Case Western Reserve University

NIH Research Projects · FY 2025 · 2024-07

It is well-established that Type 1 diabetes (T1D) is an independent risk factor for cardiovascular disease (CVD), and young adults with T1D face substantial variability in risk and life expectancy across cardiovascular health (CVH) factors and behaviors. CVH includes four health behaviors (diet, physical activity, nicotine exposure, and sleep duration) and four health factors (body mass index, glucose, low-density lipoprotein cholesterol [LDL-C], and blood pressure [BP]) at optimal levels. Achieving ideal CVH is associated with greater CVD-free survival, longevity, and higher quality of life. However, differences in CVH outcomes remain across Individuals with T1D, including those living within various community settings. The purpose of this F31 training plan and proposed descriptive study is to examine the associations among contextual and psychosocial factors related to CVH, as well as describe the lived experience of stress among young adults aged 18–31 years with T1D at University Hospitals, Case Western Reserve University, Cleveland, Ohio. In Aim 1, we will examine the association between contextual challenges and stress (a path), 1a. stress and CVH (b path); 1b. contextual challenges and CVH (c path); 1c. the role of stress as a mediator; and 1d. multiple intersecting characteristics in these associations among 125 young adults ages 18–31 years with T1D living in Ohio. In Aim 2, we will describe the lived experiences of stress among 15–22 young adults with T1D residing in Ohio. We will prospectively enroll adults with T1D from University Hospitals, a large regional healthcare system in Ohio. Our central hypothesis is that higher contextual challenges and greater stress are associated with lower CVH among young adults with T1D. These pathways may serve as important targets for improving cardiovascular outcomes in groups facing contextual challenges, where such clinical gains might otherwise be difficult to achieve.

NSF Awards · FY 2024 · 2024-07

Nontechnical abstract: Quantum bits or ‘qubits’ are the building blocks of quantum technologies for sensing, networking, communication, and computing. One promising platform for implementing a qubit is as an individual atomic defect in diamond, known as a nitrogen-vacancy center. The magnetic property of these defects – the spin – has robust quantum coherence, even at room temperature. Already, these defect spin qubits have found application as versatile quantum sensors in a solid-state platform. However, one of the most significant challenges facing this qubit platform is the lack of an efficient, scalable means to address and couple high density arrays of multiple qubits. Most significantly, controlled coupling between qubits is essential to realize the true promise of quantum technology through quantum entanglement. This project is working to forge a path to overcome this challenge, using nanometer-scale magnetic structures to provide strong, local, controllable magnetic fringe fields for addressing and coupling spin qubits. A primary challenge is that the same features that make a magnetic material or structure desirable often also lead to increased magnetic field noise that causes degraded qubit performance. This project is working to understand this trade-off of coupling for enhanced functionality vs. degraded coherence, and how materials and structures can be designed to optimize that trade-off. Success of this work will enable a pathway towards new solid state, room-temperature quantum technology. In doing so, a diverse cohort of students will be trained for the quantum and semiconductor workforce. Technical abstract: The hypothesis underlying this work is that there exist magnetic nanostructures whose magnetization state and magnetic excitations can be used to address and couple proximal defect spin qubits, without introducing excessive qubit decoherence. To test this hypothesis, we are working to better understand the phenomena by which magnetic nanostructures induce decoherence in a proximal spin qubit. The research team is using nitrogen-vacancy defects in diamond coupled to permalloy magnetic disks, magnetized into a vortex state, as a flexible test-bed system. With knowledge gained from this test-bed system, other materials and structures are being explored to optimize addressability and coupling vs. decoherence. For example, materials with different Gilbert damping coefficient have different magnetic noise characteristics due to the fluctuation dissipation theorem, and different nano-structures allow tuning of magnetic fringe fields and the spectrum of magnetic excitations. In particular, artificial spin ice structures provide a magnetic metamaterial platform with rich opportunities for tailoring fringe fields and magnon dynamics. Addressing the hypothesis above also requires defining the thresholds for necessary qubit addressability and coupling vs. sufficient qubit coherence. To do this, the research team is developing benchmark figures of merit for proposed applications for defect qubit entanglement. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Driver mutations confer increased fitness to cancer cells but can also encode neoantigens that stimulate an anti- cancer immune response. This anti-tumor immunity is mediated primarily by T cell receptor (TCR) recognition of mutation-derived peptides presented on Human Leukocyte Antigen (HLA) complexes. L858R promotes unchecked growth and is the most common epidermal growth factor receptor (EGFR) mutation in lung cancer, accounting for 40% of all observed mutations in the protooncogene. How L858R may stimulate an anti-tumor immune response is not yet understood. The objective of the proposed work is to understand the mechanisms through which the EGFR L858R mutation affects tumor biology in provoking anti-tumor immunity. My preliminary data show that L858R-derived peptides are capable of binding to and stabilizing HLA-A*03:01 and HLA-A*11:01 complexes. In two orthogonal assays, L858R peptide-HLA (pHLA) complexes stimulate CD8+ T cells more strongly than wild-type EGFR pHLA complexes. Finally, using pHLA multimer flow cytometry, I have identified CD8+ T cells from healthy donor PBMCs that recognize the L858R pHLA complex through their TCRs. I hypothesize that the EGFR L858R mutation generates an immunogenic neoantigen that provokes T cell- mediated anti-tumor immunity due to the high clonality of the mutation. In Aim 1, I will fully define determinants of L858R immunogenicity by characterizing the EGFR L858R-derived neopeptide and its ability to activate T cells. I will employ HLA immunoprecipitation coupled to liquid chromatography mass spectrometry to identify the L858R peptides presented on HLA, determine the relative contributions of CD4+ and CD8+ T cells in the immune response, and examine exhaustion phenotypes in L858R-specific T cells from patients using single cell RNA and TCR sequencing. In Aim 2, I will determine the ability of EGFR L858R-specific T cells to suppress tumor growth. I will also determine how mutation clonality and pHLA expression affect the anti-tumor immune response. This study employs cutting edge genetic tools and computational approaches to generate a detailed understanding of adaptive immunity against somatic mutations in tumors. Furthermore, this proposal is tailored for a physician-scientist in training, as it investigates clinically relevant determinants of a T cell-mediated immune response against EGFR-mutant cancers, and will inform the development of an adoptive T cell therapy for a large subset of lung cancer patients.

NIH Research Projects · FY 2025 · 2024-06

Abstract Pseudomonas aeruginosa is a leading cause of blinding corneal infections worldwide. The type III secretion system (T3SS), a molecular syringe that allows the bacterium to inject effector proteins into host cells, is critical for P. aeruginosa virulence. P. aeruginosa isolates do not produce many effector proteins and even more curiously, genes for the effectors ExoS and ExoU are distributed in a mutually exclusive fashion. This distribution materially affects the virulence of the strains. ExoS producing strains can invade epithelial cells in vitro, are slower to elicit overt lysis of host cells, and cause a less fulminant infections with less tissue destruction in vivo. ExoU producing strains, on the other hand, tend to cause more severe disease, and are linked to increased antibiotic resistance. While ExoS producing strains predominate in the environment and in patients with cystic fibrosis or ventilator-associated pneumonia, ExoU-producing strains are significantly enriched among corneal isolates from keratitis patients. The correlation between production of ExoU, increased disease severity in the clinic, and elevated frequency of multidrug resistant isolates has been documented epidemiologically for decades. However, the molecular underpinnings of this correlation are not well understood. The exoU gene is encoded on a pathogenicity island, which can vary greatly in size, ranging from as little as 4 kb to 81 kb. The role of the accessory genes present on the ExoU pathogenicity island is unclear, but our preliminary work demonstrates that they play an important role in pathogenesis. However, which ExoU-island genes are important for virulence and whether these pathogenicity island genes can also help explain the increased frequency of antibiotic resistant isolates is unclear. The goal of this proposal is to test the hypothesis that ExoU islands encode virulence functions other than ExoU and that, at least in some instances, they also contribute to the increased antibiotic resistance associated with this class of P. aeruginosa strains. The proposal is divided into two aims, that will dissect the virulence role of the two largest ExoU islands: the 30kb, type B ExoU island of strain 19660 (Aim 1), and the 81 kB, type A ExoU island of strain 6077 (Aim 2). Strain 6077 is a multidrug resistant corneal isolate that belongs to the globally distributed, high-risk ST235 sequence type. We will also examine the role of the type A ExoU island as it relates to antibiotic resistance. Taken together the proposed program of research will uncover new virulence functions which will expand our understanding of the molecular toolbox available to bacterial pathogens. The proposal is aimed squarely at understanding the virulence of the most pathogenic and difficult to treat P. aeruginosa infections encountered in the clinic.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT Objective: The overarching goal of our research is to replace invasive radical prostatectomy with targeted, mini- mally invasive image-guided focal resection of prostate cancer. We propose to accomplish this by combining novel low-field MRI techniques with a new kind of surgical robot capable of delivering two needle-sized manipulators into the prostate through a standard transurethral endoscope. Significance: 1 in 8 men will be diagnosed with prostate cancer in their lifetime, and it is second only to lung cancer in the number of men it kills every year in the USA. The gold standard treatment, radical prostatectomy, involves complications including all those of major surgery, as well as high rates of impotence and incontinence. Recently, pioneering surgeons have noted the promise of patient-specific transurethral focal resection to reduce complication rates. However the approach is currently fundamentally limited by the fact that cancerous tissue cannot be visually differentiated from healthy tissue in endoscope images, forcing the surgeon to “guess” where the cancer is, based on memory of preoperative MRI images. Ultrasound-MRI fusion cannot improve things, since the ultrasound probe compresses the prostate, which collapses the urethra and precludes transurethral interventions. We propose to eliminate the guesswork and enable accurate, precise, personalized focal resections by fusing high-resolution preoperative MRI with intraoperative low-field MRI and a novel robotic system. Innovation: The central innovation of this project is to enable use of the emerging generation of inexpensive, portable, and open low-field MRI scanners to guide focal prostate resection. Additional innovation comes from the robotic system which will enable precise and accurate use of imaging information. The robot will be the first MRI-conditional robot able to deliver multiple manipulators through an endoscope. It will feature needle- sized, tentacle-like manipulators and deploy them into the prostate through a standard-diameter transurethral endoscope, for precise resection and retraction of tissue. This will make the focal resection process much easier and more accurate for the surgeon to accomplish. Approach: We will create our MRI-guided robotic system through three Specific Aims. Aim 1 achieves fast in- traoperative imaging to update the surgeon's image guidance display as they remove tissue. In Aim 2 we build a novel MRI-conditional robot and integrate it with the low-field MRI scanner. In Aim 3 we validate the integrated system in anthropomorphic phantoms with urologic surgeons. Note that clinical translation of our system will be rapid at the successful conclusion of this R01. This project includes two industry partners, Promaxo, Inc. which has recently released an FDA-approved low-field prostate MRI scanner, and Virtuoso Surgical, Inc. which is de- veloping a (non-MRI-conditional) transurethral robot slated to be on the market by the time this R01 concludes. Thus, successful completion of this R01 will pave the way for commercial translation and clinical trials, enabling us to rapidly bring the benefits of this research to doctors and their patients.

NIH Research Projects · FY 2026 · 2024-06

In this project, we aim to develop and improve the delivery of various therapies, including adeno-associated viral (AAV) and nanoparticle (NP) gene therapy to the heart. The impetus for this project is a high unmet need for cardiomyopathies that do not have current treatments. Cardiomyopathy is an umbrella term for disorders of cardiac muscles. Collectively, these disorders are highly prevalent, and many lack specific treatment options. Because most gene therapies are one-time, single-dose treatments, improving heart targeting becomes critical to achieve adequate efficacy. Systemic delivery of AAV or NP vectors in adult, often overweight, patients is fraught with challenges related to the low transduction of cardiomyocytes and the life-threatening immune response. By enhancing the delivery of genetic information to the heart and reducing its sequestration by the liver, we would be able to increase efficacy and improve safety of these therapeutics. Based on the discoveries in our lab, we hypothesized that by co-delivering AAV, NPs, oligonucleotides, antibodies or other therapeutics with an engineered polymeric adjuvant, a synthetic enhancer, will improve the therapeutic index of these therapeutics. We also hypothesized that this technology that we call heart-redirected targeting (HRT) has a potential to enhance the delivery of any therapeutic entity. This hypothesis is supported by the preliminary studies on mechanism of action of HRT and examples of delivery of various therapeutic modalities. Therefore, in this proposal, we aim to: 1) test the risk/benefit of HRT; 2) investigate the generality and reproducibility of the HRT; 3) elucidate the mechanism of action of HRT in human-relevant cellular models; 4) test the long-term efficacy of HRT with AAV carrying frataxin (FXN) transgene in genetic mouse model of Friedreich’s ataxia (FA). In order to decrease mortality in FA, it is critical to treat cardiomyopathy, which is the dominant cause of death among FA patients. If successful, this work will have an unprecedented impact on drug delivery and gene therapy, because the HRT system is agnostic to the delivery vehicle, opening a possibility of cardiac targeting with a wealth of approaches developed to date.

NIH Research Projects · FY 2025 · 2024-06

Project Summary The proposed project aims to develop the first-ever data-driven autonomous gaze coach for robot-assisted minimally invasive surgical (RAMIS) virtual reality simulation training. A surgeon’s skill level is correlated with patient outcomes. It is known that expert surgeons adopt different gaze patterns from novices, and that gaze training is a proven, but labor-intensive coaching method that improves a trainee surgeon’s surgical skills, especially under stress. Our proposed coaching system will increase the accessibility of high-quality gaze coaching, even in areas where there is a shortage of expert instructors, and will free up valuable time for surgical experts for clinical and higher-order instructional work. The acceleration of skill acquisition, will, in turn, decrease the time and cost for training competent surgeons across the country. The project will comprise three specific aims. In Aim 1 we collect gaze and performance data from experts and novices in six virtual reality RAMIS drills. We will analyze the data to find good candidate drills in which to develop our autonomous gaze coaches by identifying those in which expert performance and gaze patterns differ most from those of novices. In Aim 2, we use the data collected in Aim 1 to train expert gaze-synthesizing neural networks that can generate a fixation point or a gaze map given surgical video streams. We validate the networks’ abilities to replicate expert gaze using a held-out test set. In Aim 3 we develop approaches to display the gaze synthesized by the neural networks from Aim 2 and test the effectiveness of our gaze coaching system to improve the surgical skills of novices. Outcome skill measures of this user performance study are the surgical skill measures such as economy of motion and the completion time, and task-specific penalties. These include instrument and apparatus collisions, dropping of apparatus, instruments out-of-view, durations of excessive force application, wrong energy application, dissection outside of defined zones, and repeated needle pierces. Outcome gaze measures include the increase in the amount of overlap between the novice gaze and expert gaze after training, and the increase in time spent focusing on expert-defined areas of interest in the surgical scene. The results of this development and validation of the system in virtual reality simulation will inform our long-term goal of developing autonomous gaze coaching systems for use in more complex clinical-like training scenarios, such as cadaver or porcine models.

NIH Research Projects · FY 2025 · 2024-06

This T35 application requests funding for the Case Western Reserve University School of Medicine (CWRU SOM) Medical Student Summer Research Program in Aging and Alzheimer’s Disease (MSSRPA). The overall goal of the program is to promote career development for physician scientists who will include biomedical investigation as a career goal, with particular focus on Alzheimer’s disease, aging, and related research. The program will educate medical students using a mentor-based research approach over a 12-week training period between their 1st and 2nd years of medical school. Program mentors are based at the CWRU SOM and all four affiliated hospitals: University Hospitals, the Cleveland Clinic, MetroHealth, and the Louis Stokes VA Medical Center. The 19 mentors have a track record of collaboration manifest by joint publications, MPI grants, co-investigatorships on grants, and participation in a funded Alzheimer’s Disease Research Center or the CDC-supported Center for Prion Surveillance, and garner more than $14 million annually in external direct research support, an average of $738,000 per investigator. They represent a wide range of ranks, backgrounds, and research expertise from molecular to community-based research. Our mentors have strong training records and there is formal institutional instruction in mentoring. The Case MSSRPA will draw from a highly qualified pool of medical students through a formal application and evaluation process that identifies a research project and mentor from investigators working in a research area related to Alzheimer’s disease and aging. Program evaluation and student progress is overseen by the T35 Executive and Internal Advisory Committees. When the summer research is completed, students submit a written abstract and present their findings during Lepow Medical Student Research Day. Though the centerpiece of the program is the mentored research experience, we include an innovative curriculum that features weekly group meetings with the director and others, didactic lectures, and a three-day hands-on course held at the start of the 12-week research period, as well as instruction in the responsible conduct of research, rigor and reproducibility. Much of this curriculum will be shared with another highly successful funded T35 from NIDDK. Programmatic evaluation will use direct feedback and end-of-program surveys of students and mentors, with appropriate response from the Executive Committee. To assess the long-term impact of the program, we will collaborate with the Medical Education and Alumni Affairs offices to track medical students for 20 years after graduation. Our mentors currently train over 25 medical students in their labs, CWRU SOM requires an original research thesis for graduation, and there are more than 175 eligible students in each class, so we are confident that we can support training of the proposed 10 students per year in the MSSRPA. The academic environment is ideal to sustain the overall objectives of this short-term training program.

NIH Research Projects · FY 2026 · 2024-05

Background. This proposal entitled “The impact of poly-substance use on the crosstalk between microglia, astrocytes, and neurons that regulates HIV latency" is submitted in response to RFA-DA-24-001: Ex Vivo Models for Studies at the Intersection of HIV and Poly-Substance Use”. Although combination antiretroviral therapy (ART) dramatically lowers the levels of HIV RNA in the brain, it does not reduce the prevalence of HIV- associated neurocognitive disorders (HAND), which still develops in up to 50% of people with HIV (PWH). Poly- substance use in PWH increases the risk of developing HAND, creating a significant unmet medical challenge. Our goal. Our proposed ex vivo studies of poly-substance exposure are based on newly developed methods to derive authentic microglia, astrocytes, and neurons from induced pluripotent stem cells (iPSC). We will study the responses of these cells to HIV and poly-substance exposure in mono-, di-, tri-cultures, and organoids. Our previous work has shown that HIV latency is established due to signals from healthy neurons and astrocytes that drive infected microglia into a homeostatic state. The latent virus becomes reactivated in response to inflammatory cytokines and neuronal damage. For example, adding methamphetamine (METH) at a physiologically relevant concentration (100 nM) to co-cultures of microglia and neurons induces HIV reactivation and neuronal damage. Also, it sensitizes HIV-infected microglia to reactivation by inflammatory stimuli such as TNF-α. We will test the hypothesis that poly-substance use (combinations of methamphetamine and opioids) deregulates the cortical/dopaminergic system and disrupts the homeostatic regulation of microglia, leading to HIV reactivation and increased neuronal damage. In addition to measuring the impact of poly-substance exposure on HIV reactivation, we will use single-cell RNA sequencing to study the changes in cellular signaling and activation induced by substance exposure. How will we advance the field? To define how intracellular signaling between neurons, astrocytes, and microglia is dysregulated by poly-substance exposure, we will first investigate how METH and opioids affect the expression of crucial signal/receptor pairs (CD200/CD200R, CX3XL1/CX3CR1, glucocorticoid/GR, DA/DRD1-5) in the presence or absence of HIV. In addition, since we discovered unexpectedly that adenosine is a potent silencer of HIV in iMG cells, we will investigate how extracellular ATP produced by neurotoxicity and astrocyte activation is metabolized to adenosine by surface receptors on microglial cells and promotes HIV silencing. Understanding these mechanisms at the molecular level will set the stage for devising effective anti-inflammatory strategies to ameliorate HAND in the context of poly-substance use. challenging studies because it is only by working within the context of We are undertaking these technically authentic human microglial cells in an environment that better reflects the HIV-infected CNS that the underlying physiology is accurately represented.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract: In the United States, over 10,000 new diagnoses of the pediatric lung disease, bronchopulmonary dysplasia (BPD), are made annually in surviving premature infants, with costs exceeding $2.5 billion. Treatment options, such as adrenergic receptor agonists, have variable efficacy for the obstructive airway manifestations that characterize this disease. Furthermore, these patients have an elevated risk of mortality and early onset chronic obstructive pulmonary disease. In a neonatal hyperoxia mouse model of BPD and airway hyperreactivity, the PI’s new data identify a viable therapy for this oxidant-related disease. Treatment with S-nitrosoglutathione (GSNO) reverses airways hyperresponsiveness in oxygen exposed juvenile mice and room air recovered adults. GSNO is a potent endogenous bronchodilator and anti-inflammatory, critical for the airways diseases of asthma and cystic fibrosis. In this model, hyperoxia increases the catabolic breakdown of GSNO caused by increased expression and activity of the enzyme, S-nitrosoglutathione reductase (GSNOR), in-part through hyperoxic downregulation of a microRNA (miR-342). Furthermore, mice that do not express the GSNOR gene are protected from hyperoxia induced alveolar simplification, airway hyperreactivity, and end-organ pulmonary hypertensive changes. This proposal will test the overall hypotheses that (1) molecular GSNOR catabolism of beneficial GSNO in relevant cells drives the development of BPD and (2) genetic or pharmacologic targeting of the GSNO/GSNOR pathway will mitigate inflammation and disease. This proposal will evaluate the effects of neonatal hyperoxia in genetic GSNOR knock-outs by investigating the molecular mechanisms in which GSNO confers protection, distinguish gene expression profiles at a single-nucleus level in lung tissue from wild type and GSNOR knock- outs, elucidate the roles of GSNOR in alveolar & airway epithelial cells or myeloid immune cells using Cre/loxP cell-specific knock-outs, and test pharmacologic GSNOR inhibition or exogenous inhaled GSNO during hyperoxia. These studies are clinically important because inhaled GSNO and GSNOR inhibitors are being studied for airway diseases such as asthma and cystic fibrosis which could ultimately serve as viable new therapies for BPD.

NIH Research Projects · FY 2025 · 2024-04

Microbiome impacts cancer development and therapeutic efficacy. In addition to the guts, microbes reside in different tissues influencing the pathophysiology of the tissue microenvironment. These tissue-resident microbes are largely attributed to translocation of gut microbes. In the breast, such passage is termed ‘gut- breast axis’, helping establish microbiotas of breast tissue and milk. Nevertheless, gut-breast axis has been mostly conceptualized around pregnancy, and it is completely unknown whether this axis indeed exists outside pregnancy to impact breast health and carcinogenesis. Our long-term goal is to dissect how microbiome contributes to breast pathophysiology. Especially, the objectives of the present study are to determine i) whether gut-breast axis occurs on a regular basis; ii) whether this involves discrete sets of bacteria for healthy cohorts vs. cancer patients, and iii) what are their roles. Our central hypothesis is that gut-breast axis takes place on a regular basis, involving distinct sets of bacteria to confer anti-tumor effects on healthy cohorts vs. pro-tumor effects on cancer patients. The proposed research is based on our preliminary studies allowing us to harvest specific gut microbiotas from tumor-protected or -susceptible animals. We reported that supplementing sepiapterin (SEP)—the endogenous precursor of tetrahydrobiopterin (the cofactor of nitric oxide (NO) synthase)—normalized arginine metabolism and improved the immunogenicity of HER2-positive mammary tumors. We then orally applied SEP to mice prone to HER2-positive mammary tumors and saw strong tumor prevention. These mice also showed increases in NO levels and NO-producing bacteria in the guts. Besides, extracts of these gut bacteria activated innate immune cells, suggesting the roles of these gut bacteria in anti- tumor immunity. Here, we will determine whether these gut bacteria physically translocate to the breast to exert tumor preventative effects. Our hypothesis will be tested through two SPECIFIC AIMS: 1) Determine whether gut microbiotas of a) tumor-protected vs. b) -susceptible mice exert anti-tumor vs, pro-tumor effects; and 2) determine whether distinct sets of gut microbes are translocated to mammary glands to exert anti-tumor vs. pro-tumor effects. In Aim 1, we will transplant gut microbiota of a) tumor-protected (SEP-treated) or b) - susceptible (DMSO-treated) HER2 mice into recipients and give the inverse drug treatments. We will test whether the transplanted microbiotas antagonize the treatments. In Aim 2, gut microbiota of a) tumor-protected (SEP) vs b) -susceptible (DMSO) mice are differentially labeled, and the 50:50 mixture is given to the recipients undergoing SEP or DMSO treatment. Labeled microbes are analyzed for their gut-breast translocation; their ratios in the breast; and the contributions of breast microbiota to the drug effects. The proposed study is innovative because this is the first time to corroborate gut-breast axis and its contributions to breast pathophysiology. The study is significant because it will have a positive translational impact by justifying the development of a new breast cancer treatment or prevention strategy focused on breast microbiota.

NIH Research Projects · FY 2026 · 2024-04

Pancreatic ductal adenocarcinoma (PDAC) is the most deadly of the common cancers, with limited treatment options. Chemotherapy is marginally effective, while targeted or immunologic agents have little benefit. We recently showed that wild-type IDH1 (wtIDH1) is required for PDAC cells to survive their harsh and nutrient- limited microenvironment (TME). The cytosolic enzyme, IDH1, converts isocitrate to α-ketoglutarate (αKG), using NADP+ as a cofactor. In the setting of nutrient scarcity, the reaction products (NADPH and αKG) help neutralize free radicals and boost mitochondrial function, respectively. Under TME-associated conditions, we discovered that allosteric IDH1 inhibitors, designed and approved to selectively treat mutant-IDH1 tumors, actually target the wtIDH1 enzyme. Tumors have very low Mg2+ levels, which permits drugs like FDA-approved ivosidenib to outcompete the cation in the allosteric pocket, leading to increased efficacy against wtIDH1 PDAC across tumor models (see Nature Cancer, 2022). While anti-wtIDH1 therapy is promising, especially in combination with chemotherapy, in this proposal we identify practical, safe, and chemo-sparing treatments that optimize anti- wtIDH1 therapy based on our recently acquired insights. Specifically, strategies (pharmacologic or dietary) that further enhance PDAC reliance on antioxidant defense and mitochondrial metabolism for survival are particularly effective. Relevant to this work, olaparib is the only FDA-approved targeted treatment of PDAC. The drug inhibits PARP1-mediated DNA repair and is indicated for BRCA-mutant PDAC (<10% of cases), which all exhibit homologous recombination (HR) deficiency. PARP blockade shifts metabolism towards oxidative phosphorylation. A ketogenic diet also reprograms metabolism in this direction by reducing glucose availability. In Aim 1, we pair wild-type IDH1 (ivosidenib) and PARP1inhibitors (olaparib) in both HR deficient and proficient PDAC using GEMM and PDX models. We will show for the first time that wtIDH1 blockade directly inhibits PARP (through increased NADP+) and induces a BRCA-like phenotype (through decreased αKG and histone hypermethylation), resulting in strong synergy between drugs, even in HR proficient PDAC. The intent of this combination is to expand the indications for olaparib to the majority of PDAC. In Aim 2, we will demonstrate that anti-wtIDH1 therapy is potentiated when combined with a ketogenic diet. The two treatments synergize mechanistically, as a ketogenic diet drives the production of free radicals and shifts metabolism towards oxidative phosphorylation, which magnifies PDAC’s need for wtIDH1. We also show that both therapies reduce histone acetylation: low glucose from a ketogenic diet depletes a carbon source, while reduced TCA cycle activity after wtIDH1 inhibition also affects acetyl CoA pools. In Aim 3, we will analyze PDAC patient samples from an ongoing clinical trial (NCT05209074) for ivosidenib activity against wtIDH1, compared to control samples. Metabolic and DNA repair changes will be assessed. We will also compare tumoral Mg2+ levels to serum. These aims will inform future studies and trials seeking to optimize anti-IDH1-based therapies in patients.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract Alzheimer’s disease and the related disorder Frontotemporal dementia (FTD) represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. While a critical barrier to improving the quality of life for people suffering from or caring for those with FTD is a lack of mechanistic understanding of the causes, there is substantial evidence that T cell dysfunction and the balance of T cell subsets contributes to disease pathogenesis and may explain heterogenous patient outcomes. This suggests that strategies to stabilize patient T regulatory cells and/or reduce levels of pro-inflammatory Th17 cells are likely to benefit FTD patients. A key knowledge gap is how environmental signals such as those derived from the gut microbiome interact with common FTD genotypes to affect T cell function and disease progression. A repeat expansion in a non-protein-coding region of the gene C9ORF72 is the most common cause of FTD and the related motor neuron disorder Amyotrophic lateral sclerosis, responsible for approximately 10% of all diagnoses. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration. The expansion is transcribed into a long repetitive RNA that sequesters RNA binding proteins before being translated into aggregate-prone repetitive dipeptide proteins. The mutation also leads to reduction of the endogenous C9ORF72 gene product that functions in endo-lysosomal pathways and suppresses systemic and neural inflammation. In preliminary work, we have demonstrated that signals derived from gut bacteria modify the penetrance and expressivity of neural inflammation in mice with reduction of C9orf72. Additionally, we have established that C9orf72 functions in cells of both the myeloid and lymphoid lineages to oppose autoimmunity and neural inflammation. The first AIM of this proposal will seek to elucidate how C9orf72 functions within T cells to govern cell fate choice. The second AIM of this proposal will seek to determine how a C9orf72 genotype influences pathogenic T cell responses to intestinal microbes and to determine the extent to which pro-inflammatory cytokine Interleukin-17A participates in neural inflammation when C9orf72 levels decline. In the third AIM of this proposal, we will evaluate whether the changes in T cell fate and function we observe in our animal model also occur in humans with a C9ORF72 mutation that converts to FTD but not in carriers of the mutation that are protected from neurological disease. The proposed studies have potential to shed mechanistic insight into regulation of FTD/ALS disease course by T cells and to identify novel prognostic markers and therapeutic targets for Alzheimer’s disease and related dementias.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT Mutations in glycine receptor alpha 2 (GlyRα2), an anionic-selective pentameric ligand-gated ion channel, have been implicated in neurodevelopmental disorders such as autism spectrum disorder and epilepsy. This receptor plays an important role in neurodevelopment and mediates tonic inhibition in specific regions of the adult brain. Functional studies have shown that GlyRα2 has slower activation and desensitization kinetics compared to other GlyR subtypes. However, the precise mechanistic differences between GlyRα2 and other GlyR subtypes remain unknown. Furthermore, while there is increasing evidence of diverse mechanisms of lipidic modulation on ion channels, there is a lack of information regarding the lipidic profile of GlyRα2. Given the importance of lipids in regulating the function of membrane proteins, it is important to investigate the specific lipidic profile of GlyRα2 and how lipidic modulators affect channel function. The overarching goal of this study is to examine the structure-function relationship and investigate the allosteric modulation of GlyRα2. The study is divided into two aims. Aim 1 will test the hypothesis that GlyRα2 conformational changes differ from GlyRα1 upon glycine binding, channel opening, and desensitization. This aim will be assessed using cryogenic electron microscopy (cryo-EM) and patch-clamp electrophysiology with site-directed mutagenesis. Preliminary results have shown high resolution structures in distinct conformational states with various ligands. Aim 2 will test the hypothesis that GlyRα2-specific modulators alter the conformation of the receptor, and that their specificity is attributed to site-specific or globally distinct features of GlyRα2. These modulators are expected to induce conformational differences that correspond to changes in the channel's function. Additionally, Aim 2 will test the hypothesis that GlyRα2 preferentially interacts with different lipid species than GlyRα1, corresponding to the distinct membrane environments these two channels are found in. This aim will expand our knowledge of GlyRα2-specific lipidic modulation and the effect lipids have on channel function. Native mass spectrometry will be used to investigate lipidic interactions, and these findings will be correlated to observable lipid densities from our cryo-EM structures. Overall, the findings from this study will provide a better understanding of the role of GlyRα2 in neurogenesis and adult physiology and pathology. In addition, this work will set the stage for the future development of pharmacologic therapies targeting GlyRα2.

NIH Research Projects · FY 2026 · 2024-02

Abstract The long-term research program in the Xiao lab focuses on structural and biochemical studies of innate immune signaling, particularly the inflammasome pathways. Activation of inflammasomes may lead to the maturation and secretion of proinflammatory cytokines IL-1b and IL-18, as well as pyroptosis. Pyroptosis is a highly inflammatory form of cell death mediated by gasdermin D (GSDMD) and other gasdermin family members downstream of diverse signaling pathways implicated in infections and autoimmune or autoinflammatory disorders. As such, understanding the mechanisms of gasdermin regulation is highly significant. Despite recent progress on the identification of gasdermins as effectors of pyroptosis, and on the mechanisms of GSDMD activation by inflammatory caspases, contributed by the Xiao lab and others, the molecular mechanisms underlying the regulation of gasdermin function remain incompletely understood. In particular, gasdermin processing by different caspases and other proteases that may activate or suppress pyroptosis remain understudied. Even though protease processing, an irreversible form of post-translational modification (PTM), is the most intensively studied mechanisms of gasdermin regulation, emerging evidence suggests that gasdermins are regulated by several other PTMs such as ubiquitination and Cys modifications. The regulation of gasdermins by host and microbial proteases, ubiquitin ligases, and palmitoyltransferases remain key knowledge gaps that have hampered mechanistic understanding of pyroptosis regulation under physiological and pathological conditions. This proposal is based on emerging evidence from the rapidly evolving field of gasdermin biology that serve as strong scientific premise and rationale. The proposed studies leverage our expertise in structural and biochemical studies of gasdermin activation by inflammatory caspases, and target critical gaps in our understanding of gasdermin regulation using complementary structure-function approaches. We hypothesize that post-translational modifications of gasdermins by host and microbial enzymes, such as proteases, ubiquitin ligases, palmitoyltransferases, and other enzymes, regulate their function in pyroptosis. Better understanding of how gasdermins are regulated will not only furnish new insights into pyroptosis modulation, but also stimulate the development of novel therapeutics that target gasdermins and pyroptosis. Overall, this proposal builds upon the PI’s past research program that enables the long-term pursuit of the mechanisms for gasdermin regulation on a scale that is broadly compatible with the MIRA mechanism.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY/ABSTRACT On February 3, 2023, a Norfolk Southern train carrying hazardous chemicals, including vinyl chloride and butyl acrylate, derailed in the village of East Palestine, Ohio. Nearly half of the local 4,800 residents were evacuated within hours. A subsequent controlled combustion of five tankers was undertaken, resulting in the release of phosgene and hydrogen chloride into the atmosphere. While initial air sampling did not show evidence of vinyl chloride or hydrogen chloride concentrations above air quality standards, testing is ongoing. Contaminated run off was detected in two surface water streams. This has had significant ecologic impact — more than 40,000 fish deaths were identified within a 5 mile radius of the site in the days following the derailment. The subacute and long-term health impacts of this environmental and public health disaster remain unknown. For residents of East Palestine and the surrounding communities, concern about the long term environmental and health impacts of these exposures remains high. Due to the multi-pollutant nature of this chemical exposure, and the potential for pre-existing exposures due to clustering of heavy industry within the area surrounding East Palestine, a quantitative approach based on biospecimens is crucial to guide subsequent disease surveillance. While chemical exposure assessment is typically done via interrogation of biospecimens in blood and urine for specific contaminants, this approach only provides a snapshot of short-term chemical exposure. The somatic mutation rate (SMR), however, provides a global overview of chemical exposures, as demonstrated by previous research, and serves as a proxy for environmental chemical exposures. Here, we propose utilizing SMR to establish a baseline for acute chemical exposure and long-term monitoring with respect to health and disease risks. Our time-sensitive response, as proposed here, “Healthy Futures Research Study: Linking somatic mutation rate with baseline exposure in East Palestine”, establishes the baseline impact of a subacute chemical exposure utilizing a genomic biomarker as a surrogate measure for direct chemical concentration levels given the mixture of potential contaminants. Our research proposal will i) develop and engage participatory research in East Palestine and the greater region; ii) utilize a cross-sectional study to assess the correlation between the SMR, a genomic biomarker, with geographical proximity to the train derailment epicenter; and iii) elucidate perceived experiences post-disaster with qualitative approaches. This proposal will establish and develop a shared partnership with community residents, formally organizing a Community Advisory Board among community members, and providing a baseline biomarker for chemical exposure thus serving as a baseline for longitudinal studies. Our responsive team is comprised of epidemiologists, community outreach researchers, and healthcare advocates. Overall, this proposal establishes a cornerstone working with the community, health departments, and other research institutions across the region to fully comprehend the short- and long-term health impacts in the East Palestine community.

NIH Research Projects · FY 2026 · 2024-02

Triple-negative breast cancer (TNBC) is an aggressive and molecularly heterogeneous subtype of breast cancer that frequently exhibits resistance to chemotherapy leading to poorer clinical outcomes. African American (AA) women in the United States not only suffer from higher incidence rates of TNBC as compared to their European American (EA) counterparts, but they also endure poorer survival outcomes. Racial disparities in TNBC outcomes are multifactorial and not fully explained by treatment variations and socioeconomical inequalities. As such, investigations into how the pathophysiology of TNBC differs between AA and EA women may offer new insights into the manner through which biologic and socio-demographic factors converge in creating outcome disparities in TNBC. By sequencing the transcriptomes of primary TNBC tumors obtained from 3 independent patient cohorts, we detected aberrant activation of MIZ1 in ~70% of AA tumors, an event that was strongly associated with poorer overall survival solely in AA patients. Based on these and other compelling findings, we hypothesize that (i) MIZ1 activation underlies disparate outcomes and poor overall survival rates of AA women, and (ii) targeting mechanistic vulnerabilities in MIZ1 signaling will provide for novel therapeutic approaches to significantly improve AA TNBC outcomes. To test this hypothesis and to elucidate the molecular mechanisms whereby MIZ1 governs TNBC aggressiveness in AA patients, we endeavor to perform the following Specific Aims: (1) determine the mechanisms whereby MIZ1 drives AA tumorigenicity; (2) determine the mechanisms whereby MIZ1 impacts cellular heterogeneity and macrophage polarization of AA TNBC tumors; and (3) determine the association of African ancestry with MIZ1 activation in AA TNBC and define the role of this event in TNBC progression. This project marks the first effort to harness mechanistic vulnerabilities in MIZ1 activation and function to improve clinical outcomes of AA TNBC patients. Collectively, our innovative concept is highly impactful and could potentially redefine the clinical practice of treating AA TNBC patients, doing so by developing novel biomarkers, new drugs, and drug targets to improve clinical outcomes of AA TNBC patients.

NIH Research Projects · FY 2026 · 2024-02

Patients with metastatic colorectal cancer (mCRC) have substantially worse outcomes than those with primary and localized CRC. Over 80% of CRC metastases occur in the liver, which has a unique endothelial cell (EC)- rich microenvironment. Distinct from precedent EC studies focused on angiogenesis and vascular remodeling, we discovered that liver ECs secrete soluble factors to promote mCRC development in a paracrine fashion. Specifically, we found that human epidermal growth factor receptor 3 (HER3, also known as Erbb3) is a key mediator of EC-induced mCRC growth in the liver. However, we found that liver ECs activate HER3 independent of the only known HER3 ligand, neuregulins. Here, we made the paradigm-shifting discovery that leucine rich alpha-2-glycoprotein 1 (LRG1) secreted from liver ECs is a novel HER3 ligand that activates CRC-associated HER3 and promote CRC cell growth. Moreover, systemic inhibition of LRG1 attenuates the growth of CRC subcutaneous (subQ) xenografts and increases mouse survival in an orthotopic mCRC model. The GOAL of this proposal is to determine the role of LRG1 as a novel HER3 ligand in promoting mCRC development, and to elucidate the mechanisms by which LRG1 binds and activates HER3. We HYPOTHESIZE that LRG1 is a novel HER3 ligand and that the LRG1-HER3 signaling axis plays a critical role in CRC liver metastases development. We will test this hypothesis in two SPECIFIC AIMS: Aim 1 will determine roles of EC-secreted LRG1 in promoting mCRC initiation and outgrowth in clinically relevant mCRC models with EC-specific LRG1 knockout mice, a LRG1 neutralizing antibody, and patient-derived xenografts and organoids. Aim 2 will elucidate the mechanisms by which LRG1 binds and activate HER3, and determined the correlations between HER3 activation and mCRC patient outcomes. INNOVATIONS of this project include determination of a novel role of LRG1 in promoting mCRC development, identification of LRG1 as a novel HER3 ligand, and elucidation of the mechanisms of LRG1 activating HER3. Successful completion of the proposed studies will also identify HER3 activation as a potential prognostic biomarker for patients with mCRC, and lay a foundation for developing new therapeutic strategies for targeting LRG1 and other amenable component(s) in the LRG1-HER3 signaling cascade.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT As a sleep-medicine physician, I seek to understand how sleep health affects the progression and long-term consequences of chronic disease and, ultimately, implement sleep-based interventions to improve the health of patients. Sleep disorders are highly prevalent among people with HIV (PWH), and emerging evidence suggests that sleep disorders may increase the risk of cardiovascular disease in PWH. Sleep disorders, such as obstructive sleep apnea (OSA) and insufficient sleep duration, are recognized as indepdent risk factors for cardiovascular risk. However, little is known about how sleep disorders worsen chronic inflammation among PWH. One understudied pathway by sleep disorders may increase inflammation and cardiovascular risk is by promoting monocyte activation. PWH experience chronic monocyte dysregulation despite antiretroviral therapy, and those with a greater burden of monocyte activation are at an higher risk of developing cardiovascular disease. Monocytes from individuals exposed to OSA or insufficient sleep exhibit markers of monocyte activation, such as greater production of proinflammatory cytokines and expression of cellular adhesion markers. Various stimuli have been found to contribute to excessive monocyte activation, but the impact of sleep disorders on monocyte activation in PWH has not been investigated. I hypothesize that PWH are vulnerable to amplified monocyte activation from exposure to the “second hit” of a sleep disorder. In Aims 1 and 2, I will utilize stored samples to evaluate monocyte activation in PWH by chronic and acute sleep exposure, respectively. Aims 1a and 1b will investigate if OSA and insufficient sleep are a) associated with a monocyte activation phenotype in PWH and b) explore if there is a differential effect of sleep disorder exposure on monocyte activation profiles by HIV status. In Aim 2, I will quantify the impact of acute sleep deprivation on monocyte activation among PWH who participated in an acute sleep deprivation protocol. In Aim 3, I will prospectively enroll PWH with OSA and evaluate the impact of OSA treatment on reducing monocyte activation among PWH. Lastly, in Aims 4a and 4b, I will utilize stored and prospectively enrolled samples utilized in Aims 2 and 3 to investigate differences in gene expression in circulating monocytes a) before and after acute sleep deprivation and b) before and after treatment of OSA, respectively. If successful, this proposal will identify a biological mechanism by which sleep disorders contribute to HIV-associated inflammation, identifying a targetable pathey to reduce CVD risk in PWH by either sleep-based or pharmacologic interventions. Through completing the proposed experiments alongside formal didactic education and intensive mentorship, I will develop my expertise in HIV-associated inflammation and immunophenotyping, develop new skills in systems immunology, and gain experience in conducting human subjects sleep research. This proposal takes advantage of the robust resources and research environment at the University of Pittsburgh, which includes my excellent mentorship team to support my development as an independent-physician scientist.

NIH Research Projects · FY 2026 · 2024-01

The goal of this competitive renewal is to interrogate a paradigm-shifting hypothesis that a combination of CB- 839, a glutaminase inhibitor, and 5-FU induces neutrophil extracellular trap (NET) in PIK3CA mutant colorectal cancers (CRCs), which in turn kills these cancer cells. NETs are extracellular web-like structures of cytosolic and granule proteins assembled on de-condensed chromatin. NETs trap and kill bacteria, fungi, viruses, and parasites. Although some studies implicate NETs in tumor metastasis, whether NETs can kill cancer cells is largely unexplored. This proposal is built on the novel findings that we made during the current funding period: 1) PIK3CA mutations render CRCs more dependent on glutamine; 2) CB-839 preferentially inhibits xenograft growth of PIK3CA mutant CRCs; 3) the combination of CB-839 with 5-FU induces xenograft tumor regression of PIK3CA mutant CRC in nude mice; 4) the combination of CB-839 and 5-FU preferentially induces NETs in PIK3CA mutant CRCs; 5) depletion of neutrophils in nude mice significantly attenuates the efficacy of the drug combination; 6) disruption of NETs by DNase I treatment in xenograft tumors also attenuates the efficacy of the drug combination. These exciting observations lead us to hypothesize that NETs induced by the drug combination kill PIK3CA mutant CRCs. Two aims are proposed to test this exceptionally novel hypothesis. Aim 1 will determine if the combination of CB-839 and 5-FU induces NETs in immune-competent mice and human CRC patients. Aim 2 will elucidate the mechanisms by which NETs kill PIK3CA mutant CRCs. Although we focus on colon cancer in this proposal, our proposed studies may have a broader impact beyond colorectal cancer because PIK3CA is mutated in ~ 20% of all human cancer. Moreover, the mechanisms identified in the study may also apply to other NET-related diseases.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY (See instructions): Understanding the molecular mechanisms of how cells respond to changing environmental cues and integrate various signals, especially in the context of an intricate tissue or organism, is a major challenge. In the mammalian intestine, inputs from diet and the commensal microbiota can occur in the form of metabolites that act on neighboring intestinal epithelial cells and impact physiology. One such class of metabolites are short chain fatty acids (SCFAs), which are generated by microbes through the breakdown of dietary fiber. Recently, SCFAs have been detected as chemical modifications on histone proteins, called histone acylations. While certain histone acylations have been reported to positively regulate transcription, including the well-studied histone acetylation, the mechanistic functional role of other acyl marks and especially their physiological roles, are largely unknown. In addition, alterations in the chromatin landscape can have consequences on the regulation of gene expression and downstream cellular functions. Thus, my overall goal is to gain mechanistic understanding of how histone acylations are regulated and govern cell function in vivo. My central hypothesis is that different histone acylations have distinct functions in gene regulation through playing different roles in particular tissues and gene sets, and that exogenous cues regulate the balance of histone acylations that can drive cellular phenotypes. I will use the murine intestinal tract as a model system, which will likely elucidate physiological functions and delineate regulatory mechanisms of histone acyl marks. During the mentored phase of this award, I focused on the following Aims: (1) Studying how acyl reader complexes regulate gene expression under particular cell contexts, (2) Determining how histone acylations regulate intestinal epithelial cell fate. In this next independent phase of this award, I will continue studying mechanisms of how different acyl marks are regulated and focus on Aim 3: Investigating the regulation of histone acylations through cellular metabolism. This proposed work will utilize skills built during my postdoctoral training and the mentored phase of this award to foster my success as an independent scientist. Together, completion of this research proposal will elucidate the connection between metabolism and chromatin and further advance our understanding of the physiological roles of novel histone acyl marks.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY Nearly 1 in 10 Americans has type 2 diabetes mellitus (T2DM), and the incidence continues to rise as the US population both grows heavier and ages. T2DM is characterized by insulin resistance, where the insulin target tissues become under-responsive to insulin stimulation, leading to unregulated blood glucose and tissue damage. Despite multiple therapeutic approaches to increase insulin production and to enhance insulin receptor sensitivity, there are no drugs that directly ameliorate insulin resistance by targeting mechanisms that drive insulin resistance, in part because these mechanisms remain poorly defined. We have identified novel machinery that regulates S-nitrosylation of the insulin receptor (INSR) and its key downstream mediator, insulin receptor substrate 1 (IRS1), including the enzymes SCAN and SCoR, which catalyze S-nitrosylation and denitrosylation of INSRβ/IRS1 respectively. Under normal conditions, insulin-stimulated S-nitrosylation of INSRβ/IRS1 by SCAN transiently inhibits signaling to prevent hypoglycemia. In obesity, sustained and excessive S-nitrosylation of INSRβ/IRS1 by SCAN in skeletal muscle chronically inhibits insulin signaling, leading to insulin resistance. Excessive SCAN activity and consequent hypernitrosylation of INSRβ/IRS1 are also induced by aging and by glucocorticoid treatment, representing a widespread cause of insulin resistance. In human skeletal muscle and adipose tissue, SCAN expression increases with Body Mass Index and correlates with INSRβ S-nitrosylation, suggesting this mechanism is relevant to human insulin resistance. Our goal is to define the role of this novel pair of enzymes (SCAN and SCoR) in insulin signaling and to elucidate their clinical significance. We will 1) characterize a newly discovered S-nitrosylation-based feedback loop in insulin signaling; 2) define the pathological role of SCAN and SCoR in insulin resistance; 3) determine the clinical significance of SCAN in insulin resistance. Successful completion of these Aims will define the functional role of S-nitrosylation of INSRβ/IRS1 by SCAN and SCoR in both health and disease. More broadly, our work promises both new understanding of obesity-, aging-, and glucocorticoid therapy -associated T2DM and new therapeutic opportunities for treating metabolic disorders and T2DM.

NIH Research Projects · FY 2025 · 2024-01

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Several randomized controlled trials (RCTs) support the efficacy of music therapy (MT) for improving pain and symptom management among several patient populations including cancer, sickle cell disease, and orthopedic surgery. MT is the clinical use of tailored music interventions (e.g., active music making and music-assisted relaxation) to accomplish individualized goals within a therapeutic relationship by a credentialed professional (i.e., board-certified music therapist). Despite evidence for MT’s efficacy from RCTs and the increased delivery of MT in clinical settings, few clinical effectiveness studies have evaluated the real-world impact of MT within health systems. Evaluating integrative pain management approaches such as MT is a vital need, especially as health systems seek effective nonpharmacologic pain management solutions to reduce risks stemming from opioid use. Substantial gaps remain in understanding MT’s clinical effectiveness. These include: 1) identifying socio-demographic, clinical, and MT intervention characteristics associated with changes in patient-reported outcome measures (PROMs); 2) comparing outcomes (e.g., medication use and length of stay) between patients receiving MT and similar patients receiving usual care; and 3) examining longitudinal effects on PROMs beyond the initial MT session. Using a large electronic health record (EHR) dataset of 31,359 MT sessions provided to 15,460 patients (mean age 63.6 years, 33.5% Black/African American) across 20,405 hospital admissions, I propose applying regression models, propensity-score matching, and longitudinal mixed effects models to examine the clinical effectiveness of MT. My Specific Aims are: AIM 1) investigate which socio-demographic characteristics (e.g., age, sex, insurance status, and income), clinical characteristics (e.g., diagnoses and care setting), and/or MT session characteristics (e.g., length and MT interventions utilized) are associated with changes in PROMs (i.e., 0-10 measures of stress, pain intensity, anxiety, and coping); AIM 2) compare outcomes including length of stay, medications administered for pain and anxiety, and longitudinal pain intensity scores between inpatients receiving MT and propensity-score matched controls; and EXPLORATORY AIM 3) examine longitudinal effects on PROMs over the course of hospital admissions among patients receiving MT. This proposal will provide the applicant with foundational knowledge and experience needed to conduct future practice-based clinical effectiveness research not only in MT, but across multiple integrative therapies (e.g., acupuncture and massage therapy) deployed within health systems. As health systems develop EHR-based quality improvement tools and implement nonpharmacologic pain modalities, the skills acquired within this proposal will be especially important for understanding the real-world impact of integrative health and medicine modalities and improving evidence-based patient care.

NIH Research Projects · FY 2026 · 2023-12

This proposal seeks funding for ‘Research Immersion in Brain, Spinal cord (RIBS), and peripheral nerve disorders’ for high school students during their academic summer break. Through this program, we aim to excite, motivate, and increase awareness of common neurologic conditions, and provide hands-on research experience to the students in active laboratories on Case Western Reserve University (CWRU) campus. The proximity of CWRU campus to Cleveland Metropolitan School District (CMSD) responsible for educating economically disadvantaged youth, and the availability of multiple (~40) NINDS-funded Faculty with active laboratories provides an optimal opportunity for this program. Two specific aims are proposed to achieve these goals. Aim 1 will lay the Foundation for Research Immersion by introducing the structure and function of the brain, spinal cord, peripheral nerves, and common disorders associated with these structures in weekly educational sessions. A didactic session of 20 minutes will be followed by small group discussions aided by the HoloLens virtual image technology, YouTube videos, and 3D models. The group sessions will be led by 2nd and 3rd year medical students to boost the confidence of students through student mentoring. In Aim 2, each student will be matched with a laboratory based on his/her interest for 8 weeks of hands-on Research Immersion. During this period, the student will be guided by the principal investigator (PI) and laboratory personnel, who will describe the overall research goal of the laboratory, and the specific project in which the student will be involved. They will help the student in formulating a hypothesis-driven research question based on the literature, assist in relevant research methods, collect and analyze data, and draw relevant and meaningful conclusions. Every week, the student will be instructed by the PI on various topics of Responsible Conduct of Research for 30 minutes. In addition, one laboratory personnel, in most cases a postdoctoral fellow, will work closely with the student on college admission test quizzes and college admission essay. Deliverables for the student will include an abstract of 1 page stating the hypothesis and experimental plan after 1 week, a full paper of 6 pages with all sections completed after 6 weeks, a college admissions essay after 7 weeks, and a poster complete with all sections for presentation to diverse audience after 8 weeks. The student will be expected to attend scientific talks hosted by the Departments of Pathology, Neuroscience, and Biomedical Engineering on CWRU campus. After each talk, the invited speaker will be requested to spend 15 minutes of exclusive time with the students. We believe that the RIBS program will develop the skills, instill enthusiasm, and boost the confidence of high school students to pursue a career in neurologic research and healthcare.

NIH Research Projects · FY 2026 · 2023-12

We propose to continue to serve as a Regional Coordinating Center (RCC) for StrokeNet that will continue to perform stroke related clinical trials, bring new trials to the network and train new stroke investigators. Our RCC includes University Hospitals of Cleveland (UH), Cleveland Clinic (CC), MetroHealth Medical Center (MH) and the Louis Stokes Cleveland VA Medical Center (LSVA), allaffliated with Case Western Reserve University (CWRU). Our RCC, initially funded in 2013 and renewed in 2018, subsequently expanded to include additional sites in Toledo (Mercy St Vincent Medical Center or Mercy St Vincent), Columbus (OhioHealth), Grand Rapids, MI (SpectrumHealth, now Corewell),Morgantown, WV [West Virginial University (WVU)] and Pittsburgh, PA [AlleghenyHealth (AH)]. We also trimmed the number of sites by removing several sitesthat were not actively screening or enrolling in StrokeNet. Our RCC contains a variety of hospitals types including a county hospital with a large emergency department, a VA hospital, multiple urban academic medical centers, and an academic medical center in a rural state ensuring a diverse patient and study population. Our key personel represent investigators from Neurology, Neurosurgery, Emergency Medicine, Neurointerventionalists, Neurointensivists, Pediatric Neurologists, Neuroradiologists and Vascular surgeons, Physical Medicine and Rehabilitation specialists choosen on the basis of merit. Our RCC has a track record of enrolling patients in acute treatment, prevention and rehabilitation studies. We have brought new projects to the network and have representatives on all of the working groups. Our RCC includes 8 Comprehensive Stroke Centers, state of the art transportation resources including critical care air transport with physicians and nurse practicioners on board and hospital systems with mobile stroke units that administer thrombolytics in the field or en route to the hospital. We have special expertise in penumbral imaging, acute endovascular therapy and rehabilitation,especially functional electrical stimulation. We propose to continue the current leadershipWith co-PIs Dr Sophia Sundararajan and Dr. Ken Uchino and representatives from each of the nine hospitals. David Haney will continue as Project Manager and Dr Irene Katzan will continue as the Training Director. This will oversee the RCC, but also provide mentorship for more junior investigators. Our leadership succession plan has already successfully mentored Drs Sundararajan and Uchino who assumed roles asCo-PIs with the 2018 renewal of the RCC. With the expertise and resources detailed in this application, the Case Western Reserve University RCC will be well positioned to enhance the structure and organization of our RCC and further accelerate participation in clinical trials for stroke acute intervention, prevention and rehabilitation in both adults and children.