translation potential that drives tumor growth. We propose that while high levels of ISR effectively block global protein translation, mild ISR signaling, such as one caused by therapy, reprograms translation and selectively enhances the translation of a subset of mRNAs to confer cytoprotection and promote survival. To test our hypotheses and to address how conventional GBM therapies or the abnormal tumor microenvironment supports tumor progression and confers therapeutic resistance, we propose to carry out the following aims: Aim 1. Defining the role of eIF2B in translational regulation, tumor growth, and therapy response. Aim 2. Investigating the role and mechanism of translational reprogramming in GBM therapy response. Aim 3. Selective Targeting of aminoacyl-tRNA synthetases to enhance the efficacy of GBM Therapies. The proposed work will determine whether modulating the ISR could impair tumor growth and increase the efficacy of targeted therapeutics currently used in the clinic. Cell culture or in silico models cannot closely mimic the tumor environment, compounds pharmacokinetics and brain penetrance of small molecules, therefore the use of animals is warranted in our study.

NIH Research Projects · FY 2026 · 2026-06

Autoimmune diseases share many genetic risk factors, manifestations and treatment responses, yet are often studied in individual research silos without consideration of their rich overlapping pathophysiology. By studying these diseases in combination, we create a multifaceted evaluation that 1) enhances the shared mechanisms uniting these diseases, and 2) highlights the unique factors that mechanistically distinguish one disease from another. The studies within this proposal use systems immunology approaches to demonstrate commonalities and distinctions in peripheral T cells at a cellular and transcriptional level in autoimmunity (Aim 1). Dr. Nestor has already created a large integrated dataset of 3.5 million cells across 11 autoimmune conditions for use in these studies, which is notable for 10 distinct regulatory T (Treg) cell populations, 2 of which are markedly upregulated in lupus. Lupus is a complex heterogeneous autoimmune disease that can have devastating consequences yet still only has limited treatment options. To validate the above findings, a prospective cohort of patients from the Lupus Biobank that Dr. Nestor created, will be characterized using multiomics techniques with a focus on isolating the Tregs of interest and defining their functionality (Aim 1). To further investigate the role of Tregs in the pathophysiology of lupus and determine their potential as therapeutic targets, a novel interleukin-2 (IL-2) mutein will be assessed in the MRL/lpr mouse model of lupus for its ability to induce Treg expansion and ameliorate disease (Aim 2). Low-dose IL-2 has yielded positive results in lupus previously, but the IL-2 mutein proposed for use in these experiments has an extended half-life and increased specificity allowing for less frequent dosing and minimizing off-target side effects. The studies proposed above illustrate a well-defined research pathway that leverages a large cross-autoimmunity dataset to identify shared and disease-specific perturbations in T cells and the downstream validation of these findings in both patients and a mouse model of lupus. The enclosed proposal entails a rigorous career development plan and robust research proposal that will ensure Dr. Jacquelyn Nestor’s success over the five-year funding period and beyond. Dr. Nestor is an Associate Physician at Massachusetts General Hospital (MGH) and Instructor in Medicine at Harvard Medical School (HMS). Under the guidance of her mentors, Drs. Andrew Luster and Alexandra-Chloé Villani, and within the greater MGH, HMS and Broad Institute immunology research communities, she will have access to the necessary mentorship, scientific expertise, and technology required to complete her proposed studies. Her proposal will build skills in single-cell sequencing, computational analysis, and Treg identification and functional evaluation. This expertise, in combination with her already outstanding research background in lupus, will support her ultimate R01 proposal and successful transition to independence as a productive physician scientist with a basic-translational research program utilizing systems immunology approaches in lupus.

NIH Research Projects · FY 2026 · 2026-06

Title: R-loop-induced CGG contraction as a therapeutic approach for Fragile X syndrome PROJECT SUMMARY Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder and one of the most common monogenic causes of inherited intellectual disability and autism spectrum disorders (ASD). FXS has a higher incidence among males (~1:3000) than females (~1:6000). Approximately 60% of FXS individuals demonstrate autistic features, 86% have an anxiety disorder, and almost all exhibit cognitive, motor, and developmental delays. Disease-modifying treatments have been of major pharmaceutical interest. Clinical trials have largely targeted pathways downstream of FMR1 or alternative pathways to modulate disease phenotype, such as arbaclofen and metabotropic glutamate receptor 5 (mGluR5) antagonists, with a phosphodiesterase-4D (PDE4D) allosteric inhibitor recently shown to improve cognitive function. However, because FMRP — the gene product of FMR1 — has many functions in the brain, the molecular, synaptic, and circuit dysfunctions seen in FXS may not be easily corrected by targeting a single downstream or parallel pathway. Despite intensive efforts to better understand the etiology, there remains a dearth of disease-specific treatments. It is now known that restoring FMR1 expression can at least partially rescue FXS phenotypes. Towards this goal, we recently identified a new approach that corrects the underlying genetic defect by reactivating the silenced FMR1. By investigating conditions favorable to FMR1 reactivation, we found that two compounds (“2i”) — a MEK and a BRAF inhibitor — could fully turn back on FMR1 in cellular models. We traced the mechanism to 2i-mediated DNA demethylation and formation of site-specific R-loops that then recruit endogenous DNA repair mechanisms to excise the CGG repeat. We went on to demonstrate that the CGG contraction and gene reactivation could be recapitulated by driving site-specific R-loop formation using dCas9 and an FMR1-specific gRNA. These discoveries lead to a model in which R-loops induce a positive feedback cycle comprising DNA demethylation, de novo FMR1 transcription, and reinforcement of R-loops at the CGG repeat — which in turn drive recruitment of endogenous DNA repair mechanisms to remove the aberrant RNA:DNA structure. Excision of the long CGG repeat then enables the reactivation of FMR1. We observed that repeat contraction is specific to FMR1 and fully restores production of FMRP protein. Our study thereby identifies a novel and potential method of treating FXS. In the proposed research, we aim to obtain proof-of-concept that R-loops form and induce contraction of the CGG repeat in post-mitotic neurons and that the contraction can lead to FMR1 reactivation in a human 3D disease model for FXS. If successful for FXS, the R-loop approach could be a potential therapeutic for other tandem repeat disorders as well.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY As US hospitals continue to close their labor and delivery units, more than 2.3 million women of childbearing age live in maternity care deserts without local access to specialized care. When pregnant or postpartum women require unplanned, emergent care, they may seek care from low-obstetric-resourced settings, such as the local, general emergency department (ED). General EDs without specialized inpatient obstetric services available may not be optimally equipped to recognize, diagnose, and treat obstetric and postpartum-related conditions, leading to worse patient outcomes. One recent approach to addressing maternal morbidity and mortality in low-obstetric- resourced EDs has been to improve obstetric readiness, or the capability (i.e., equipment and training) to provide high-quality care for a patient before, during, and after birth. However, there are currently no standardized means of implementing and assessing obstetric readiness in EDs nor evaluation of obstetric readiness and its association with quality of care. The overarching objective of this 4-year R01 project is to identify the settings that would benefit most from obstetric readiness efforts, improve our understanding of the resources needed for EDs to be ready to provide emergency obstetric care, and if readiness plays a role in improving outcomes. We will leverage our existing National ED Inventory database—containing information on all non-federal, non- specialty, US hospital-affiliated EDs—linked to patient-level data from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project’s State Emergency Department Discharge and State Inpatient Discharge datasets in eight diverse states to investigate ED obstetric readiness. In Aim 1, we will determine if urbanicity and stage of pregnancy is associated with seeking emergency care in low-obstetric-resourced EDs to identify optimal settings for future interventions. In Aim 2, we will survey EDs to measure obstetric readiness using the Alliance for Innovation on Maternal Health’s framework for obstetric readiness to establish if higher readiness is associated with higher quality of emergency obstetric care. In Aim 3, we will use in-depth qualitative interviews with high- and low-performing EDs to identify key components of obstetric readiness that cannot be ascertained in surveys, such as functional readiness to provide care rather than structural readiness (e.g., presence of equipment), as well as facilitators and barriers to provision of high-quality emergency care for pregnant and postpartum patients. Based on preliminary data, we estimate identifying approximately 1 million admissions for birth, with over 80% power for the statistical analyses in Aims 1 and 2. The present R01 project will provide a unique opportunity for the first large-scale evaluation of ED obstetric readiness. This study directly responds to the NICHD priority to improve treatment of women at risk for pregnancy-related morbidities and mortality; the Healthy People 2030 objectives to reduce maternal deaths (MICH-04) and severe complications (MICH-05); and particularly focuses on the NICHD’s Goal 3 on pregnancy outcomes.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract The objective of this project is to develop and evaluate the feasibility of an integrated mechano-arthroscope for minimally invasive assessment of joint tissue pathology and micromechanics. Joint tissues, such as cartilage and meniscus, perform crucial mechanical function of bearing and dissipating loads imparted upon the joints. To support this functional role, joint tissues possess specialized solid and liquid extracellular matrix constituents that provide the necessary interplays of elastic stiffness and viscous dissipative behaviors. Degenerative joint disease (arthritis) disrupts these intricately designed mechanical machineries, directly degrading tissue function, causing pain and reduced mobility. Arthritis is a global health crisis that affects more than 500 million people worldwide, with prevalence and years lived with disability attributable to the disease projected to continue to rise. This crisis is exacerbated by the fact that an effective cure is yet to be found. A fundamental roadblock in the medical treatment of arthritis is the lack of effective ways to assess the deficiencies of joint tissues and their restoration of functional integrity following treatments in living patients. Despite mechanics being the direct determinant of function, current diagnostic paradigm for joint pathologies does not, in fact, include any direct measures of the mechanical quality of joint tissues. Diagnostic imaging provides structural metrics such as joint space narrowing and cartilage lesion size, while arthroscopy, the gold standard for grading cartilage defects and repair, provides visualization of gross appearance and manual palpation of intra-articular structures. This does not allow orthopedic surgeons to precisely evaluate the functional mechanical integrity of joint tissues to guide surgical treatments and monitor the status of tissue repair and healing following treatments. This gap not only hinders the direct medical care of patients with joint pathologies, but also severely restricts the development of effective therapies on a larger scale due to the absence of crucial mechanical outcome measures in living patients. This project directly addresses this critical gap. We propose to develop a new imaging tool termed ArthSHEAR, in the form of a needle-sized integrated mechano-arthroscope, that will permit minimally invasive assessment of both gross appearance and underlying micromechanical properties of intra-articular tissues in the doctor’s office. ArthSHEAR is based on the core technology of Speckle rHEologicAl microscopy (SHEAR) that enables passive, noncontact mapping of viscoelastic behavior in gross tissues without indenting or otherwise manipulating the sample. The first phase of project will develop and validate the ArthSHEAR instrument and data processing algorithms to permit arthroscopic mapping of the indices of mechanical firmness and viscous dissipation. The second phase will conduct an in vivo longitudinal imaging study in a swine model of osteoarthritis (OA) to evaluate the feasibility of ArthSHEAR for discerning and tracking the micromechanical changes due to degenerative disease. This study will provide the first in vivo longitudinal data that tracks micromechanical transformation over the full course of OA progression from healthy to complete joint damage.

NIH Research Projects · FY 2026 · 2026-06

Three-dimensional imaging of preclinical and clinical samples to assess the amount, shape and quality of tissues is essential for research studies in musculoskeletal biology, regenerative medicine, and other fields. One established imaging technique for non-destructive assessment of specimens is microcomputed tomography (microCT), which utilizes the differential attenuation of X-rays by various tissues to provide high resolution (0.5 to 10 ìm) 3D images and to facilitate quantification of tissue morphology. MicroCT has been used extensively to characterize bone density and bone morphology, and is an indispensable tool for investigators in a variety of fields, including musculoskeletal biology, developmental biology, fracture healing, organ cross-talk, tissue engineering and regenerative medicine. Advances in imaging technology and contrast agents now allow the use of microCT for characterization of non-mineralized tissues (e.g. cartilage, tendon, & blood vessels), enabling broad usage of this technology. Here we propose to purchase a cabinet, cone beam, ultrahigh-resolution nano/microCT system (ìCT50, Scanco Medical AG). This advanced system acquires images at voxel sizes ranging from 0.5 to 100 ìm and can accommodate sample sizes up to 105 mm in diameter and 120 mm in height. The system is capable of high-throughput imaging due to an integrated automated sample changer, large X-ray detector and powerful computer workstation. The system will benefit a large group of 11 major and 14 other/minor users who have a track record of using microCT to advance their research. These investigators are funded by 23 current NIH research grants from 7 different NIH institutes (NIAMS, NIDDK, NICHD, NIA, NHLBI, NINDS, and NIDCR). The projected usage of the system by NIH-funded investigators is 90% of the accessible use time (AUT, 69% by major users and 21% by other/minor users). The new scanner will be replacing a 17-year-old microCT system that will no longer by supported by the manufacturer due to lack of access to replacement parts (including the x-ray tube, a critical component of the system). Furthermore, the computer workstation required to operate the machine is no longer produced, and any future repairs and service would need to be sourced by a 3rd party vendor. With strong institutional support, this new state-of-the-art nano/microCT system will be embedded in the Translational Imaging and Phenotyping Core, which is part of the NIH P30-funded Center for Musculoskeletal Research. Importantly, the PI has extensive expertise in use of this technology and has successfully operated this imaging core for over a decade. Altogether, the acquisition of a new nano/microCT system via this shared instrumentation grant will have an immediate and sustained benefit to investigators in the greater Boston area and beyond.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The gastrointestinal tract is colonized by a complex community of commensal bacteria living in harmony with the host. It is now well known that the composition of this microbiome and its interaction with the immune system can have a profound impact on health and disease, not only in the gut environment but throughout the whole body. As such, microbial dysbiosis in the gut is linked to not only inflammatory bowel diseases (IBD), but also several types of autoimmunity, metabolic diseases, and cancer. Indeed, many autoimmune diseases are associated with the prevalence of particular commensal taxa, suggesting a causative link between immune responses against the microbiota and autoantigens. This idea, known as the mucosal origins hypothesis, involves the concept of immune epitope spreading where adaptive immune responses spread from foreign antigens in microbiota to autoantigens in the joints (in the case of rheumatoid arthritis) or other tissues. Epitope spreading may be facilitated by similarities in T cell and B cell epitopes expressed by the two entities, a concept known as molecular mimicry. While there has been much evidence for molecular mimicry and epitope spreading during the etiology and progression of autoimmune diseases, very little is known about the mechanisms contributing to it, largely due to the absence of suitable experimental systems to carry out detailed mechanistic studies. A better understanding of the fundamental biology underlying epitope spreading from commensal bacteria to autoantigens would greatly promote our understanding of autoimmune disease development and promote future therapies. The overall goal of this project is to develop a robust in vivo model of molecular mimicry between T cell antigens of intestinal commensal microbiota and host tissues to enable detailed studies of T cell epitope spreading during the development of autoimmunity. We hypothesize that the transgenic expression of identical or similar model T cell antigens in commensal bacteria and mouse tissues coupled with the use of peptide:MHC tetramer reagents in SKG autoimmune mice will provide a very powerful experimental system for studying the development of crossreactive T cell responses to these antigens. We will establish this powerful and important tool for the field by 1) generating commensal bacteria expressing model self antigens, 2) validating T cell recognition of model antigens in mice colonized with these transgenic bacteria, and 3) tracking T cell responses to shared model antigens during the development of autoimmunity in SKG mice.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Peripheral artery disease (PAD) is increasingly prevalent with advancing age and often necessitates revascularization with endovascular surgery to improve limb perfusion. However, thrombosis of endovascular interventions occurs in approximately one in five patients within 6 months post-surgery and is the leading cause of amputation in older adults (≥65 years). Prognosis after amputation is poor, with up to 50% of older patients dying within a year. Post-menopausal women face double the risk of arterial thrombosis compared to men and are more likely to die post amputation. Therefore, preventing arterial thrombosis is a critical surgical need in older patients after endovascular revascularization, especially for postmenopausal women. The current thromboprophylaxis standard of care (SOC) for preventing arterial thrombosis is 1) dual antiplatelet therapy (DAPT) with aspirin and clopidogrel or 2) low-dose rivaroxaban (an anticoagulant) with aspirin. While this “one size fits all” approach is intended to reduce the risk of major lower extremity thrombosis, 20% of patients still experience post-surgical thrombosis and this high failure rate of the current SOC underscores the urgency of developing novel strategies to prevent arterial thrombosis, thereby reducing amputations in older patients. To address this critical gap, our team has developed and piloted the Thromboprophylaxis for Arterial Revascularization to Guide Elderly Therapy (TARGET) protocol, which personalizes thromboprophylaxis based on individualized coagulation profiles. An individual’s coagulation profile is evaluated through a widely available point of care (POC) assay called thromboelastography with platelet mapping (TEG-PM). TARGET is a novel approach that allows clinicians to use objective coagulation data to personalize the administration of commonly used thromboprophylaxis medications thereby mitigating thrombosis without increasing bleeding. The goal of this R01 proposal is to conduct a multicenter, randomized controlled trial (RCT) to evaluate efficacy of the TARGET protocol in reducing thrombosis post lower extremity revascularization. Our central hypothesis is that the TARGET protocol will significantly reduce thrombosis rates compared to the SOC, and that women will be less responsive to DAPT due to differences in their platelet P2Y12 signaling pathway. Our aims are to 1) Evaluate the effectiveness of the personalized TARGET protocol to thromboprophylaxis in reducing thrombosis rates compared to the SOC, and 2) Identify the mechanisms contributing to sex-specific differences in platelet response to antiplatelet medications.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract: Current hormonal contraceptives work by disrupting the hypothalamic-pituitary-gonadal axis and preventing follicle development only in its last stage leading to ovulation. All current hormonal contraceptives share unwanted side effects due to the wide tissue distribution of sex steroid receptors. In contrast, anti-Müllerian hormone (AMH) functions by inhibiting the earliest steps of primordial follicle activation and early pre-antral follicle growth, which are gonadotropin-independent. Furthermore, AMH receptor (AMHR2) expression is highly restricted to reproductive organs. Our preliminary data has validated AMHR2 as a contraceptive target by demonstrating that recombinant AMH can rapidly and reversibly induce long-term contraception in multiple mammalian models, with no overt toxicity, and no significant loss of sex steroid production. However recombinant AMH protein and gene therapy treatments are currently impractical and not cost-effective for long-term human contraception. We therefore propose to develop a novel class of female contraceptives that target AMHR2 and work by inhibiting pre-antral follicles. Our long-term goal is to identify a lead candidate AMHR2 agonist that is safe and effective at producing contraception in preclinical models and could be translated to a clinical trial in women. In Aim 1 we will investigate the druggability of AMHR2, and the mechanism of action of small molecule agonists. We will also develop new in silico models and cell-free in vitro binding assays based on binding to the kinase domain of AMHR2 and induction of type I receptors. In Aim 2 we will design and evaluate analogs of CYC116, a hit identified in previous, screening efforts, using an iterative approach to enhance potency, and specificity. Biological activity of CYC116 analogs will be confirmed using ex vivo cultures of mouse ovaries and rat fetal urogenital ridges. In Aim 3 we will perform in vivo preclinical evaluation of CYC116, and other lead candidate agonists, to determine their pharmacokinetics, pharmacodynamics, and toxicity. AMHR2 agonists will be evaluated in mating studies in mice to evaluate their effectiveness at producing contraception, effects on the reproductive system, reversibility, and teratogenicity. We expect these studies to demonstrate whether small molecules that agonize AMHR2 have a potential utility as non-hormonal female contraceptives.

NIH Research Projects · FY 2026 · 2026-06

PROJECT ABSTRACT / SUMMARY Transarterial Radioembolization (TARE) is growing in interest as a viable curative radiation therapy treatment, particularly for liver tumors such as hepatocellular carcinoma (HCC). Taking advantage of the dual blood supply in the liver, a microcatheter is used to perfuse radioactive yttrium-90 (Y-90) microspheres into the branches of the hepatic artery with a twofold objective: to cut off the tumor nutrients supply by embolizing the tumor-feeding vasculature and kill the tumor cells by emitting ionizing beta radiation. Increasing the radioactivity leads to a higher dose and, therefore, a greater effect. In this context, recent clinical trials have shown promising results associated with a personalized tumor-absorbed dose. However, current clinical dosimetric methods do not address quantitative predictive dosimetry. They use inaccurate surrogates to predict the spatial distribution of Y- 90 after administration and ignore the non-uniformity pattern to calculate the absorbed dose. The main goal of this proposal is to overcome the current clinical limitations by designing a novel quantitative TARE dosimetry framework capable of predicting realistic Y-90 dose distributions. To achieve this goal, I will work on the following specific aims: (1) to develop a patient-specific liver vasculature model; (2) to develop an HCC-specific uptake model; (3) to design a TARE dosimetry schema including the previous models. A retrospective cohort of treatment-naïve HCC patients who presented a solitary liver-confined lesion ≤ 8 cm, treated with the radiation segmentectomy technique at Massachusetts General Hospital, will be used. Routine pre-treatment vasculature studies will be employed to extract liver patient-specific vasculature. This will guide an in-house algorithm to create a patient-specific liver vasculature model. Pre-treatment uptake evaluations will be utilized to inform the HCC-specific uptake model. Lastly, these models will be integrated into a robust dosimetry schema alongside our recently developed TARE simulator, which predicts the activity distribution within the tumor and normal liver as compartments. Finally, a Monte Carlo toolkit will be used to transform the activity predicted into patient-specific dose distributions. The principal investigator will use the experience and expertise of his mentoring team (Dr. Alejandro Bertolet, Dr. Harald Paganetti, Dr. Eric Wehrenberg-Klee, and Dr. Ted Hong) to learn the skills and abilities necessary to accomplish the proposed research. He will also attend seminars, coursework, and conferences on liver cancer, radiobiology, medical physics/nuclear medicine, clinical trials design, grant writing, and leadership skills. This plan will prepare the principal investigator to lead an independent research program and establish a lab with a unique expertise.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT White matter damage plays an important role in the pathophysiology of cerebrovascular disease, including vascular contributions to cognitive impairment and dementia (VCID). Oligodendrocytes, the primary cells in the white matter, do not proliferate on their own; instead, their progenitor cells, known as oligodendrocyte precursor cells (OPCs), are essential for the generation of new oligodendrocytes during the remyelination process following white matter injury. Although OPCs are essential for white matter recovery and repair, the mechanisms regulating their proliferation and differentiation, key processes in compensatory oligodendrogenesis, still remain poorly understood. Subcortical ischemic vascular dementia (SIVD) is the most common subtype of VCID and is often associated with aging. It is clinically manifested by cognitive decline due to subcortical infarcts and persistent cerebral hypoperfusion leading to progressive white matter deterioration. As the global population ages, the incidence of SIVD is expected to increase, underscoring the urgency of developing effective treatments. Understanding the cellular and molecular basis of white matter damage and repair, with a focus on the role of OPCs in compensatory oligodendrogenesis, is critical. While the regulatory mechanisms behind OPC proliferation and differentiation during development are relatively well understood, the processes in the adult brain under pathological conditions remain elusive and represent a significant gap in our current knowledge. Notably, polypharmacy among elderly patients has become a serious societal problem worldwide, and it is important to pursue the therapeutic option of exercise as a non-pharmacological approach to mitigate cognitive decline in patients with SIVD or other dementias. We and others have shown that daily exercise is effective in promoting compensatory responses in mouse models of cerebrovascular disease, including stroke and VCID. Given the link between exercise, circadian/diurnal rhythms, and OPC function, our study proposes two specific aims to test the overarching hypothesis that exercise preconditioning promotes compensatory oligodendrogenesis by regulating the time-dependent expression changes of Bmal1, a key clock gene, in SIVD. In Aim 1, we will evaluate the effects of exercise preconditioning on OPC function and Bmal1 circadian/diurnal changes in mouse models of SIVD. Aim 2 will demonstrate that Bmal1 deficiency in OPCs reduces the efficacy of exercise preconditioning on compensatory oligodendrogenesis and cognitive function in SIVD mice. Our study is expected to pave the way for new non-pharmacological therapeutic strategies for SIVD and other types of dementia.

NIH Research Projects · FY 2026 · 2026-06

Traumatic brain injury (TBI) is a strong environmental risk factor for dementia. The heterogeneity of TBI phenotypes (e.g., focal contusion vs. diffuse injury) is thought to contribute to the failure of clinical trials. Though pathoanatomically distinct, controlled cortical impact (CCI) and diffuse closed head injury (CHI) models each activate interleukin-1b, but cognitive outcome in IL-1 receptor 1 knockout (IL-1R1 KO) mice is improved after CHI but worse after CCI1, suggesting that targeting IL-1b may be harmful in some TBI patients. While provocative, these studies are inconclusive because of the potential for off target and developmental effects in constitutive IL1R1 KO mice. Alternatively, the divergent effects of IL-1R1 KO in the two models could depend on differences in cell-specific IL-1R1 signaling, or the timing of IL-1R1 signaling (e.g., beneficial early but detrimental later after injury). Preliminary data show improved cognitive outcome after repetitive CHI in constitutive neuronal IL-1R1 KO, and after CCI in endothelial IL-1R1 KO mice. However, whether IL-1R1 signaling is important initially, or whether persistent IL-1R1 activation in the chronic period of CHI or CCI maintains functional deficits and induces neurodegeneration remains unknown. This proposal leverages mice engineered for precise cellular and temporal control of brain IL-1R1 expression that will allow for rigorous determination of where (what cell type) and when targeting IL-1R1 can be beneficial in CHI vs. CCI. Our central hypothesis is that persistent neuronal IL-1R1 signaling drives cognitive deficits, synaptic dysfunction, and impaired neuronal proteostasis after CHI whereas endothelial IL-1R1 drives these neuronal processes after CCI. To test this hypothesis, we propose two Specific Aims: (1) Define brain cell type(s) that mediate post-injury motor and cognitive deficits via IL-1R1 in the chronic period of CCI and CHI, and (2) Test the contributions of endothelial and neuronal IL-1R1 to synaptic dysregulation and neurodegeneration in the chronic period of CCI and CHI.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Obsessive-compulsive disorder (OCD) is a severe psychiatric illness affecting 1–3% of the population, causing debilitating distress and impairing everyday functioning. Up to 20% of individuals with OCD remain severely symptomatic despite standard treatments, making deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) a promising neurosurgical option. However, DBS therapy for OCD remains challenging due to the absence of objective, reliable neural biomarkers of symptom severity, leading to prolonged trial-and-error programming, unpredictable clinical outcomes, and limited access for eligible patients. Early intracranial electrophysiology studies have shown that neural activity in the VC/VS is closely linked to OCD pathophysiology, with low-frequency VC/VS oscillations reflecting processes such as symptom intrusions, error monitoring, and reward processing. These discoveries have advanced our understanding of OCD neurophysiology. Recent advances in sensing-enabled DBS technology now offer a unique opportunity to chronically record neural oscillations (local field potentials, LFPs) directly from DBS electrodes in freely moving patients, enabling longitudinal, real-world tracking of neural activity. Yet critical questions remain regarding the robustness, ecological validity, and clinical utility of VC/VS oscillations as biomarkers of OCD symptom states. This project aims to rigorously establish VC/VS alpha oscillations as an objective biomarker for OCD symptom states and translate this knowledge into clinical practice. First, I will determine whether chronic fluctuations in VC/VS alpha oscillations systematically track real-world transitions between symptomatic and non-symptomatic states by combining at-home DBS recordings with wearable sensor-based behavioral tracking and ecological momentary assessments. Next, I will leverage intraoperative neural recordings—uniquely available during DBS implantation surgeries—to map acute electrophysiological responses in the VC/VS and related frontal circuits during personalized symptom-provocation tasks, providing functional guidance for surgical lead placement. Finally, I will operationalize VC/VS alpha oscillations as a practical biomarker during outpatient DBS programming, using immersive virtual reality-based OCD symptom challenges combined with real-time neural and physiological measurements to identify optimal stimulation parameters. In addition, this award will allow me to complete a multifaceted career development plan. Since my background is primarily in engineering and my clinical exposure to OCD patients is limited, I will acquire fundamental clinical knowledge of OCD symptom dimensions and standard inpatient and outpatient treatments, facilitating the integration of clinical and research efforts. My training will be guided by leading experts at MGH, one of the world’s leading institutions in the clinical and research work with this patient population. I will further attend seminars and conferences, to develop not only a researcher, but also as an independent leader and science communicator. Together, this will provide me with the necessary set of skills for my transition to independence.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Although environmental exposures are recognized as risk factors for allergic and infectious diseases, the ways in which these exposures influence the virome—distinct from the bacteriome—and their effects on health are not well understood. Dr. Peggy Lai’s research has examined how the environment and microbiome affect lung health, and recent investigations into viral communities have uncovered a striking association between indoor humidity and the virome. The long-term goal of Dr. Lai’s research program is to identify modifiable environmental factors across the lifespan that can modulate the risk of allergic and infectious lung disease while mentoring the next generation of patient-oriented researchers. The short-term goal is to strengthen the evidence base to justify a future school-based randomized controlled trial targeting indoor humidity to reduce respiratory infection risk. This proposal will leverage two existing NIH-funded randomized controlled trials of air pollution interventions in children (NCT02291302: Boston, USA, n=247 children; NCT01335490: Kintampo, Ghana, n=800 children), where extensive longitudinal data on environmental exposures (including relative humidity ranging from 18-65% in Boston and 34-87% in Kintampo), human microbial populations, and respiratory infections are already collected. Using these resources, the following specific aims are proposed: (1) Elucidate the biological pathways through which humidity influences infection risk (e.g. microbiome and virome modulation, host immune alterations, exposure to respiratory viruses); (2) Disentangle school vs. home acquisition of respiratory viral infections in school-age children using hybrid-capture based viral metagenomics sequencing of built environment and nasal samples. Equal in importance, the mentoring aims are: (1) Provide mentoring in environmental, microbiome, and virome research to a total of 25-30 predoctoral students, residents, postdoctoral fellows, and junior faculty; (2) Develop a formal curriculum for mentees that uses generative artificial intelligence (genAI) tools to accelerate acquisition of skills for patient-oriented research (POR). This proposal will also provide mid-career development opportunities for Dr. Lai, a highly regarded research mentor, to gain additional didactic training in mentorship, leadership, cutting-edge virome approaches, community-based clinical trials, and use of genAI for research education. The proposal is innovative, because it evaluates an understudied exposure, humidity, as a potential modifiable target for respiratory infection risk in POR, leverages novel approaches for viral source tracking using hybrid-capture based viral metagenomics of built environment and human samples, and will harness exciting genAI tools to educate patient-oriented researchers. Outcomes will directly inform the design of a future multicenter school- based randomized trial targeting indoor humidity as an innovative intervention to mitigate respiratory infection risk, while simultaneously providing valuable training opportunities in patient-oriented research.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Robust antigen-specific CD4⁺ T cell responses are critical for effective immunity against cancer and infection. Despite advances in adjuvant development and cytokine modulation, strategies to optimize antigen delivery for MHC-II presentation remain underdeveloped. This proposal introduces a modular platform for antigen engineering—termed LyGens (lysosome-targeting antigens)—that leverages natural and de novo designed ligands for lysosomal trafficking receptors (LTRs), with the goal of enhancing lysosomal delivery and antigen presentation. Aim 1 prototypes LyGens that fuse microbial antigens to ligands of two well-characterized LTRs: insulin-like growth factor 2 (IGF2) for the mannose-6-phosphate receptor (M6PR) and transferrin receptor binding peptide (TfRBP) for the transferrin receptor (TfR). Using antigens from Listeria monocytogenes and Mycobacterium tuberculosis, we will test if fusion constructs enhance co- localization with lysosomes and increase peptide-MHC-II complex formation, as measured by immunofluorescence, T cell reporter assays, and targeted immunopeptidomics (SureQuant). Aim 2 addresses the potential signaling concerns of natural ligand use by engineering LyGens fused to EndoTags—de novo designed LTR binders that target M6PR and TfR at sites orthogonal to native ligand binding domains. These EndoTag-LyGens are evaluated for their trafficking efficiency, MHC-II presentation, and signaling bioorthogonality using phospho-protein profiling and IGF2 competition assays. Together, these studies establish the design rules for a new class of engineered antigens that efficiently harness natural intracellular trafficking pathways to potentiate CD4⁺ T cell responses. The platform's modularity, translational potential, and compatibility with existing vaccine technologies suggest broad applicability to cancer, infectious disease, and autoimmunity. Ultimately, this work lays the foundation for programmable antigen delivery systems that can be tailored to elicit precise immunologic outcomes.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Omega-3 fatty acids (N3FA) have evidence for prevention of type 2 diabetes, chronic kidney disease, and other cardiometabolic diseases, acting via established anti-inflammatory and lipid-related mechanisms. N3FA supplements, primarily fish oil, are safe and inexpensive, making them highly compelling for clinical use. However, N3FA intervention trials have shown mixed results, with substantial heterogeneity in treatment effects across population groups. It is important to understand the contribution of genetics to this heterogeneity in N3FA response so that N3FA supplements can be targeted to the individuals who will benefit most. Gene-environment interaction (GxE) analysis can capture this type of genetically driven heterogeneity in observational datasets, but requires appropriate interaction-focused methods and large datasets to achieve sufficient statistical power. Recent work has shown improvements in GxE detection by leveraging molecular quantities, such as plasma N3FA status, and the use of interaction-focused polygenic scores (iPGS) that aggregate over individually small GxE signals genome-wide. We hypothesize that polygenic and molecularly-informed GxN3FA interaction testing can inform genetic scores that predict changes in cardiometabolic risk factors (CRFs) in response to N3FA supplementation in targeted trials. We propose to explore this hypothesis through two aims. First, we will generate a series of molecularly-informed iPGS quantifying differences in the magnitude of N3FA-CRF association across large-scale observational data sets. GxE meta-analysis will be conducted in eight TOPMed cohorts and the UKB for five key glycemic, inflammatory, and lipid CRFs. Separate models will consider genetic modification of the standard (N3FA-CRF), “absorption” (N3FA-plasma N3FA), and “transduction” (plasma N3FA- CRF) relationships. Meta-analyzed interaction estimates will be aggregated into iPGS, with iPGS optimization and interaction replication conducted in the All of Us cohort. Second, we will test whether observational GxE- based genetic predictors predict the CRF response to N3FA supplementation in an intervention trial context. We will generate iPGS using genetic data from the FAS fish oil supplementation trial (N=208) and test whether these iPGS predict six-week changes in the same set of CRFs. This work promises to both provide preliminary data supporting the generation of genetic and omics data in samples from large intervention trials in future work, and provide a methodological model for similar explorations of other dietary traits.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Each year, over 1.25 million people experience homelessness in the US. An estimated 7-16% of these individuals have opioid use disorder (OUD), as compared to less than 1% in the non-homeless population. Drug overdose is the leading cause of death among homeless adults, accounting for 1 in 4 deaths at rates up to 30 times higher than in the general population. Opioids contribute to over 90% of these overdose deaths. Despite the effectiveness of medications for OUD, adherence remains suboptimal in this population, with high rates of early disengagement and elevated mortality risk after discontinuing treatment. Although numerous opioid overdose risk models have been developed in recent years, none have been tailored to or validated in homeless populations. These models also fail to incorporate the dynamic, time-varying treatment patterns and social determinants that drive risk in this group. This project aims to fill these critical gaps by leveraging 20 years of clinical and mortality data on a large cohort of adults experiencing homelessness in Boston to: 1) derive and validate a prediction model for a) opioid overdose mortality and b) all-cause mortality, and 2) characterize 6-month OUD treatment trajectories and examine their association with subsequent a) opioid overdose mortality and b) all-cause mortality. To accomplish Aim 1, we will use an ensemble of 5 supervised machine learning models – regularized logistic regression, extreme gradient boosting, support vector machines, random forest, and a fully connected neural network – to identify predictors of opioid overdose mortality and all-cause mortality among individuals with clinically diagnosed OUD. To accomplish Aim 2, we will use group-based trajectory modeling to identify latent classes of treatment trajectories among adults with OUD over the first 6 months of establishing care based on 3 clinical parameters: buprenorphine adherence, opioid abstinence, and appointment attendance. We will then examine the association between these treatment trajectory classes and subsequent opioid overdose mortality and all-cause mortality over the ensuing 12 months. Both aims will be supported by an existing dataset that includes 71,914 adults (including 10,663 with OUD) seen at Boston Health Care for the Homeless Program (BHCHP) between 2003-2022, linked clinical data on these individuals from the BHCHP electronic data warehouse, and linked Massachusetts death records for this cohort over the same years (revealing 2,769 opioid overdose deaths and 11,605 all-cause deaths). This work will identify individuals at highest risk of opioid overdose death, elucidate how and when risk evolves, and inform real-time clinical decision support tools to reduce preventable deaths in this structurally vulnerable population. Results will provide a foundation for precision prevention efforts in homeless health care systems and offer a scalable analytic framework for future implementation and external validation.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract The “Opioid Crisis Response Act of 2018” is a key legislative effort to address the opioid epidemic in United States, recognizing opioid overdoses as one of the nation’s most pressing public health threats. Opioid related deaths have surged since 1999, with over 82,000 deaths in 2022 alone, driven primarily by synthetic opioids like fentanyl. To combat this crisis, there is an urgent need for new translational tools and strategies to better understand the neurobiology of opioid addiction. The mu opioid receptor (MOR) plays a critical role in regulating the respiratory system and neuropsychiatric functions, directly impacting the key concerns of the opioid epidemic – respiratory failure and addiction. Despite its importance in various diseases, the full scope of its role of MOR and its ligands in complex addiction mechanism in human brains remains unclear. To address this, we are developing a new translational tool to study the molecular and cellular mechanisms of receptor dysregulation that contribute to substance abuse and mental health disorders. Non-invasive, quantitative positron emission tomography (PET) imaging of MOR in the human brain will provide crucial perspective into how MOR density and occupancy are linked to its dysregulation. While a handful of conventional MOR-PET probes exist and offer valuable insights through preclinical and clinical imaging studies, they are either too potent or not sensitive enough for studying neurobiology of MOR in the living brain. This proposal focuses on the final preclinical evaluation of a safe, widely accessible PET neuroimaging probe18F-fluorocarfentanil (18F-FCFN). Our team recently developed four derivatives of 18F-FCFN and validated their in vivo suitability as PET neuroimaging probes in rats through proof-of-concept studies. Based on our prior findings, published in 2025, two 18F-FCFN candidates emerged with promising features – high brain uptake, favorable selectivity and specific binding to MOR. We now propose completing final evaluations in higher species to select the best 18F-FCFN candidates for clinical translation. In AIM 1, we will assess the in vivo pharmacokinetics, selectivity, and binding potential (BPND) of these two 18F-FCFN candidates in non-human primates (NHPs) and select the top candidate for further evaluations. In AIM 2, we will determine the whole-body biodistribution and radiation dosimetry of the selected 18F-FCFN candidate in NHPs, along with conducting acute toxicology studies to assess its safety for human use. This work is critical for selecting and advancing the top 18F-FCFN candidate to first-in-human trials.

NIH Research Projects · FY 2026 · 2026-05

Challenges. Endometrial cancer (EC) exhibits increasing incidence and mortality rates, contrasting with trends observed in most other cancers. Notably, uterine serous carcinoma (USC) is a distinct subtype typically presenting at advanced stages with an associated poor 5-year survival (<20% for stages III and IV) and high recurrence rates (up to 80%) even when caught early. This prognostic disparity and clinical peril highlight the critical need for a new diagnostic and tracking strategy that can i) detect early lesions and perhaps minimal residual disease and ii) identify aggressive subtypes, particularly USC, to inform optimal treatment and its timing. A preferred test format would be minimally invasive liquid biopsies to facilitate broad implementation and patient access. Extracellular vesicles (EVs) are promising analytes in liquid biopsy and could serve as significant sources of USC biomarkers, offering a less invasive and cost-effective alternative to current modalities such as transvaginal ultrasound and hysteroscopy. Innovations. We recently achieved a technical breakthrough in EV assays through the novel use of a CRISPR approach. CRISPR-associated proteins first recognize their specific mRNA target, triggering RNA replication and signal amplification. This unique dual- function mechanism enables the assay to differentiate between single-nucleotide polymorphisms while achieving a detection limit in the sub-attomolar range. Goals. Building upon the promise of our CRISPR assay, we aim to advance the next generation of USC diagnostics, termed SLEUTH (Sensitive Liquid biopsy for Endometrial cancer Using Tumor-derived Hallmarks). We seek two primary objectives: i) implementing a SLEUTH platform for multimodal EV analysis, and ii) rigorously evaluating EVs' clinical utility for USC diagnostics. In Aim 1, we will develop a fully automated SLEUTH assay system. The core component will be a disc-based cartridge to streamline EV lysis and RNA extraction, CRISPR reaction, and fluorescent signal detection. In Aim 2, we will apply the SLEUTH assay to analyze EVs collected from patient-derived organoids (PDOs). This preclinical study will identify a panel of USC-specific EV markers. In Aim 3, we will evaluate SLEUTH's clinical utility for USC detection by analyzing prospectively collected urine samples from women with benign or malignant endometrial conditions. EV profiling results will be used to construct a diagnostic model to differentiate USC from benign conditions and other EC subtypes. Team. We have assembled a unique team with expertise in EV detection technology, gynecologic oncology, cancer biology, and biostatistics. We also have access to outstanding resources (a well-annotated biorepository of gynecologic specimens and a collection of PDOs) for the identification of clinically relevant EV markers. Impact. The new SLEUTH platform will be a transformative solution for EV molecular profiling in urine and eventually other biofluids. Its capabilities for automation, high throughput, and multimodal detection surpass existing technologies. This proposal is thus highly responsive to PAR-25-336 and its emphasis on scalable nano-based translational testing.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY More than one million children who are HIV-exposed but uninfected (CHEU) are born to pregnant women with HIV (PWHIV) every year. CHEU have poorer early-life outcomes than HIV-unexposed peers, including significant neurodevelopmental deficits and a >2-fold risk of growth stunting. The pathophysiology and causes of adverse CHEU outcomes are incompletely understood, but mounting evidence suggests that adverse outcomes are multifactorial, with contributions from placental abnormalities, microbiome changes, exposure to maternal antiretrovirals, early-life infections, environmental exposures, and social determinants of health. Prior studies of the impacts of each of these individual factors and their contributions to CHEU outcomes have been limited by small sample sizes, poorly-characterized cohorts, short follow-up duration, outdated antiretroviral regimens, lack of advanced statistical analyses, and incomplete adjustment for confounders. There is a need for comprehensive analysis of well-characterized longitudinal studies that capture the complex pregnancy, placental, birth, early life, and environmental complexity of PWHIV and CHEU. Our central hypothesis is that adverse growth and neurodevelopmental outcomes in CHEU are complex and multifactorial, and that comprehensive analysis of large datasets from well-characterized cohorts is urgently needed to disentangle the contributions of individual factors and identify areas for intervention. We will leverage already-collected data from participants and linked placental, stool, blood, and hair sample analyses, and apply advanced statistical methods to comprehensively analyze existing robust clinical, laboratory, sociodemographic, and developmental outcomes data from our well- characterized cohort of PWHIV, their paired CHEU, and HIV-uninfected/HIV-unexposed comparators (n = 793 dyads) to identify multifactorial predictors of adverse neurodevelopmental and growth outcomes in CHEU through child age 6 years. Aims: 1) Identify clinical, laboratory, environmental, sociodemographic features that predict 1a) neurodevelopmental and 1a) growth outcomes in CHEU. 2) Estimate the effect of HIV exposure in utero and while breastfeeding on 2a) neurodevelopmental and 2b) growth outcomes in CHEU and evaluate whether this effect is mediated through placental abnormalities, and 3) Estimate effects of dolutegravir versus efavirenz antiretroviral exposure in pregnancy and breastfeeding on: 3a) neurodevelopmental and 3b) growth outcomes in CHEU. Leveraging existing data from an ongoing cohort, this uniquely comprehensive data analysis project will identify clinical, laboratory, environmental, and sociodemographic features associated with CHEU health outcomes and estimate the causal effects of HIV- and specific antiretroviral exposure. These aims directly address NIH priorities to understand mechanisms of comorbidities associated with HIV and complications of antiretroviral therapy and calls for comprehensive cohort studies to elucidate the complex co-occurring exposures in CHEU and identify potential interventions and has high potential for domestic and global impact to improve outcomes by informing antiretroviral selection and early identification and intervention for at-risk children.

NIH Research Projects · FY 2026 · 2026-05

Abstract: Alcohol-Associated Liver Disease (ALD) is a major public health problem, accounting for nearly half of all liver-related deaths in the United States. Despite the clear benefits of alcohol abstinence, achieving and maintaining abstinence remains a significant challenge for many ALD patients. Contingency Management (CM), an evidence-based behavioral intervention that provides tangible rewards for positive behavior change, has shown promise in promoting abstinence in alcohol use disorders. However, the application of CM in ALD patients has been limited, partly due to challenges in monitoring alcohol use over extended periods. This study proposes a novel approach that integrates CM with phosphatidylethanol (PEth) testing, an innovative alcohol biomarker with a longer detection window, to promote alcohol abstinence in ALD patients in the hepatology clinic. The specific aims are: 1) to establish the feasibility and acceptability of PEth-based CM for alcohol use in the hepatology clinic for ALD patients; 2) to evaluate the preliminary efficacy of a PEth-based CM intervention in achieving alcohol abstinence; and 3) to explore sociodemographic and clinical factors that are associated with treatment response (alcohol abstinence and alcohol reduction). The study will conduct a pilot randomized controlled trial (REINFORCE Trial) to compare the effectiveness of a 12-week PEth-based CM intervention against a control group receiving treatment as usual in a cohort of ALD patients with alcohol use in the hepatology clinic. The primary outcome will be alcohol abstinence, with secondary outcomes including alcohol reduction, treatment engagement, liver disease severity, and health-related quality of life. Exploratory analyses will examine potential moderators of treatment response. This innovative study addresses a critical gap in the treatment of alcohol use in ALD patients and has the potential to significantly advance scientific knowledge, improve clinical practice, and reduce the public health burden of alcohol-related liver disease. The findings will inform the development of personalized treatment approaches and guide the design of future large-scale clinical trials.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) are FDA-approved for >20 cancer types and have transformed the landscape of cancer treatment. However, the associated widespread T-cell activation can cause a broad range of immune-related adverse events, including acute kidney injury (ICI-AKI), which primarily manifests as acute interstitial nephritis. Data to guide treatment of ICI-AKI are limited, with current guidelines recommending 4-8 weeks of glucocorticoids (GCs). However, GCs have numerous side effects and can attenuate the anti-tumor response induced by ICI therapy. Moreover, receipt of prolonged courses of GCs can lead to temporary or permanent discontinuation of ICIs and other life-saving anti-cancer therapies. Up to one third of patients with ICI-AKI treated with GCs either do not have full renal recovery or experience recurrence of ICI-AKI when GCs are discontinued. Accordingly, there is an urgent need to develop novel treatment strategies for ICI-AKI that are more effective and durable than GCs alone, and that also allow patients to resume ICI therapy faster. Infliximab is an FDA-approved monoclonal antibody that inhibits tumor necrosis factor-α and is used to treat a variety of autoimmune diseases, as well as steroid-refractory extrarenal immune-related adverse events. A strong biologic rationale exists for its use in patients with ICI-AKI, and case reports suggest some benefit in steroid-refractory ICI-AKI; however, there are no randomized clinical trial (RCT) data to guide the up- front use of infliximab in ICI-AKI. In response to PAS-25-102 (“Small R01s for Clinical Trials Targeting Diseases within the Mission of NIDDK”), we propose an open-label, pilot and feasibility RCT (N=44), comparing a single dose of up-front IV infliximab paired with 2 weeks of GCs to the current standard-of-care (6 weeks of GCs alone) for ICI-AKI. The primary outcome is the rate of sustained renal recovery at 12 weeks. Key secondary outcomes include time-to-sustained renal recovery, time-to-ICI-AKI recurrence, and time-to-rechallenge with anti-cancer therapy. Additionally, we will characterize the safety profile of infliximab, as well a 6- vs. 2-week course of GCs, using the Glucocorticoid Toxicity Index. Executing these aims will generate key preliminary data regarding the efficacy and safety of infliximab, a novel immunosuppressant treatment for ICI-AKI, along with feasibility data on recruitment, retention, and study conduct. Our pilot trial will inform the design of a larger, definitive RCT testing infliximab vs. standard of care GCs in a U01 grant, where we will leverage our extensive collaborations with onconephrologists across the US.