Henry Ford Health + Michigan State University Health Sciences

NIH Research Projects · FY 2026 · 2026-06

Title: Develop a human pluripotent stem cell-derived preclinical model for NUT Carcinoma Project Summary: NUT Carcinoma (NC) is a devastating cancer with no effective treatment. A deeper understanding of its oncogenesis mechanism is vital for developing treatments that improve its prognosis. Although NC cases are strongly associated with Nuclear Protein in Testis (NUTM1) fusion genes, predominantly BRD4::NUTM1 (70% of cases), their oncogenic functions have been under debate. Using one of the first two NC genetically engineered mouse models we created, we demonstrated that inducing an endogenous chromosome translocation that forms the Brd4::Nutm1 fusion gene in progenitor cells in tissues as distinctive as oral mucosa, thyroids, lungs, and pancreas can induce carcinomas recapitulating human NC. Our results provided the long-awaited proof of NUTM1 fusion genes as the oncogenes for NC. Our new GEMM provided a critical tool to deepen our understanding of the molecular mechanisms of NC oncogenesis and develop effective treatments. However, the 90 million years’ evolution distance between humans and mice posed two significant challenges for translational studies of NC using the mouse model: · Due to the evolutionary divergence of protein and sequence structure, targeting agents including CRISPR-CAS9-based gene therapy agents and NUTM1-degrading molecular glues cannot be effectively tested using mouse model. · Due to the relatively loose evolution constraints on regulatory sequences, the genetic regulatory network (GRN) controlled by the NUTM1 fusion genes could differ between the two species. This could hamper the effective identification of BRD4::NUTM1 targets for future therapeutic development. To overcome these challenges, we propose to develop a human pluripotent stem cell (hPSC) derived NC model. We will use a genetic design demonstrated in our GEMM to build human PSC cell lines for modeling NC. To gain access to the progenitor cells of respiratory epithelial tissues, from which lung NCs that account for more than 50% of reported human cases likely originate, we will use human PSC-derived teratoma in immunocompromised mice as the platform to generate NCs. We will first create and characterize the human PSC-NC model (Aim 1) and then use this model to demonstrate the BRD4::NUTM1 dependency and thus the proof-of-principle of the effectiveness of NUTM1-targeted therapy for NC. (Aim 2). Overall Impact. Our project will provide a critical human-relevant in vivo preclinical model for studying NC. It will provide a proof-of-principle demonstration of NUTM1-targeted therapy. Our study will also provide a novel generalized road plan for developing in vivo human-relevant models for fusion gene-driven cancers.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract All essential 24-hr operations (e.g., first responders, hospital services) rely on nightshift workers who forgo nocturnal sleep for work. These essential services are available to us because of the 20% of the workforce who work nightshifts; however, they are provided little to no support in managing inverted sleep-work schedule, putting them at elevated risk for Shift Work Disorder (SWD). Because industries that rely on nightshift workers are often safety-sensitive, the consequences of impaired performance can be catastrophic (eg, Three Mile Island nuclear reactor meltdown, the American Airlines Flight 1420 crash, and the Exxon Valdez oil spill). Given this landscape, there is an urgent need for precision circadian medicine solutions. With support from multiple NIH awards, Dr. Cheng has laid the requisite foundation for vertical advancement in precision circadian medicine for SWD. For example, he pioneered the validation and creation of the first open-source, free, and widely accessible tool to track circadian rhythms in nightshift workers using wearable technology (ie, a free web portal). Furthermore, his work has also led to the understanding that a unitary focus on circadian misalignment for SWD may be overly reductionistic. This proposal seeks to enable the scaling-up of precision circadian medicine for nightshift workers by 1) leveraging digital health technologies (eg, consumer-based wearables), and 2) transforming the etiological framework of SWD from a unidimensional to a multi-level construct informed by a socioecological lens. In collaboration with a team of national leaders in sleep and circadian rhythms, Dr. Cheng will break ground in new directions of research. Potential directions include 1) examining the use of consumer-based wearable technology for precision circadian medicine, 2) establish the appropriate dose of light for a therapeutic response and remission in SWD, 3) improving the accuracy of circadian rhythms tracking with personalized parameters, 4) mechanistic evaluation of a multilevel etiological framework for SWD treatment, and 5) establish mechanistic targets for prevention of SWD. Additionally, the proposal also seeks to advance workforce development in precision circadian medicine by expanding training programs for undergraduates, doctoral students, and postdoctoral fellows. As a clinical psychologist with expertise in sleep and circadian physiology, Dr. Cheng is ideally positioned to lead this program of research to move the field of precision circadian medicine forward. He has demonstrated productivity in this area; his portfolio of work is well-cited, with a mean relative citation ratio of 2.88, which is higher than the 90% percentile of all scientific publications (NIH Office of Portfolio Analysis: iCite Tool). The proposed work would also advance five of objectives in the NHLBI Strategic Vision, and stands to significantly advance precision sleep medicine for this population, ultimately impacting outcomes related to occupational health, performance, safety, and public health.

NIH Research Projects · FY 2026 · 2026-05

Type 1 diabetes (T1D) results from the selective and progressive destruction of pancreatic beta-cells within the islets of Langerhans. Most current therapies for T1D focus on symptom management; while insulin administration helps control hyperglycemia and delay complications, it does not offer a cure. With the growing recognition of beta-cells as central players in T1D pathogenesis, there is renewed interest in developing therapies that preserve and restore beta-cell function. Therefore, new treatments that address the underlying mechanisms of beta-cell loss, particularly by protecting beta-cells from autoimmune attack, are urgently needed. Iron oxide nanoparticle-based theranostic nanodrugs have shown promise for targeted drug delivery to pancreatic beta-cells. However, systemic administration of these nanoparticles often results in off-target effects and toxicity, limiting their clinical utility. To address this challenge, a beta-cell-targeted nanoparticle platform is proposed to enable both selective delivery and noninvasive in vivo tracking of therapeutic agents that prevent beta-cell damage and promote beta- cell survival. The nanodrugs will be designed with an iron oxide core functionalized with Exendin-4 peptides to target the glucagon-like peptide-1 receptor (GLP-1R), which is highly expressed on pancreatic beta-cells. For the therapeutic component, beta-2 microglobulin (β2M) siRNA will be conjugated to the nanoparticles to reduce CD8+ T cell-mediated beta-cell destruction. In addition to delivering therapeutic siRNAs, the nanodrugs will be administered via the intrapancreatic duct and imaged using dual-modality positron emission tomography (PET) and magnetic resonance imaging (MRI). The Exendin-4 peptide will be radiolabeled with 64Cu for PET imaging, and the iron oxide core will provide MRI contrast. Both targeted and non-targeted control nanodrugs will be synthesized to evaluate and compare specificity, cellular uptake, and functional efficacy in beta-cell lines in vitro. In vivo, evaluation in T1D mouse models will include intrapancreatic ductal administration of nanodrugs, followed by PET/MRI tracking to determine biodistribution, pharmacokinetics, and beta-cell accumulation. Therapeutic outcomes will be assessed by monitoring blood glucose levels, insulin production, and performing correlative histological analyses. This approach aims to deliver a targeted, image-guided nanodrug platform capable of siRNA delivery to islet beta-cells, offering a novel strategy for beta-cell protection and improved treatment of T1D.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT More than 80% of breast cancer survivors and nearly all family caregivers experience unmet supportive care needs during cancer treatment and throughout survivorship. These unmet supportive care needs are key factors that contribute to poor quality of life for cancer survivors and their caregivers. Emotional, informational, and relational needs are among the most reported unmet needs by cancer survivors and their caregivers, and result from gaps in cancer care services. Interventions to support the unmet needs of cancer survivors have provided no evidence of an underlying mechanism for reducing unmet needs for the survivors, and many caregiver interventions have yielded small effects. Given the known interdependence between cancer survivors and family caregivers’ well-being and the promising effects of mindful resilience-based interventions in other populations such as transplant patients, a systems-level resilience-based approach may be key in addressing these unmet needs. Family resilience, or the ability of family to rebound and grow from adversity, is associated with greater quality of life in cancer survivors and their caregivers. While the relationship between family resilience and unmet needs is unknown, there is evidence that more individual or intrapersonal resilience is associated with fewer unmet supportive care needs. Furthermore, as unmet needs change over the course of the illness trajectory and throughout survivorship, identifying a mechanism that adapts over time and leverages the strengths of the family to cope and manage needs is crucial. This observational cross- sectional study aims to determine the relationship between unmet supportive care needs, family resilience, and quality of life in breast cancer dyads (survivors and caregivers) during two phases of cancer care (active treatment and reentry phase). Using latent variable structural equation modeling, specifically the Actor-Partner Interdependence Model, we will examine whether family resilience partially mediates the relationship between unmet supportive care needs and quality of life in cancer dyads. This advanced statistical method allows us to simultaneously evaluate the actor effects (how we affect ourselves) of survivors’ unmet needs and family resilience on their own quality of life as well as the partner effects (how we affect each other) on their caregivers’ quality of life, and vice versa. A total of 260 dyads will be recruited from a large NCI designated Cancer Center serving over 47 communities in the Midwest and through online platforms throughout the US. Results from this study will identity a critical underlying mechanism, informing future research to design, test, and disseminate mindful resilience-based interventions for families experiencing cancer. The training plan consists of mentorship, courses, and workshops that will facilitate the development of expertise in dyadic research within the context of breast oncology as well as future mindful resilience-based intervention development.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Mustard vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) are alkylating vesicants that cause severe skin, eye, systemic and lung toxicity. Phosgene oxime (CX), an urticant or nettle agent, is the least studied but most potent vesicant with instantaneous toxic effects and penetration that poses a threat of mortality and long-term morbidity. The secondary lung toxicity and its mechanism from dermal route of exposure to these vesicants due to their systemic effects have not been explored and there are no approved and effective therapies to treat such injuries that can lead to mortality and long-term effects. Recent novel findings from our laboratory demonstrate that acute dermal exposure of mice to mustard vesicant NM or nettle vesicant CX leads to the development of not only acute skin but also lung injury with qualitatively similar pulmonary lesions characterized by acute, diffuse intramural edema and hemorrhage. These pulmonary toxic lesions were accompanied by an increase in mast cell degranulation and inflammatory cytokines like Interleukin (IL) 33 indicating that mast cell activation and immune cell recruitment could be a mutual mechanism of vesicant lung injury from their skin exposure. Overall, our studies have implied a role of mast cells in vesicant NM inhalation-related lung injury (published) and CX dermal exposure related skin injury; however, mast cell activation and related signaling in lung injury from their dermal exposure is not explored. Also, there are no reported studies on CX lung toxicity and, hence, these studies are novel and critical area of research. This proposal aims to further establish the role of mast cells and delineate related mechanism(s) of acute and long-term lung toxicity from both mustard and nettle vesicating agents following their dermal exposure in mice. We hypothesize that dermal NM or CX exposure causes systemic toxicity induced lung injury, and mast cells significantly contribute to the mechanism of toxicity. To test this hypothesis, the proposed specific aims are: SPECIFIC AIM 1: Establish the role of mast cells in lung toxicity from acute dermal exposure to vesicating agents. We will use mast cell deficient (B6.Cg-KitW-sh/HNihrJaeBsmJ; MCD) and wild-type C57BL/6 (WT) mice to examine the role for mast cells in vesicant related lung injury following their dermal exposure. Following acute CX or NM cutaneous exposures, we will conduct time-response studies from 2h up to 3 months to characterize the acute and long-term lung toxicity in both the WT and MCD mice. SPECIFIC AIM 2: Determine and compare the mast cell associated mechanisms of lung injury from acute dermal exposure to vesicating agents. We will utilize the BALF, blood plasma samples and lung tissues from Aim 1 studies, for both NM and CX exposures, to determine the a) bioactive lipid profiles and b) differential transcriptome profiling and changes in immune cells (Visium Spatial Gene Expression) with adverse pulmonary morphology in WT and MCD mice. These studies will establish if mast cell activation and related signaling parallel in skin, systemic and lung injury from mustard and nettle vesicating agents’ dermal exposure with a goal to identify novel broad-spectrum treatment strategies.

NIH Research Projects · FY 2026 · 2026-04

Project Description Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors with restricted interests. The lifelong social and behavioral challenges, along with a lack of therapeutic agents designed to treat core symptoms, places ASD as a significant priority in health care. There are four established risk factors for ASD. First, ASD is diagnosed four times more often in males than females, so male sex is an ASD risk factor. Second, exome sequencing studies of tens of thousands of individuals with ASD identified >200 high-confidence ASD genes with rare mutations. Prominent among these ASD high-confidence genes is chromodomain helicase DNA binding protein 8 (CHD8), which is strongly associated with ASD by de novo loss-of-function mutations. The exome sequencing data indicated that CHD8 insufficiency strongly predicts ASD diagnosis, so CHD8 loss-of-function mutations are an ASD risk factor. We and others published papers showing the downstream effects of CHD8 insufficiency in human neural progenitor cells. Third, epidemiologic studies provide strong evidence that the environmental factors valproic acid and air pollution fine particulate matter exposure contribute to ASD risk. We recently discovered that exposure of human cerebral organoids to either valproic acid or particulate matter results in decreased CHD8 expression. The finding that ASD-associated environmental factors can lead to the molecular endpoint of CHD8 insufficiency suggests a convergent biological pathway. Fourth, genome wide association studies (GWAS) have identified two replicated loci associated with ASD on chromosomes 5p14.1 and 20p12.1. We discovered and published that two long noncoding RNAs (lncRNAs) are among the functional elements revealed by the GWAS peaks. Each of these lncRNAs is expressed at higher levels in postmortem brains of individuals with ASD, is increased in expression following model air pollutant exposure, and causes decreased CHD8 expression when the lncRNA is over-expressed in human neural progenitor cells. Based on these convergent data indicating environmental and epigenetic control of the high-confidence ASD gene CHD8, we propose two aims. Aim 1 will test the responses to valproic acid and fine particulate matter of human cerebral organoids derived from individuals with mutations in CHD8, ASD risk genetic variants on chromosomes 5p14.1 and 20p12.1, and both sexes. Aim 2 will test the ability of lncRNA transcriptional gene silencing and CHD8 derepression to rescue the phenotypes of CHD8 insufficiency. The outcomes will include single cell gene expression, quantitative neuronal differentiation, and synaptic physiology. These studies will contribute to understanding the neurodevelopmental impacts of environmental exposures, CHD8 insufficiency, and environmental and epigenetic control of CHD8. We expect the research program will lead to biologically based treatment options for a subset of patients and provide a platform to study epigenetic control of additional genes that contribute to neurodevelopmental disorders.

NIH Research Projects · FY 2026 · 2026-04

Project Summary The objectives of this proposal are to optimize and validate detection and modeling of the multicomponent vascular and glymphatic systems in cerebral waste clearance (CWC) using superparamagnetic iron oxide (SPIO)-enhanced susceptibility weighted imaging (SWI, SPIO-SWI), and then to investigate CWC in the vascular and glymphatic systems during progression of Alzheimer’s Disease (AD). Emerging data indicate that the waste clearance from the brain parenchyma plays an important role in neurological diseases, especially neurodegenerative diseases. CWC is closely related to alterations in small blood and perivascular spaces of the brain. The glymphatic system and its peri-vascular pathway for waste clearance have been shown to be sensitive biomarkers for neurological diseases. Despite many milestone achievements, conclusive findings on the brain waste clearance relationships among the blood and perivascular spaces and their contributions to AD are absent. To date, CWC changes in the vascular and glymphatic systems and the outcomes during disease development as well as their relationships have not been investigated, which could provide mechanistic information about β- amyloid (Aβ) status during progression of AD. We have employed highly sensitive MRI methods using the SPIO- SWI to detect cerebral microvessels. Our preliminary data indicate that clearance of intracisternal injected MRI contrast agent decreases with AD severity and concomitantly with increased Aβ around the vasculature and functional deficits in a rat model of AD. Based on our novel preliminary data, we posit that the SPIO-SWI technique will significantly increase detection of microvessels in vascular and glymphatic systems and thereby permit detailed investigation of the interaction among the changes in cerebral blood vessels and perivascular spaces during progression of AD. To test these hypotheses, we will first (Aim 1) further optimize and validate our analytical and imaging approaches and then (Aim 2) investigate CWC under progression of AD. Data generated from this proposal will provide new insights into the relationships among the changes in small blood vessels, perivascular spaces, and the outcomes of diseases under AD condition. Moreover, all the MRI markers developed in this proposal can potentially be employed in the clinic for analysis of CWC in AD patients as well as patients with other neurodegenerative diseases.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Polysubstance use (PSU) is highly prevalent among people with HIV (PWH) and increases the burden of comorbidities, accelerates HIV progression, and raises mortality. In the U.S., non-AIDS comorbidities such as alcohol-related liver disease and smoking-related pulmonary and cardiovascular conditions are among the leading causes of death among PWH. The interaction between PSU and HIV exacerbates immune dysregulation, chronic inflammation, and susceptibility to infections, creating a cycle that heightens the comorbidity burden. The complex interactions between substances, variations in dosage and frequency, and cumulative health effects make accurate measurement and risk assessment challenging. Despite the clinical importance of PSU, current screening approaches rely on self-report or short-term biomarkers, leaving them vulnerable to recall bias, underreporting, stigma, and limited detection windows. Importantly, no objective, biologically grounded tools exist to assess and stratify PSU risk or to quantify its impact on comorbidity risk in PWH. Prior research has demonstrated that DNA methylation (DNAm), a key epigenetic modification, provides a robust biological marker of internal and external exposures, including substance use. DNAm profiles have been shown to capture cumulative biological impacts and can differentiate between individuals with varying substance use histories. Our prior work demonstrated that DNAm features improved the prediction of hazardous alcohol consumption beyond a traditional alcohol biomarker. However, existing research has focused on individual substances in isolation, overlooking the complexities and interactions of PSU. To date, no DNAm-based tools have been developed to quantify PSU, stratify risk, or assess its contribution to the comorbidity burden in this vulnerable population. To address this gap, we propose to develop and validate the first DNAm-based epigenetic risk score that quantifies the cumulative biological impact of PSU. We hypothesize that distinct PSU patterns are associated with specific DNAm signatures and that integrating these signatures with biological and clinical factors will improve the prediction of comorbidity risk and enable precise risk stratification and early intervention. This approach is innovative because it will leverage cutting-edge epigenetic and predictive modeling techniques to capture the complex, cumulative, and individualized effects of PSU, offering a transformative advance toward precision HIV care. We will test this hypothesis through two specific aims: Aim 1 will develop and validate a DNAm-based risk score for PSU by integrating epigenome-wide data with detailed substance use patterns; Aim 2 will incorporate PSU-associated DNAm markers and key biological and clinical factors into predictive models of comorbidity risk in PWH, with external validation in independent cohorts. This work will provide objective, biologically grounded tools to improve PSU detection and comorbidity risk stratification, laying the foundation for precision HIV care and reducing disease burden in this vulnerable population.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Cannabis use in pregnancy has become increasingly prevalent since the recreational legalization of cannabis in many jurisdictions across the United States. Evidence supports adverse neonatal outcomes associated with prenatal cannabis exposure, including small size at birth, preterm birth, and admission to the neonatal intensive care unit. Moreover, prior research suggests a relationship between cannabis use and certain maternal outcomes, such as gestational hypertension. Despite poor health outcomes, cannabis use has yet to be adequately addressed in prenatal care. Further, most pregnant patients who use cannabis do not perceive it to be harmful. As such, there exists a critical need for systematic screening and intervention among pregnant patients using cannabis, with a focus on non-treatment-seeking patients. Electronic screening and brief intervention (eSBI) is an evidence-based approach touted for its privacy and effectiveness in identifying and addressing substance use through patient-centered counseling approaches that employ motivational interviewing techniques to change behavior. Research suggests that eSBI is effective in ‘teachable moments’ such as during pregnancy, a life event that often motivates individuals to readily adopt risk-reducing health behaviors. Tailored text messaging, moreover, may serve to extend the effects seen in eSBIs. As such, in alignment with NIDA’s 2022-2026 Strategic Plan Priority Area #2 to develop and test novel harm reduction strategies with the requirement that interventions are informed by the lived experience of the individuals who will benefit from them, this study will develop an eSBI and tailored text messaging intervention to reduce cannabis use in pregnancy by establishing a patient advisor committee. By partnering with patient advisors in a co-investigator capacity to develop intervention components at the design phase, it is expected that intervention acceptability, effectiveness, and sustainability will be enhanced. An open trial will be conducted to beta test the eSBI and tailored text messaging intervention for usability and acceptability, followed by a pilot randomized controlled trial to examine intervention feasibility. Moreover, this K01 application outlines specific training goals to complement research activities and achieve the PI’s long-term objective of becoming an independent investigator. Training goals include: (a) developing competency in patient-engaged research, (b) advancing skills in qualitative research methodology, and (c) gaining proficiency in RCT methodology. The training and research activities described in this application will position the PI for an R01 award to assess the efficacy of the intervention in a fully powered trial, and aid her in developing her program of research as an independent maternal health services researcher focused on addressing substance use.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY To inform the origin and treatment of mental health and neurological disorders, there is a need to access specific cell types of the brain and determine how their interactions produce cognition, affect, and behavior. The long- term goal of this project is to understand the biology of an understudied cell type, semilunar granule cells (SLGC), in hippocampus-dependent processes. The dentate gyrus (DG) is a “gate” to the hippocampus. The principal cells of the DG, Granule Cells (GC), broadly excite CA3 pyramidal cells, which in turn excite CA1 pyramidal cells. Therefore, tight control of GC activity prevents hippocampal hyperexcitability that could impair memory and produce seizures. It is thus critical to understand how this gate functions, to determine how GC activity is constrained. In this proposal, the central goal is to develop tools to test the hypothesis that SLGCs function in vivo to limit GC activity. Based upon literature from ex vivo slice work, it has been determined that, in response to excitatory input, SLGCs fire persistently and activate interneurons to inhibit GCs. Thus, SLGCs are poised in the circuit to limit GC activity, but this model has gone untested. Whereas the in vivo roles of GCs are well defined thanks to genetic tools for their specific access, a barrier to progress has been a lack of tools that grant experimental access to SLGCs in vivo. This project pursues methods for recombinase expression in SLGCs of the mouse in vivo and the implementation of these tools to test the hypothesis that SLGCS constrain GC activity. To pursue this objective, 2 Aims are pursued. In Aim 1, strategies for recombinase expression in SLGCs of the mouse will be optimized. Aim 1 will be achieved through two independent strategies. The recombinase Cre is broadly utilized, e.g. Cre-on viral tools or conditional knockout of floxed alleles. In Aim 1, a tamoxifen-Inducible strategy Cre in SLGCs will be optimized. The approach is to characterize at least three promising mouse lines. However, SLGCs and GCs are spatially intermingled and have a high degree of transcriptional similarity, so a single gene approach may not succeed. Therefore, the second strategy of Aim 1 is an Intersectional method to achieve action of the alternative recombinase Flp in SLGCs. The approach is to utilize virus mediated expression of Flp, the expression and activity of which is gated by the SLGC selective expression of two different genes. By either strategy, this project will yield the first methods to selectively access SLGCs in vivo. Aim 2 is to determine if SLGC prevent GC hyperactivity in vivo. The strategy is to utilize recombinase mediated silencing of SLGCs and determine the impacts upon GC physiology and upon hippocampal circuit function using varied ex vivo and in vivo electrophysiology, imaging, and behavioral assays. This project will facilitate studies of the cell and circuit basis of learning and memory and will inform models of hippocampal development and pathologies, serving NIMH Goal 1 to Define the Brain Mechanisms Underlying Complex Behaviors.

NIH Research Projects · FY 2026 · 2026-02

Adolescents with intellectual disabilities (ID) face significant health issues, particularly in managing chronic conditions such as cardiovascular (CV) health risks. These issues are exacerbated by limited physical activity (PA), health literacy challenges, and a lack of evidence-based health interventions. This project aims to address these gaps by engaging adolescents with ID and their stakeholders supporting ID as co-researchers to design, adapt, and pilot-test a virtual reality (VR)-based PA intervention tailored to their needs. The long-term goal is to dismantle factors to improve health outcomes for adolescents with ID through innovative, collaborative research that enhances health literacy, increases PA, and lowers CV health risks. With this goal in mind, the proposed K Mentored Research Scientist Development Award will direct Dr. Patricia West toward an established innovative independent research program. Guidance for her transition to independence will be provided in a strong institutional research environment at Michigan State University with dedicated interprofessional expert scientists and collaborative resources both internal and external to the University. The objectives of this application will address three specific aims: 1) adapt and validate research instruments by collaborating with adolescents with ID and their ID stakeholders to incorporate common language in measures for assessing health outcomes; 2) evaluate and select VR-based PA programs by engaging co-researchers in identifying effective VR exergame interventions for improving health outcomes through PA; and 3) pilot-test the VR PA intervention, which incorporates peer support. We will assess feasibility, acceptability, and preliminary efficacy of our 16-week VR exergame PA intervention using co-adapted measures and biologic CV risk measures. A quasi-experimental mixed-methods approach will be used, guided by our Logic Model. Preliminary evidence highlights the potential of interactive, technology-driven PA to address CV risks while fostering peer engagement and optimal self-efficacy to manage health. The expected outcomes are: 1) validated measures through greater health literacy, and 2) a co-designed intervention to reduce CV risks that helps adolescents with ID to take an active role in their health. By addressing critical gaps in health literacy, self-efficacy, and PA, this work advances healthcare practices and supports long-term improvements in public health.

NIH Research Projects · FY 2026 · 2026-02

Each year, the Annual Scientific Conference and Workshop Program of the American Psychopathological Association is designed to provide bench science, clinical, and population health researchers with a high quality educational overview of specific timely topics regarding psychopathology defined to encompass alcohol, nicotine, and other drug use disorders and addictive processes. The meeting is open to all interested scientists and professionals with pertinent expertise, including ‘lived experience.’ Each annual program now features a thematically organized conference with evidence-grounded lectures by renowned experts as well as talks given by ‘rising stars.” Recent novel additions to the conference program include: (a) throughout the year, periodic invited webinar workshops on conference themes, covering both subject matter and methods issues; (b) poster sessions open to trainees, early stage investigators, and their mentors; (c) mentee-mentor matching and engagement processes. Invited conference speakers write chapters for a special edited volume published in the Harvard Review of Psychiatry as a lasting dissemination monograph for future scholarship and research. This R13 proposal seeks to replace a successfully reviewed proposal for funding of APPA programs in 2024- 2026, then terminated on 20 March 2025 due to NIH policy priority changes. With offending elements removed, we now request support for the 2026 and 2027 APPA program with an initial two year ‘Phase 1” interval to replace the terminated award, and with a planned three year ‘Phase 2’ interval for programmatic support in years 2028-2030, as explained in our proposal. The Phase 1 conference-centered conference themes focus on ‘the affect revolution’ (2026; APPA President Maria Kovacs) and ‘family/work balance’ and other ‘occupational epidemiology’ facets of psychopathology and addiction research (2027: APPA President Jim Anthony). The Phase 2 programs include a 2028 focus on ‘population neuroscience and intersections of psychiatric epidemiology and brain research’ (APPA President Henning Tiemeier). Consistent with past APPA traditions, themes for 2029-30 will be chosen by APPA members when they elect future APPA Presidents who must propose a specific candidate-theme as part of APPA’s democratic election process. Maintaining a 115 year tradition, APPA can and will hold its conference-centered programs during 2026-2030 even without the proposed R13 funding. The main aim of this proposal is to enhance the participation and attendance of ‘the newest of the new’ psychopathology research workforce across the trainee-ESI spectrum. This aim will be accomplished by focusing essentially all of the requested funds on (a) travel awards for meritorious trainee-through-ESI applicants judged by an APPA Awards Committee, and (b) trainee-ESI- associated programmatic costs. Always with a reach from bench to bedside to community, the APPA conference promotes cross-fertilization and encourages accelerated translation of evidence toward implementation science, clinical practice, and public health tactics.

NIH Research Projects · FY 2026 · 2026-02

Summary The inflammatory disease tuberculosis (TB) remains a major cause of mortality worldwide. The long treatment times required for drug therapy highlight the urgent need for new approaches to protect against TB disease. Complicating treatment efforts is the heterogeneity of disease states observed in humans. To address these knowledge gaps, we are using the Collaborative Cross (CC) a mammalian genetics resource that comprises of over 70 mosaic strains of mice, created by intercrossing 8 genetically distinct founder strains. Using the CC, we are identifying unique models of distinct TB disease states. However, cell-type complexity in animals complicates our understanding of the underlying mechanisms. In particular, a critical knowledge gap exists in our understanding of how early infection events drive distinct TB disease trajectories. These early host-Mtb interactions are almost exclusively with airway resident alveolar macrophages (AMs) that are functionally distinct from myeloid-derived macrophages but challenging to study. To overcome this experimental limitation, we developed fetal liver-derived alveolar-like macrophages (FLAMs), a genetically tractable ex vivo AM model that mimics lung AM function. This proposal will create an indexed library of FLAMs derived from the CC panel to test they hypothesis that heterogeneous Mtb-AM interactions contribute to distinct trajectories of TB disease. In Aim 1 we will create and validate the CC-FLAM library by barcoding FLAMs across CC strains, enabling tracking of genotype-specific responses during infection. In Aim 2 we will employ single-cell RNA sequencing and quantitative trait locus (QTL) mapping to define transcriptional networks and genetic loci associated with inflammatory cytokine production, comparing these findings with published disease-outcome QTLs. The work will identify mechanistic drivers of AM heterogeneity linked to TB progression, offering insights into patient risk of disease. By integrating genetic heterogeneity with ex vivo and in vivo models, this exploratory study lays the groundwork for developing therapies targeting early host-pathogen interactions while developing an innovative CC-FLAM platform that will be broadly useful to dissect pulmonary inflammation in other respiratory diseases.

NIH Research Projects · FY 2026 · 2026-02

Summary. The prevalence of antibiotic resistant (AR) bacterial infections continues to grow. Although the development of novel antimicrobial compounds is one approach to combat AR infections, phage therapy or using lytic phage to treat bacterial infections, offers another solution that has many attractive benefits, including the specificity of infection, leaving the healthy microbiome intact, low toxicity, and the diversity of phages available. However, before phage therapy can be widely used in the clinic, one of the significant challenges that must be addressed is the selection of which phage to use for a given bacterial pathogen. Phage infection specificity is complicated by the fact that bacteria encode a diverse array of phage defense systems that block phage infection, typically expressed by horizontally transferrable DNA elements. The bacterial pathogen must also encode and express the phage receptor and any bacterial host factors that the phage requires for successful replication and phage production. Currently, bacterial pathogens are manually screened against large phage biobanks to select phage cocktails that can provide effective in vivo killing. Although this has been effective, such an approach is costly and, more importantly, time-intensive, and it will be challenging to scale up as phage therapy becomes more widely used. The field, therefore, needs rapid and cost-effective approaches to identify effective phages for any bacterial pathogen, given the genome sequence of the bacteria and phages. The MPIs of this proposal, Ravi and Waters, will use their diverse expertise in bacterial pathogenesis, phage biology and defense, AR, microbial genomics, and computational biology, to develop an ML-based prediction model that can identify effective phage and phage resistance-associated molecular features for any given E. coli strain. Another critical outcome of this work will be the gold-standard data set generated in Aim 1 that will define the successful infection of 69 dsDNA E. coli phage in the well-characterized BASEL phage collection with ~600 sequenced pathogenic and non-pathogen E. coli strains generating ~42,000 unique data points. Aim 2 will first define all known phage defense, AR, and virulence elements in this collection of E. coli and merge these annotated features with the phage host infection phenotypes generated in Aim 1 using (un)supervised ML-based approaches (e.g., logistic regression, random forest) to generate models that can predict effective phage infections of any given E. coli host, along with the underlying molecular features (genes, proteins, domains) culminating in resistance/susceptibility. This model will be validated with 50 new E. coli strains. Successful completion of this proposal will generate a clinically useful predictive model for E. coli and lay the framework for generating such predictive models for phage therapies against other bacterial pathogens. Moreover, the model will lead to the discovery of novel phage defense elements and bacterial factors that impact phage infection, and a deeper understanding of how bacterial pathogens evolve resistance to phage infection, knowledge, which can be used to effectively tailor phage therapy to prevent widespread emergence of resistance.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT As the most female-predominant autoimmune disease with a female-to-male ratio of 14:1, primary Sjögren's Disease (SjD) provides a unique opportunity to address the knowledge gap in the molecular basis of sexual dimorphism in autoimmunity. Emerging findings support the role of the X chromosome in impacting the female bias in SjD. However, the exact molecular underpinnings of X-chromosomal dysregulation in SjD remains elusive. Using minor salivary gland-derived mesenchymal stromal cells (MSCs), we discovered striking, global skewing of X-linked genes in SjD, but not control, subjects. Mechanistically, we identified miR6891-5p, a HLA- encoded noncoding RNA, as a critical gatekeeper of X chromosomal allelic balance in MSCs. In pilot studies, we demonstrated that SjD MSCs exhibited reduction in miR6891-5p expression, that inhibition of miR6891-5p in control MSCs led to skewing, and that restoration of miR6891-5p expression in SjD MSCs reversed skewing of X-linked genes. On the chromatin level, miR6891-5p expression restricted CTCF activity in its restoration of allelic balance. Focusing on the phenomenon of X skewing, in this project we propose to address three broad questions, namely 1) the molecular mechanism of miR6891-5p-CTCF-mediated regulation of allelic balance, 2) targeted strategies to reverse skewing in SjD, and 3) the clinical significance of X skewing in SjD patients. Collectively, we will test the hypothesis that miR6891-5p loss leads to X skewing in SjD and targeting of the miR6891-5p pathway has the potential to restore X-chromosomal allelic balance by the following aims: Aim 1. Establish the molecular mechanism of miR6891-5p-regulated X skewing and identify molecular targets to correct skewing Aim 2. Determine the potential of reprogramming as a strategy to globally restore allelic balance in SjD Aim 3. Establish the relationship between miR6891-5p-regulated X skewing and SjD pathogenesis With successful completion of the work proposed, we will have gained insights into the molecular basis underlying sexual dimorphism in SjD. By establishing the miR6891-5p-regulated pathway as a central regulator of X chromosomal allelic balance, we will identify molecular and cellular targets for the reversal of X skewing and personalized management of SjD.

NIH Research Projects · FY 2026 · 2025-09

As many as 24% of the 6.8 million patients who seek treatment for a musculoskeletal injury each year continue opioid use long-term, which can lead to negative consequences including opioid use disorders, overdose, and death. Because tapering patients off chronic opioid use is challenging, interventions are needed to assist patients in opioid cessation during the acute pain phase. Pain and opioid use are impacted by modifiable psychological factors, yet there are no routine psychological treatments after an injury to mitigate these variables. The purpose of the proposed study is to optimize and examine feasibility and acceptability of an adaptive psychological intervention for patients who are medically hospitalized after an injury. The proposed adaptive intervention begins with a low-cost, low-intensity, 15-minute computerized brief intervention (CBI) in which participants will be provided with education on the consequences of long-term opioid use and complete a mindfulness activity to assist with managing pain. Those still using opioids after 10 days will engage in a more intensive, 4-session psychological intervention with a trained therapist. Sessions are composed of evidence-based strategies to improve pain and distress (i.e., mindfulness and acceptance-based strategies); however, these have not yet been used for acute pain after injury to transition patients off opioids. Without this early intervention, patients are high-risk for long-term opioid use. The CBI will begin inpatient, and if warranted, subsequent weekly sessions will follow inpatient or through telemedicine (e.g., video visits) once the patient is discharged. Patient interviews (N= 20) will be utilized to refine the adaptive intervention and study design. The intervention will be further revised based on therapist and participant feedback from an open trial (N= 10). A sequential, multiple assignment, randomized trial (SMART) of 80 patients will then be conducted to evaluate this adaptive intervention. Patients will first be randomized to CBI or the usual treatment comparison group. After 10 days, those remaining on opioids will begin a guided opioid taper. Non-responders in the CBI will also be re-randomized to receive only the opioid taper, or the opioid taper plus the 4-session psychological intervention. All participants will be evaluated at baseline, and at 10-day, 40-day, and 90-day follow-ups. We expect that this intervention and design will be feasible and acceptable. The results obtained from this study will be used as preliminary data to inform a fully powered SMART to test the efficacy of the adaptive psychological intervention. This project is innovative because it targets patients at high-risk for long-term opioid use during the acute pain stage, and uses a psychological intervention that adapts to individual needs. Further, the intervention will be evaluated with a SMART design through a real-world medical setting, which is expected to increase patient access and engagement. The long-term goal is to evaluate whether an adaptive psychological intervention delivered after a musculoskeletal injury can successfully transition patients off opioids and prevent prolonged opioid use and the development of an opioid use disorder.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The objectives of this proposal are to optimize and validate detection of microvessels in the cerebral vascular, glymphatic and meningeal lymphatic (ML) systems using superparamagnetic iron oxide (SPIO)-enhanced susceptibility weighted imaging (SWI, SPIO-SWI), and then to investigate the cerebral waste clearance in the vascular, glymphatic and ML systems during progression of Alzheimer’s Disease (AD). Emerging data indicate that the waste clearance from the brain parenchyma plays an important role in neurological diseases, especially neurodegenerative diseases1-9. Waste clearance from brain is closely related to alterations in small blood and lymphatic vessels and perivascular spaces of the brain7-9. The glymphatic system and its peri-vascular pathway for waste clearance have been shown to be sensitive biomarkers for neurological diseases8,10-15. Despite many milestone achievements, conclusive findings on the brain waste clearance relationships among the blood and lymphatic vessels, and perivascular spaces and their contributions to AD are absent. The paucity of research into the relationships among the changes in cerebral blood vessels, lymphatic vessels, perivascular spaces, and the outcomes of diseases may be attributed, in part, to technical difficulties. Although the currently used two-photon imaging (TPI) is excellent for vessel detection in small surface areas, it is invasive and is not suitable for whole brain studies. MRI can overcome the weak points of TPI and provide non-invasive whole brain real-time imaging of the vascular, glymphatic and lymphatic systems. However, conventional MRI sensitivity is insufficient to investigate microvessels of the vascular, glymphatic and lymphatic systems. We have optimized highly sensitive MRI methods using the SPIO-SWI to detect ~10 micrometer cerebral microvessels (Fig. 1-4)16,17. Our preliminary data indicate that clearance of intracisternal injected MRI contrast agent decreases with AD severity and concomitantly with increased beta-amyloid around the vasculature and with functional deficits in a rat model of AD. Based on our novel preliminary data, we posit that the SPIO-SWI technique will significantly increase detection sensitivity of microvessels in vascular, glymphatic and ML systems and thereby permit detailed investigation of the interaction among the changes in cerebral blood vessels, lymphatic vessels, and perivascular spaces during progression of AD. To test these hypotheses, we will first (Aim 1) optimize and validate our approach to enhance the detection sensitivity for both glymphatic and ML microvessels. In Aim 2, using the optimized SPIO-SWI technique, we will perform longitudinal measurements to investigate the interaction among vascular, glymphatic and ML systems for waste clearance during progression of AD. Data generated from this application will provide new insights into the efflux pathways of brain waste clearance with progression of AD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Endometriosis is a non-malignant disorder defined by the presence of endometrial-like tissue outside the uterus and is associated with debilitating pelvic pain and impaired fertility. Retrograde menstruation is a primary etiologic pathway. The on-average 7-10 years between the onset of symptoms and definitive diagnosis of endometriosis places an enormous emotional and financial burden on both the patient and the healthcare system. Despite the significant health care costs and long-term health risks associated with endometriosis, its molecular etiology remains largely unknown, and non-invasive diagnostic and non-hormonal treatment options remain elusive. Therefore, a critical need exists to understand the pathogenesis of endometriotic lesions, which will ultimately lead to early treatment interventions and prevention of disease progression. Although, most studies on endometriosis have focused only on adults, patients with endometriosis report that their pain symptoms emerged during adolescence and young adulthood. Our baboon model has provided significant insight into the early pathophysiology of the disease and the mechanisms associated with aberrant gene expression. Furthermore, the peritoneal disease induced in our baboon model phenocopies changes associated with endometriosis in women including transcriptomic changes in the eutopic endometrium and lesion gene expression. Therefore, the Specific Aims of this proposal are to integrate single cell, spatial, and bulk transcriptomics analyses of peritoneal endometriotic lesions at 12 months after the induction of disease in the baboon and explore translation of these discoveries to human adolescents at early stages of endometriosis. Specifically, in Aim 1 we will determine the early inflammatory transcriptomic events in peritoneal endometriotic lesions by single cell and spatial transcriptomics analyses in our baboon model at 12 months of disease and correlate these changes with spatial transcriptomics analysis of endometriotic lesions from adolescent patients with endometriosis at 12-months post- onset of symptoms. In Aim 2 we propose to identify new drug candidates using Reversal of Gene Expression Score (RGES) to compute a drug’s potency to reverse disease gene expression based on bulk RNA-seq gene expression signatures from baboon lesions and human superficial peritoneal lesions from adolescent patients within 12 months since onset of symptoms. Drugs, filtered to target cells/pathways identified as pathologically relevant, will be tested in an endometriotic spheroid model of invasion followed by RNA-sequencing of spheroid epithelium to validate the mechanism of action. Successful completion of this research project will identify the key inflammatory transcriptomic changes over time in endometriotic lesions during their early developmental timepoints and will pave the way for early biomarker discovery, and identification of drugs for targeted therapies, which will be of direct relevance to the early disease identification and treatment for women with endometriosis.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The ground-truth definition, experimental control, and therapeutic treatment of neuronal circuits requires technologies that perform well in vivo. Powerful tools that control and report signal transduction, neuronal activity, and gene expression continue to emerge, but the field lacks robust technologies to deliver those tools throughout long-distance neuronal circuits in the mammalian brain. The state-of-the-art relies on viruses that spread from neurons to their retrograde (e.g. rabies) or anterograde (e.g. HSV1) partners. However, these viruses are pathogens that can exhibit neurotoxicity and spread non-specifically, infecting any type of pre- or postsynaptic neurons. This is problematic because the types of synaptic inputs to, and targets of, a given class of neuron are diverse. Consequently, the unmet need for precision trans-neuronal delivery methods severely constrains analyses of how interaction between different cell types influences brain function. While deliberate experimental designs can enable the evaluation of specific types of inputs or outputs in some model systems (e.g., in mice, zebrafish, or fruit fly), these designs rely on genetic modifications to the organism that grant access to unique cell types. There is no such method for robust access from neurons to specific types of their inputs and outputs in “higher” organisms. To address this gap, we propose a transformative project to develop tools that will go from a given neuron starter population to different user-selectable types of its synaptically-connected cells, without the need for replicative neurotropic viruses. Our central goal is to create proteins that achieve targeted trans-neuronal delivery. Our novel strategy is to encode the specificity for distinct types of connected neurons directly into designer proteins, I/O Tags. The I/O Tags will function as fusions: when appended to other proteins, the latter will be ferried into selectable classes of pre- or post-synaptic targets. The Tags will be comprised of combinations of motifs that, in concert, target payloads to synapses, enable release, achieve entry into the preferred type cells, and execute a desired action. We will screen deep libraries of Tag permutations in vivo by utilizing the mouse cerebellar cortex as a model circuit to screen and validate I/O Tags. The investigators will leverage their areas of expertise to assay I/O Tags’ delivery from Purkinje cells into their synaptic partners, ensuring biological compatibility through microscopy, electrophysiology, and behavior. With safety and utility demonstrated in mice, we will validate I/O Tags in ferrets, tree shrews, and macaques. If successful, the outcome of this high-risk proposal will be transformative technologies for trans-synaptic anterograde and retrograde delivery of biological agents. Our Tags will thus seamlessly augment and catalyze existing approaches by enabling the targeted delivery of a diverse array of existing tools, agnostic to the vector or species utilized. If successful, our project will fundamentally change the state-of-the-art to enable targeted cell-type and circuit-specific experimentation and therapy evaluation.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Obesity incidence continues to rise in the U.S. Obesity is more common in women, and women are at higher risk for developing obesity-related co-morbidities. Currently, more than 1 in 3 women are obese, and more than 1 in 4 women are overweight. By 2030, 1 in 2 women are predicted to be obese. Obesity is risk factor for various gynecologic conditions, including endometrial hyperplasia. Endometrial hyperplasia risk increases as a woman’s body mass index increases. Obese women are 4-6 times more likely to develop endometrial hyperplasia compared to non-obese women. Endometrial hyperplasia is characterized by the benign overgrowth of uterine endometrial glands and abnormal uterine bleeding. Abnormal uterine bleeding can negatively impact a woman’s quality of life. Complex atypical endometrial hyperplasia is associated with malignant transformation and progression to endometrial cancer. Obese women show increased extragonadal aromatization of androgens into estrogen and increased estrogen bioavailability. ‘Unopposed’ estrogen is defined as increased circulating estrogen relative to progesterone. In addition to reproductive tract pathologies, the hormone imbalances associated with obesity can lead to menstrual irregularities, pregnancy complications, and infertility. Younger women develop endometrial hyperplasia secondary to conditions leading to ‘unopposed’ estrogen from anovulatory cycles, such as polycystic ovary syndrome or PCOS. In pre- menopausal women with abnormal uterine bleeding, endometrial hyperplasia incidence is as high as 10%, and, in women with PCOS, endometrial hyperplasia incidence is greater than 20%. Public awareness of the associations between obesity and disease susceptibility in women remains low, and research on the adverse health effects of obesity in women remains underfunded relative to its societal burden. Intentional weight loss can lower endometrial hyperplasia risk in obese women, but certain barriers prevent obese, at-risk women from losing weight or maintaining healthy lifestyles while living in obesogenic environments. Our overarching idea is that endometrial hyperplasia risk factors impact different cell types across the endometrial microenvironment, creating a ‘tissue field of susceptibility,’ which affects the cellular and molecular crosstalk necessary for normal endometrial function and the prevention of endometrial hyperplasia. We will use genetically engineered mouse models of endometrial hyperplasia, mouse models of high fat diet-induced obesity, histopathological assessments of mouse and human endometrial hyperplasia, adoptive bone marrow transfers, and ‘omics approaches to determine the mechanisms underlying endometrial hyperplasia development and progression within the susceptible endometrial tissue field. Our aspirational goals are to inform new early detection and prevention strategies by identifying early biomarkers within the uterine microenvironment that predict endometrial hyperplasia pathogenesis and severity in at-risk obese women.

NIH Research Projects · FY 2026 · 2025-09

About 25% of Americans have salt-sensitive hypertension. Abnormal salt retention by thick ascending limbs (THALs) can cause this pathology. Flow of the forming urine stimulates THAL NO production by NO synthase 3 (NOS3) which inhibits NaCl reabsorption. Flow also augments O2- synthesis which stimulates Na reabsorption. In normotensive animals, flow-stimulated NO prevents flow-induced increases in O2-. Flow increases THAL NO via activation of TRPV4, increases in intracellular Ca (Cai), and activation of PI3 kinase, Akt and NOS3. However, the mechanotransduction process upstream of TRPV4 is unknown. Our new data show that primary cilia and the glycocalyx are the mechanotransducers. However, the molecular mechanisms by which primary cilia and the glycocalyx transduce flow into TRPV4 activation and THAL NO synthesis are unknown. Estrogen protects the glycocalyx while testosterone has no known effect. Whether there are sex differences in glycocalyx-mediated NO synthesis is unclear. TMEM184A is a newly discovered protein that binds heparin, a glycocalyx component. In endothelial cells, TMEM184A links the glycocalyx to TRPV4 activation and NO production. However, whether TMEM184A plays a similar role in THALs is unknown. Dietary salt increases blood pressure (BP) in both male and female Dahl salt-sensitive rats (SS) but more so in males. We showed that NO synthesis was lower in SS THALs than salt-resistant (SR) tubules when rats are on normal salt, and high salt exacerbated the difference. Although renal oxidative stress is elevated in SS THALs, the reduction in NO is not due to simple scavenging by O2-. Oxidative stress causes glycocalyx shedding and decreases mechanotransduction of flow. However, the roles of the glycocalyx and oxidative stress on mechanotransduction mediated by this organelle in SS THALs have not been studied. In endothelial cells flow enhances NOS3 expression. A high-salt diet increases THAL flow and enhances SR THAL NO synthesis by increasing NOS3 expression, but high salt does not increase NOS3 protein in SS THALs. Whether this is due to glycocalyx shedding is unknown. Our hypothesis is that in THALs flow-stimulated NO synthesis and NOS3 expression depends on the primary cilia displacing the glycocalyx, which activates TMEM184A and TRPV4. Oxidative stress causes glycocalyx shedding in SS THALs, thereby reducing flow-induced NO production, NOS3 expression and urinary Na excretion (UNaV) leading to salt-sensitive hypertension in a sex-dependent manner. Aim 1 hypothesis: Luminal flow bends primary cilia displacing the glycocalyx, activating TMEM184A and TRPV4, thereby stimulating NOS3 translocation and NO synthesis by THALs from normotensive rats. Aim 2 hypothesis: THAL oxidative stress damages the glycocalyx, blunting flow-stimulated Cai, NO synthesis and NO inhibition of NaCl reabsorption, and blocks salt-induced increases in NOS3 protein in a sex-dependent manner. Aim 3 hypothesis: Oxidative stress-induced shedding of the THAL glycocalyx in vivo blunts NO synthesis and UNaV, especially on high salt, causing salt-sensitive hypertension in a sex-dependent manner. Thus, we propose a novel role for the glycocalyx in BP regulation.

NIH Research Projects · FY 2025 · 2025-08

Abstract: Our long term objective is to develop a new class of radiation mitigating agents with attractive chemical, physical and biological characteristics required to be an effective drug that can be distributed widely. We have identified a small molecule, UTS-1401 [5-(methylthiomethyl) isoxazole-3-carboxylic acid] which demonstrates mitigation of hematopoietic stem cell death when administered at either 24h or 48h following whole body irradiation (WBI). Using the endogenous spleen colony assay, we demonstrated a mitigating effect in that the colony number with and without UTS-1401 was 3.5 ± 0.4 for a 24h interval and 2.3 ± 0.5 for a 48h interval. We have recently demonstrated a significant radioprotection for both mouse survival and hematopoietic stem cells for this compound when administered up to 72h before irradiation (Valeriote et al, Radiation Research, 202:16- 25, 2024). In this application, we propose to further examine solely the mitigating effect on the hematopoietic acute radiation syndrome (H-ARS) using survival as the endpoint in specific aim 1. Groups of Swiss mice will receive a series of graded doses of WBI (in 0.5 Gy increments) around the LD50 for this syndrome (approximately 7.5 Gy in females and 8.5 Gy in males) with and without the administration of 150 mg/kg UTS-1401. The single dose of UTS-1401 being used in all studies is the highest dose administrable due to its aqueous solubility (in tartrate buffered saline). The radiation mitigation factors will be calculated as the ratio of the LD50 for radiation plus UTS-1401 versus that for radiation alone. The degree of mitigation will be examined at 24, 48 and 72 h following WBI to determine the radiation mitigation fraction as a function of time after radiation exposure. Three routes of drug delivery, intravenous (iv), oral, and subcutaneous (sc), will be examined and compared. Radiation will be delivered by 16 MeV electrons from a Linac. In specific aim 2, we will examine the pharmacokinetics (PK) for 150 mg/kg UTS-1401 comparing the iv, oral, and sc routes to obtain a determination of both the drug kinetics and bioavailability. The AUC values will be correlated with the extent of mitigation. For both specific aims, both male and female mice will be separately studied. The results from these studies are expected to demonstrate an effective first-in-class compound, UTS-1401, which has a small molecular weight, is chemically stable, nontoxic, aqueous soluble and inexpensive with H-ARS radiation mitigating properties which extend for a number of days following WBI. The mechanism studies (not proposed here) are expected to demonstrate UTS- 1401 as a new class of agents for mitigating the cytokine storm consequent to the irradiation.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of the tau protein and amyloid beta (Aβ) peptide. Tau pathology is also present in several other neurodegenerative disorders known as tauopathies. Most cases of these disorders have no clear genetic cause and the disease etiology remains poorly understood. There is growing interest in identifying how exposure to toxic elements in the environment, including heavy metals like cadmium, might help initiate and promote progression of these diseases. The typical human exposure route for cadmium occurs through eating contaminated food or smoking and up to 20% of Americans have elevated levels beyond what is considered safe. Increased cadmium levels are associated with increased risk of AD, lower levels of cognition, and increased levels of AD biomarkers. Multiple studies in transgenic amyloid models identified decreased cognitive performance and increased Aβ pathology. However, no studies to date have tested the effects of cadmium exposure on tau protein. Investigators hypothesize that Cd exposure promotes progression of disease pathologies and will enhance neurotoxicity through synergistic pathogenesis. This multi-PI application takes advantage of the relative strengths of the C. elegans nematode model organism and multiple transgenic rodent models of disease to answer specific questions about these interactions through three specific aims. Aim 1 is designed to identify mechanisms by which cadmium exposure alters Aβ and tau-induced neurodegeneration in worms. Novel worm strains expressing tau and Aβ in cholinergic neurons through inducible promoters will be used as controllable models to measure cadmium’s effect on cognition, pathology development, and neurodegeneration and determine the individual contributions of tau and Aβ. Aim 2 uses two different mouse lines to model the complex system of human non-AD tauopathy. The PS19 line expresses a mutant form of tau that aggressively develops tau pathology and neurodegeneration while the MAPT KI line is a human tau knock-in that is phenotypically normal. Orally treating these mice with cadmium will test how exposure affects tau pathology and neurodegeneration progression in a developing familial tauopathy and the ability to induce a sporadic tauopathy. Aim 3 uses the TgF344-AD rats that have mutations in APP and PS1 to model Aβ and late-stage tau pathology of AD. We will repeat the experimental paradigm from Aim 2 to determine cadmium’s effects in the presence of both Aβ and tau. Through these experiments it will identified how environmental exposure to cadmium, a neurotoxic heavy metal, alters tau pathology and tau-induced neurodegeneration for the first time. This will further our understanding of interactions between toxic environmental exposures and the etiology of AD and tauopathies as well as the underlying mechanisms of disease progression and neurodegeneration which is critical for developing effective therapeutics to counteract them.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The higher incidence of preeclampsia in Black compared to White pregnant populations is one of the leading contributors to racial disparities in maternal morbidity and mortality. Due to the higher preeclampsia rate in Black populations, the U.S. Preventive Services Task Force, American College of Obstetricians and Gynecologists, and Society for Maternal-Fetal Medicine endorse a decision algorithm that includes patient race to guide the use of low-dose aspirin to prevent preeclampsia. In this algorithm, Black patients need fewer preeclampsia risk factors than do patients of other races before aspirin is recommended for prevention. Black race was included in the algorithm because of a large epidemiologic literature demonstrating disparities in both preeclampsia and preeclampsia-related morbidity and mortality between Black and White pregnant populations. However, preeclampsia research has focused almost exclusively on Black-White disparities, with little research examining rates in other racial groups. Our preliminary research suggests that the current low- dose aspirin algorithm is missing multiple racial groups who have high rates of preeclampsia but who are underrepresented in the scientific literature. Without the inclusion of all racial groups with high rates of preeclampsia, the current low-dose aspirin therapy algorithm cannot be equitably applied to all pregnant people to reduce preeclampsia disparities. The objectives of the proposed research are thus to identify the understudied minoritized racial and ethnic groups who experience disparities in preeclampsia and to model the potential to prevent preeclampsia if they were included in the low-dose aspirin decision algorithm. In Aim 1, we will use hospital discharge data from the Healthcare Cost and Utilization Project’s State Inpatient Databases to estimate preeclampsia rates in diverse racial groups and identify those with high rates of preeclampsia. In Aim 2, we will use Markov state-transition models to compare 4 strategies for modifying the low-dose aspirin algorithm to be inclusive of more racial groups and will determine which of these strategies can best prevent preeclampsia and reduce racial disparities: (1) no change to the algorithm, (2) adding new racial groups with high rates of preeclampsia, (3) removing race from the algorithm, and (4) recommending aspirin to all pregnant patients. The long-term goal of this research is to ensure that all patients have equitable access to low-dose aspirin, one of few evidence-based therapies shown to prevent preeclampsia. By modifying a clinical algorithm used nationwide, this research will have important impacts on reducing disparities in preeclampsia and associated maternal morbidity and mortality in the United States.

NIH Research Projects · FY 2025 · 2025-08

Abstract: Our long term objective is to develop a new class of radiation mitigating agents with attractive chemical, physical and biological characteristics required to be an effective drug that can be distributed widely. We have identified a small molecule, UTS-1401 [5-(methylthiomethyl) isoxazole-3-carboxylic acid] which demonstrates mitigation of hematopoietic stem cell death when administered at either 24h or 48h following whole body irradiation (WBI). Using the endogenous spleen colony assay we demonstrated a significant mitigating effect (ratio of colony number with and without UTS-1401) when drug was given 24h or 48h after radiation. We have also recently demonstrated a significant radioprotection for both mouse survival and hematopoietic stem cells for this compound for up to 72h before irradiation (Valeriote et al, Radiation Research, 202:16-25, 2024). In this application, we propose to examine solely the mitigating effect to both the hematopoietic acute radiation syndrome (H-ARS) in specific aim 1 and the gastrointestinal acute radiation syndrome (GI-ARS) in specific aim 2 following WBI (with 5% bone marrow protection for specific aim 2). Swiss mice will receive a series of graded doses of WBI around the LD50 for both syndromes with and without the administration of 150 mg/kg UTS- 1401. The single dose of UTS-1401 being used in all studies is the highest dose administrable due to its aqueous solubility (in tartrate buffered saline). The radiation mitigation factors will be calculated as the ratio of the LD50 for radiation plus UTS-1401 versus radiation alone. The degree of mitigation will be examined at 24, 48 and 72 h following WBI to determine the timeframe of mitigation after radiation exposure. Three routes of drug delivery, intravenous (iv), oral, and subcutaneous (sc), will be examined and compared. For all specific aims, both male and female mice will be separately studied. Radiation will be delivered by electrons from a Linac. In specific aim 3, we will examine the pharmacokinetics (PK) for 150 mg/kg UTS-1401 comparing the iv, oral, and sc routes to obtain a determination of both the drug kinetics and bioavailability. The AUC values will be correlated with the extent of mitigation. Finally, in specific aim 4, we will address the mechanism of action with studies focused on the role of specific cytokines induced by radiation in the so-called “cytokine storm”. We will assess the time course changes of TNF-α, IL-1β, IL-6, CSF and TGF-β in blood as well as bone marrow and intestinal mucosa over 20 days following: UTS-1401 alone, 10 Gy irradiation, and the combination of UTS-1401 and radiation at a 24h interval. The results from these studies are expected to demonstrate an effective first-in-class compound, UTS-1401, which has a small molecular weight, is chemically stable, nontoxic, aqueous soluble and inexpensive with radiation mitigating properties which extend for a number of days following irradiation. The mechanism studies are expected to demonstrate UTS-1401 as a new class of agents for mitigating the cytokine storm consequent to the irradiation.