Case Western Reserve University

NIH Research Projects · FY 2025 · 2016-09

PROJECT SUMMARY This T35 competitive renewal application requests continued funding for the Case Medical Student Summer Research Program (MSSRP). The overall goal of the program is to promote career development for physician scientists who will choose biomedical investigation as an essential component of their long-term professional development, with particular focus on the mission areas of the NIDDK and NIDDK-related research. These include: 1) Digestive Diseases, 2) Liver Diseases, 3) Diabetes & Metabolic Diseases, 4) Kidney Diseases, 5) GI Tumorigenesis, and 6) Inflammation/Infection. The program educates medical students using a mentor- based research approach over an 8-week training period between their 1st and 2nd years of medical school. The T35 program is based on strategic planning, consolidated efforts, and close academic integration of the CWRU School of Medicine (SoM), University Hospitals (UH) Cleveland Medical Center, the Cleveland Clinic, MetroHealth, and the Louis Stokes VA Medical Center, which provides a superb programmatic infrastructure. The faculty mentors from these institutions sustain a reputation of excellence based on superior clinical and basic research, ample funding from the NIDDK and NIDDK-related institutes ($39.8M annual direct costs from NIH; $15.1M from NIDDK alone), and combined research space in excess of 100,000 ft2. The Case MSSRP has an established track-record of selecting highly-qualified 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 the NIDDK mission. Program evaluation and student progress is overseen by the T35 Executive and Internal Advisory Committees. Students submit a written abstract and present their findings during the Lepow Medical Student Research Day held in September. A unique aspect of the program is the multiple PI/PD approach, which allows research to span departmental boundaries and enlist preceptors with a tradition of highly-productive collaboration and who have trained a large number of young investigators in an interdisciplinary manner. The 50 mentors from 19 departments, representing a wide range of research expertise, offer a multiplicity of research opportunities that are tailored to the scientific interest of each trainee. Our innovative curriculum includes weekly group meetings, didactic lectures, and a three-day hands-on course held at the start of the 8-week research period. To assess the long-term impact of the program, we collaborate with the Medical Education and Alumni Affairs offices to track medical students up to 20 years after graduation. Based on the high number of applicants during the previous funding period, we are requesting to expand NIDDK support by an additional 5 students per year (15 total NIDDK-supported trainees). We have strong institutional support, documented by provision of space and resources, cost-sharing, as well as support from the CTSC and NIDDK-funded Cleveland DDRCC. Therefore, the academic environment continues to be ideal to sustain the overall objectives of this NIDDK-focused T35 medical student short-term training program.

NIH Research Projects · FY 2026 · 2016-09

Summary A major gap in the “bench to bedside” paradigm is the ability to harness the glycome for the development of novel therapeutics. Although decades of research in glycobiology have established glycomic changes associated with disease, almost nothing is known about how those changes arise, the functions they play in disease initiation or progression, or how the glycome is regulated at the compositional level. Based on our recent discoveries, we propose a transformative new model for glycomic compositional regulation of secreted glycoproteins that provides a clear path for the development of the first generation of glycan- modulating therapies for a wide range of diseases. The model is based on the notion that the glycans on glycoproteins can be remodeled after release from the originating cell, and if correct, our findings will rewrite the glycobiology dogma that glycomic changes are dependent upon the slow process of protein turnover and de novo synthesis to one where change is highly dynamic, rapid, and specific to the immunologic environment. The proposal centers on the molecular action, regulation, and necessary microenvironment for the sialyl transferase ST6Gal1 to add α2,6-linked sialic acids onto IgG glycans. Our proposal focuses upon the B cell-secreted antibody IgG because alterations in sialylation alters Fc domain conformation and FcγR binding such that anti-inflammatory signaling is enhanced. We have discovered that the vascular endothelium and the FcRn-mediated recycling pathway is the dominant system through which IgG is sialylated, leading to two proposed specific aims. In Aim 1, we will define the biochemical and cellular mechanisms of FcRn-dependent IgG sialylation in the endothelium. In Aim 2, we will interrogate the regulatory features underlying changes in IgG sialylation during inflammatory responses. The overall goal is to develop a comprehensive understanding of the mechanisms underlying the regulation of IgG sialylation which will provide a lasting and profound impact on the field and human health. It is known that the suppressive activity of exogenous intravenous Ig therapy is enhanced by IgG sialylation. Through an understanding and targeting of the fundamental regulatory tenets of this novel pathway, we could finally unlock the potential to modulate the sialylation of endogenous IgG within patients with inflammatory disease.

NIH Research Projects · FY 2025 · 2016-06

Despite significant advances over several decades, very few Tissue Engineered Medical Products (TEMPs) have been clinically or commercially successful, as a significant technology gap, known as the “Valley of Death”, has prevented their scalable, consistent and cost-effective manufacture. This proposal is for the competing renewal of the current “Case Center for Multimodal Evaluation of Engineered Cartilage.” There is a growing need for TEMPs in multiple applications. We therefore believe that now is the time for a bold shift from our original focus on cartilage-centric evaluation technologies to developing, demonstrating, and deploying novel technologies to enable Quality-by-Design manufacturing of a variety of structural tissues, and to, thus, bridge the Valley of Death. The goal of the Center is the adoption of our technologies by the TEMP community at large. Consequently, the Center, will be renamed “Center for Modular Manufacturing of Structural Tissues” (CM2OST), and will apply knowledge and technology developed during the first 5 years to manufacturing-oriented challenges. The Center will be a consortium between CWRU and the Advanced Regenerative Manufacturing Institute (ARMI), and will focus on technologies that enable scalable, modular, automated, closed (SMAC) manufacturing. The Specific Aims of the proposal are to 1) Assist our CPs and SPs by pushing the technologies developed at the Center out to them. 2) Develop a cohesive set of innovative technologies, methods, and protocols that enable structural tissue manufacturing through 4 TR&D projects, described below, and 3) Develop a new, state-of-the- art, training and dissemination program. Strategically, we will break the overall R&D program into 4 TR&Ds representing key components of the TEMP assembly-line model. TR&D-1 covers dynamic control of cell pheno- type and function during the manufacturing process, and development of tissue-specific sensors for dynamic non-invasive monitoring of cell phenotype and function. TR&D-2 will develop sensor-enabled scaffolds and novel optode-based optical sensors to automate cell seeding and to monitor metabolites and provide feedback on local and bulk medium conditions. TR&D-3 will develop bio-instructive bioreactors with integrated actuators and sen- sors for feedback control, and will physically integrate them with the Tissue Foundry, an ARMI prototype auto- mated TEMP assembly line. TR&D-4 will integrate sensors and actuators with the automation and data man- agement system of the Tissue Foundry and will perform a manufacturing demonstration run. Demonstrating technologies developed in the TR&Ds will provide insights into TEMP development, process development and automation, and expose unanticipated technology gaps. Each TR&D represents a step in the TEMP assembly- line model, thus, though the technologies are developed independently, each TR&D feeds into the next. TR&Ds, Collaborative and Service Projects synergize, integrating and exploiting each other’s technologies as they come online. CM2OST will be a national resource for collaborations and a platform for developing, testing, validating, and disseminating new technology, methods, and protocols for TEMP manufacturing.

NIH Research Projects · FY 2025 · 2016-05

Abstract (450 words; 29 lines) This competing renewal builds on the success of the first 4 yrs. of the "Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda” (MITHU) training program. MITHU addresses capacity building in basic/translational biomedical research on HIV and HIV-related complications in Uganda. Persistence of the HIV epidemic, compounded by the evolving SARS-CoV-2 (COVID-19) pandemic and other emerging infections, emphasizes the importance of lab-based research capacity in immunology and molecular microbiology for tracking, prevention, diagnosis and treatment. This capacity requires biomedical faculty at Makerere University (MU) and other institutions in Uganda to train the next generation of biomedical technicians, researchers and faculty. For this competing renewal, MITHU proposes the 5 New Aims. Aim 1. To continue MITHU's success in supporting biomedical MSc training at MU. We propose to continue MSc training as a primary Aim for this next funding cycle. The best MSc students will go on to biomedical PhD training. Aim 2. To expand Biomedical PhD Training at MU by starting a Sandwich PhD program in biomedical sciences with CWRU. We propose a Sandwich PhD where outstanding MSc students will be co-mentored by faculty from MU and CWRU, spend their first yr at CWRU for selected course work in immunology or molecular microbiology, to do lab rotations, and to select CWRU and MU mentors for their thesis project. Thesis research will begin at CWRU and will be completed at MU. This Sandwich PhD program is possible because there are now 9 biomedical research faculty in MU's School of Biomedical Sciences. Six of 9 were trained at CWRU, 2 trained at MU by the Uganda-CWRU Research Collaboration and 1 at Univ. of Wash. Aim 3. To continue mentoring of junior biomedical science faculty and providing re-entry support for returning PhD trainees as they establish themselves as biomedical faculty and researchers in Uganda. MITHU will continue to coordinate a mentoring program for junior and senior research scientists with the College of Health Sciences' NURTURE program. MITHU will also continue to provide re-entry support for PhD trainees returning to Uganda. Improved internet access has greatly improved distance-learning and intercontinental interactions, allowing for remote mentoring, lab meetings and journal clubs. Aim 4. To continue to sponsor the yearly short intensive course “Host- Pathogen interactions in HIV, TB and their complications. This popular course is attended by MU biomedical MSc, MMed and PhD students. This course is a mixture of lectures, journal clubs and workshops in which MU- and CWRU-sponsored scientists present the latest biomedical results and methods related to HIV and its complications. Aim 5. To continue to leverage for MITHU the Uganda-CWRU Research Collaboration's expertise and infrastructure for HIV and TB research for training in the biomedical sciences of HIV and its complications.

NIH Research Projects · FY 2025 · 2016-02

Project Summary The vast majority of our understanding regarding the function of classical developmental signaling pathways comes from studies outside the nervous system. We are interested in the overarching question of how evolutionarily conserved signaling pathways are customized for signaling at synapses. There are significant unanswered questions regarding how these pathways interface with synaptic activity as well as how they signal in the dense microenvironment of the synaptic cleft. Our identification of Crimpy and α2δ-3 as two novel components of a synaptic Bone Morphogenetic Protein (BMP) signaling pathway provides key insights into both questions, positioning us to explore innovative hypotheses directed at understanding how growth factors organize synapses. Our published studies indicate that autocrine BMP signaling assembles multiple principal features of the presynaptic compartment. Here, we build on novel findings relating to the regulation and function of this pathway. We provide evidence that autocrine BMP signaling maintains trans-synaptic adhesion and alignment of the pre- and postsynaptic compartments. Shedding light on these phenotypes, we identified the ECM protein SPARC as a putative BMP downstream effector. Lastly, we present novel preliminary data that the ability of this pathway to nucleate new presynaptic active zones is impeded by a transmembrane protein in the LRIG family.

NIH Research Projects · FY 2024 · 2015-09

Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the population over 65 years of age. AD is a systemic disorder that affects the brain and peripheral tissues. Patients with AD suffer from declined memory, cognitive deficits, and changes in personality. In addition, AD is often associated with reduced muscle strength, even at early stages. In some AD patients, muscle strength is reduced without loss of muscle mass. However, pathological mechanisms of reduced muscle strength are not well understood. Muscle contraction requires the efficient neurotransmission at the neuromuscular junction (NMJ), a synapse between motor nerve terminals and skeletal muscle fibers. Its formation requires a proteoglycan from motor nerves, agrin, which binds to LRP4 to activate the receptor tyrosine kinase MuSK. We and others showed recently that agrin signaling is also necessary for NMJ maintenance and is compromised in neuromuscular disorders and in aged mice. Interestingly, APP, a risk gene of AD, is expressed in skeletal muscles and becomes progressively concentrated at the NMJ after birth. APP and its homolog APP-like protein 2 (APLP2) regulate NMJ formation. APP can interact with LRP4 to promote agrin-induced AChR clustering. To understand pathological mechanisms of muscle weakness in AD, we generated HSA-APPswe that specifically express in muscles mutant APP with Swedish mutations (APPswe). Remarkably, HSA- APPswe mice were weak in muscle contractile force, in particular that by nerve stimulation, and NMJs became denervated with compromised neuromuscular transmission. Initial mechanistic studies revealed diminished agrin signaling and increased cellular senescence, a process originally defined as cell growth arrest but increasingly implicated in ageing-associated processes. While these findings are exciting, they raise many questions. Is muscle weakness in HSA-APPswe mice due to NMJ decline or vice versa? What is the primary target of APPswe, pre- or post-synaptic function? How does APPswe impair the NMJ, by diminishing agrin signaling or by enhancing cellular senescence, or both? And, how? These questions will be addressed in this proposal. The overarching hypothesis at test is that APPswe causes NMJ decline in aged mice by impairing agrin signaling and causing cellular senescence in the muscle. To test this innovative hypothesis, we will determine whether APPswe promotes NMJ decline by impairing agrin-LRP4 signaling and by increasing muscle cell senescence. Results will uncover new pathological mechanisms by which AD-association APP mutations damage the NMJ and reduce muscle strength and reveal whether restoring agrin-LRP4 signaling and/or inhibiting cellular senescence prevent NMJ decline and thus improve muscle strength. Such knowledge is prerequisite to development of effective therapeutic interventions for muscle weakness in AD patients.

NIH Research Projects · FY 2024 · 2015-08

Abstract Human estrogen receptor alpha (ERα) is a molecular driver of hormone-responsive cell proliferation in breast cancer. Acquired ERα mutations—Y537S and D538G being the two most commonly found—represent a newly recognized mechanism of drug resistance due to their constitutive transcription activity. Our preliminary data and recently published reports indicate that these drug-resistant mutants are non-conventional therapeutic targets for small molecule binding to modulate their activity and inhibit cell proliferation. However, the mechanisms by which drug- resistant mutations act on the receptor to regulate hormonal signaling and the extent to which small molecule inhibitors bind the receptor for intervention are not yet known. The ERα harbors two major functional entities, i.e., the DNA-binding domain (DBD) and the ligand-binding domain (LBD). We recently reported the multi-domain assembly and revealed the mode of interactions between these two domains, through a previously uncharacterized domain-bridging interface. Specifically, mutations at the domain-interface prevent the two domains from communicating and inhibit ERα activity, highlighting the modulation of the domain- interface as an “allosteric” channel with loss/gain of receptor function. This functional significance raises the questions of (a) whether the drug-resistant mutations alter the domain-domain assembly and the mode of DBD-LBD interactions, and (b) whether/how the domain-bridging interface can be targeted by small molecules to disrupt receptor activity. Our preliminary studies show that a repurposed small molecule binds the receptor via the domain-interface and inhibits ERα-mediated cellular function. Based on these findings and other preliminary data, we hypothesize that how the ERα domains interact with one another is influenced by these drug- resistant mutations and this domain-domain interaction is critical for small molecule binding to alter receptor function. To test this hypothesis, we will characterize the multi-domain assemblies of disease-resistant mutants (Y537S/D538G) and examine the molecular and functional correlation of inhibitor-receptor binding. In contrast to the hormone-binding pocket where all current drugs bind, this study will provide novel insights into the ERα domain-interface as a new target site for small molecule binding, and ultimately offer a much-needed molecular understanding of ER-positive breast cancer therapy resistance.

NIH Research Projects · FY 2026 · 2015-07

7. Project Summary/Abstract. In the mammalian brain, early sensory areas are organized as stereotyped maps of stimulus qualities. The anatomical features of these sensory maps underlie the neuronal computations and information processing that are essential to generate appropriate perceptual experiences and behaviors. In the mammalian olfactory system primary olfactory sensory neurons (OSNs) expressing the same odorant receptor converge their axons into the same insular glomerular structure in the olfactory bulb. The mitral/tufted cells in the bulb received exclusively input from single glomeruli, but they project to various cortical areas with divergent output patterns. There are also extensive intercortical connections with no apparent anatomical mapping. It is not well understood how this pattern of strict convergence and segregation contributes materially to the processing of olfactory information and odor-driven behaviors. Nor is it understood the role played by the intercortical connections in the process of odor information. In this project, we establish a multi-disciplinary approach to determine the contribution of intercortical connections to odor representation and perception. Specifically, we will use activity marking to determine the stable representation of odors in various cortical areas and test the hypothesis that intercortical interactions stabilize odor representation.

NIH Research Projects · FY 2025 · 2015-07

Project Summary We and others have shown that altered hemodynamics and shear stress can lead to congenital heart defects (CHDs), but still there is limited information on how these forces affect molecular signaling. Studying the impact of abnormal hemodynamics and shear stress becomes even more urgent when we consider that perturbed blood flow may be a contributing factor to a large percentage of CHDs regardless of whether the initial trigger is environmental or genetic. Although our group and others have recently developed extremely useful optical imaging tools (e.g., optical coherence tomography – OCT) to assess hemodynamics and shear stress, and connected these measurements to CHDs, it has been difficult to link shear stress with the affected molecular pathways. Our group and others have performed qPCR experiments on control and shear-stress perturbed hearts to see how abnormal hemodynamics alters gene expression. However, this approach requires the entire embryonic heart for one measurement, missing all spatial and cell-type information, particularly at the endocardial layer. In order to successfully assess how shear stress affects molecular signaling throughout the looping heart, we need to improve upon our OCT methods, develop 3D methods for assessing embryonic heart gene expression, and create an advanced image processing pipeline to analyze data and relate regional shear stress to gene expression. This renewal proposal will continue our work developing tools that can lead to a more sophisticated understanding of how cardiac function (e.g., hemodynamics and electrical impulse conduction) affects heart development, enabling potential therapies to avoid or mitigate CHDs. In this proposal, we will focus on developing tools to understand how oscillatory shear stress (quantified as oscillatory shear index - OSI) influences gene expression and leads to CHDs. In our preliminary studies, we increased regurgitant blood flow (causing increased OSI) to show that alterations to OSI leads to smaller cardiac cushions (valve precursors) and ultimately, to CHDs. Increased regurgitant blood flow and smaller cushions is present in our two disease models (fetal alcohol spectrum disorders – FASD; velo-cardio-facial syndrome/Digeorge) and our FASD prevention compounds partially normalize blood flow, cardiac cushion size, and greatly reduce morbidity and CHDs. Our specific aims include 1) advance our OCT system and shear stress analysis, 2) develop fluorescence in situ hybridization (FISH) protocols to measure gene expression in 3D, 3) develop an image processing pipeline to relate gene expression to shear stress, and 4) determine the impact of shear stress on gene expression. Upon completion, we will have significantly more information on how shear stress affects molecular expression. With this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered hemodynamics, to develop earlier detection methods and potentially develop strategies to prevent CHDs more effectively.

NIH Research Projects · FY 2025 · 2015-02

OVERALL PROJECT SUMMARY This application is to continue funding for the Cleveland Digestive Diseases Research Core Center (DDRCC), a combined effort between Case Western Reserve University (CWRU) and the Cleveland Clinic Foundation (CCF). The Cleveland DDRCC's mission is to: 1) enhance the research capabilities of Center investigators, 2) develop programs to support independent development of junior investigators, 3) attract established investigators not currently involved in digestive and liver inflammation research to apply their expertise to this important field, and 4) facilitate translation of basic research discoveries to the clinical arena. This multi-disciplinary Center currently includes 38 full and 23 associate members from 23 different academic departments across CWRU and the CCF, who together comprise the DDRCC Research Base, which currently consists of $19.0 million per year in annual direct costs from peer-reviewed federal and foundation grants (48 NIH, 5 DOD, 11 private foundation), all specifically related to the Center’s re-focused central theme: Mechanisms of Digestive and Liver Inflammation. Our central theme has five areas of emphasis, each with a strong history of collaborative investigations at CWRU and the CCF: 1) IBD & Intestinal Inflammation, 2) Gut Microbiome & Inflammation, 3) Liver Inflammation, 4) Barrett’s Esophagus & Esophageal Inflammation, 5) HIV-induced Digestive Immunometabolism & Inflammation. The Cleveland DDRCC enjoys strong institutional support, including significant matching funds from both CWRU and the CCF to increase the impact of digestive and liver disease research in Cleveland, and includes three biomedical research cores (Biorepository, Histology/Imaging, and Mouse Models), all of which demonstrate high levels of use by Center members and beyond, and promote important scientific discoveries in digestive and liver diseases. Each Core includes both a set of high-volume standard services that are best provided as a shared resource to optimize cost-efficiency and quality control, as well as cutting-edge advanced services and technologies that may not otherwise be available to our Research Base investigators. The Core laboratories interface with each other and with an Administrative Core, which oversees the financial management and operation of the DDRCC and supports a successful Pilot & Feasibility Program to promote innovative research projects by mostly junior investigators new to digestive and liver inflammation, as well as a clinical element for study design and bioinformatic consultations and a dynamic Enrichment Program that supports meetings of the Midwest DDRCC Research Alliance, the Cleveland International Digestive Education and Science (IDEAS) Symposia, a Young Investigators Network, and multiple workshops. The overall objective of the Cleveland DDRCC is to increase the availability of Core resources for Center members and foster research, collaborations, and new directions in digestive and liver inflammation, leading to important scientific discoveries.

NIH Research Projects · FY 2025 · 2013-07

PROJECT SUMMARY Neurodegeneration Training Program (NTP) is an inter-departmental training program in the School of Medicine (SOM) at Case Western Reserve University (CWRU) aiming to provide trainees with the fundamental skills necessary for outstanding careers in neurodegeneration research, together with an appreciation of the challenges and complexity of diagnosing and treating neurodegenerative diseases in the clinical setting. The NTP emphasizes rigorous PHD training in fundamental aspects of neurodegeneration and mechanisms of diseases involving neurodegeneration and clinical perspectives through classroom teaching, neurodegeneration-related laboratory research and mentored neurodegenerative clinical experiences combined with educational forums that address quantitative approaches and important topics in clinical and translational neurodegeneration research. The NTP has been designed for students in year 3 and beyond to provide differentiated rigorous pre-doctoral scientific training in the field of neurodegeneration along with extensive clinical exposure. NTP will draw pre-doctoral trainees from four component PHD training program (Neuroscience, Pathology, Genetics and Physiology & Biophysics) as the departments of Neuroscience, Pathology, Genetics and Physiology & Biophysics house the majority of faculty involved in neurodegeneration research and individual training program in each of these departments provide rigorous basic training in its discipline which form the solid basis and better prepare the trainees for more specialized training in neurodegeneration as afforded by this NTP. A competitive pool of trainees will combine with 27 outstanding faculty in state-of –the-art facilities to investigate a wide range of neurodegeneration-related topics. The NTP promotes collaboration between departments and schools at Case Western Reserve University, particularly the School of Medicine, and with its affiliated institutions in the Cleveland area: University Hospitals Cleveland Medical Center (UHCMC), and the Cleveland Clinic Foundation (CCF, including the Lerner Research Institute). All of these institutions are within walking distance of each other and this rich training environment enjoys very active basic science and clinical activities. The updated curriculum provides a solid foundation for neurodegeneration research with an emphasis on experimental design, statistical methodologies and quantitative approaches. The well-received mentored neurodegenerative clinical experience has been expanded to include seven renowned clinicians enabling direct interaction with patients and caregivers in several different clinical centers close to CWRU campus providing motivation to the trainees to produce advances in disease diagnosis and therapies. The career development and professional enrichment module ensures better preparedness of our trainees to achieve their desired career goals. Together, NTP training will provide trainees a solid foundation for an outstanding neurodegeneration-related career.

NIH Research Projects · FY 2024 · 2012-04

Age-related macular degeneration (AMD) is a leading cause of vision loss in older Americans and severely impacts the independence, quality of life, and healthcare costs for those afflicted and their families. Genetic variation has a major influence on AMD, but only about half of the heritability is currently understood. Understanding the genetic architecture of AMD is critical for developing better treatments for AMD. The International AMD Genomics Consortium (IAMDGC) has assembled 33 research groups and over the past four years of this grant has enabled significant progress by extending the number of known risk loci and implicating new biological pathways. This renewal extends these efforts to multiple genetic ancestries, study designs, and more detailed phenotypic data. We propose the following aims: 1) Continue to expand the IAMDGC resource with new datasets. We have added seven new collaborators and now have access to data from >100,000 participants. 2) Use universal hubs to process and share genomic, phenotypic, and biomarker data. Regeneron Pharmaceuticals has agreed to conduct whole exome sequencing on approximately 40,000 participants at no cost to the grant. By statistical imputation on the remaining GWASed samples, we will create an extremely large dataset. We will continue to house the data in two analytic hubs (US and Europe) to simplify access and provide computational and analytic support. 3) Perform detailed analyses on the extensive resulting dataset. The dataset (87,542 cases/controls and 13,766 related individuals in nearly 6,000 families) enables testing of numerous genetic hypotheses underlying clinical subtypes, biomarkers, effects of rare variants, and variability in the genetic architecture across ancestries. The initial processing and analysis of the combined genomic data will be overseen through this application and results will be available to all members. We have an efficient process allowing members to propose additional studies and the broader research community to access these data and computational and analytical support through the appropriate analytic hub. 4) Support the logistics and administration of the IAMDGC. Successful collaboration requires constant communication and support. We will continue our yearly IAMDGC-specific face-to-face meeting, a second half- day meeting for those attending the ARVO annual meeting, and regular teleconference calls. Our goal is to greatly advance the understanding of AMD pathophysiology (using genomics as our foundational guide) and thus speed the development of better treatments and/or preventions of AMD.

NIH Research Projects · FY 2026 · 2011-09

Abstract Phototransduction is a fundamental biological process involving a set of biochemical reactions in photoreceptor cells that initiate vision. The long-term goal of this research program is to understand the molecular mechanisms underlying the biochemical events in phototransduction under normal and diseased states. The primary focus here is on rhodopsin, the light receptor in rod photoreceptor cells that initiate vision upon stimulation by light. Rhodopsin plays a central role in phototransduction as the initiator of signaling and plays an important role in maintaining the health of photoreceptor cells. The rhodopsin gene is a hot spot for mutations causing inherited retinal diseases such as retinitis pigmentosa (RP) and congenital stationary night blindness (CSNB), which currently have no cure or effective treatment. Rhodopsin is a prototypical G protein- coupled receptor and therefore findings here can provide insights on other members of this superfamily of proteins that share commonalities in structure and mechanisms of action. Despite the wealth of knowledge available for rhodopsin, gaps in our structural and molecular understanding of the receptor still exist and a mechanistic description on the effect of mutations in the light receptor causing vision disorders is incomplete. Two molecular defects in rhodopsin that cause inherited retinal disease will be examined in this proposal: misfolding/aggregation and constitutive activity. Rhodopsin must adopt a proper three-dimensional structure for its function in photoreceptor cells. Mutations in rhodopsin can cause it to misfold and aggregate, however, understanding the link between this molecular defect and photoreceptor cell death is incomplete. In aim 1, the nature of rhodopsin aggregates caused by mutations will be characterized in mouse models to gain a more comprehensive understanding about the role of rhodopsin aggregation in photoreceptor cell death and pinpoint strategies that can modulate aggregation. The structure of rhodopsin is finely tuned to prevent activation of the receptor in the absence of light stimulation. Constitutive activity of rhodopsin can lead to a variety of phenotypes and cause either RP or CSNB. In aim 2, the molecular origin of the different phenotypes caused by constitutively active rhodopsin mutations will be examined. We will examine the possibility that RP-causing mutations cause receptor aggregation and that CSNB-causing mutations result in mutants that adopt a distinct constitutively active state. This proposal combines the study of a variety of genetically modified mice with innovative biophysical and biochemical methods to answer questions raised in each aim. Results from our studies will lead to a more accurate mechanistic framework to understand dysfunctions in inherited retinal diseases, which will provide new avenues for scientific inquiry and the potential discovery of novel therapeutic targets.

NIH Research Projects · FY 2025 · 2011-09

Project Summary The Diabetes Control and Complications Trial (DCCT,1983-1993) compared intensive therapy aimed at near-normal glycemia versus conventional therapy with no specific glucose targets in 1441 subjects with type 1 diabetes (T1DM) over a mean follow-up of 6.5 years. Intensive therapy reduced the risks of retinopathy, nephropathy, and neuropathy by 35-76%. The level of glycemia was the primary determinant of complications. We also described the adverse effects of intensive therapy; assessed its effects on cardiovascular disease (CVD) risk factors, neurocognition and quality of life; and projected the lifetime health-economic impact. After the primary DCCT results were reported in 1993, intensive therapy aiming for a HbA1c <7% was adopted world-wide as standard-of-care for T1DM. The Epidemiology of Diabetes Interventions and Complications (EDIC, 1994-present) is the observational follow-up study of the DCCT cohort. Micro- and cardio-vascular complications and a wide range of established and putative risk factors, including genetic and epigenetic factors, have been measured with standardized methods, carefully documented and events adjudicated. EDIC has notably shown that the early beneficial effects of intensive versus conventional therapy on complications persisted for ~15 years despite the convergence of HbA1c levels in the two groups during EDIC, a novel concept termed metabolic memory. Prior intensive therapy was also shown to reduce substantially the risk of CVD events and mortality. The overarching goals for the next 5 years (2022-27) will be to study the occurrence and identify potentially modifiable risk factors of the more advanced microvascular and cardiovascular complications and physical and cognitive dysfunction that are occurring with increasing diabetes duration and age. With increasing longevity, the increased adiposity that has affected patients with T1DM, including EDIC participants, has potential adverse consequences. Thus, the impact of diabetes duration, aging and adiposity on morbidities and their underlying risk factors will be studied. The results will guide treatment priorities as T1DM patients age. The specific aims for 2022-2027 are to: 1) determine the incidence of advanced microvascular complications, investigate the order of their development and pattern of co-development, and identify glycemic and non-glycemic risk factors; 2) quantify impairment in functional and myocardial performance that presages heart failure (HF) and identify the risk factors for impairment in T1DM; 3) determine the prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and steatohepatitis-associated fibrosis (NASH) and symptoms suggestive of obstructive sleep apnea (OSA) in this increasingly overweight/obese T1DM study population and identify precedent risk factors and mechanisms; and 4) continue the longitudinal assessment of aging-sensitive morbidities such as cognitive and physical dysfunction, frailty, and their risk factors and their aggregate impact on quality of life, ability to self-manage T1DM, and health economic outcomes.

NIH Research Projects · FY 2024 · 2010-06

ABSTRACT This research education program offers short-term support to underrepresented or disadvantaged undergraduate and medical school students to provide them with career opportunities in cardiovascular, pulmonary, hematologic or sleep research. The research activity will expose trainees to the excitement, challenges and rewards of a career in biomedical research that are not otherwise available in their regular course of study. The CWRU short term HLB program will provide mentored research training with outstanding investigators in these four areas to 12 undergraduates and 8 medical students each year. The overall goal of this training program is to increase diversity among students who pursue academic careers in medicine and science, particularly in cardiovascular, pulmonary, hematologic and sleep research. This goal will be pursued by (1) helping trainees develop research skills, identity with the scientific profession and confidence in a research environment through well structured, mentored short term experiences that lay the foundation for biomedical research in clinical and bench settings, (2) providing exposure to diverse areas of research relevant to NHLBI (in particular, health disparities) and leaders in research with guest lectures and student presentations. Undergraduates from around the nation will be selected from more than 100 or more online applications each year after competitive review, and matched with researchers for 2 months on a full-time basis as summer research trainees. Medical students largely from this institution will be selected on the basis of the quality of the research proposal, the strength of the advisor as a research mentor and role model and the potential for a positive research experience and spend 2 full time months during the summer. Both groups of trainees will attend common weekly sessions and interact to build a community of peers. Our faculty lead outstanding programs that encompass basic, translational, clinical, population-based research programs in cardiovascular, pulmonary, hematologic and sleep research, and each has an outstanding training record and strong interest in working with students. Our evaluation system allows us to continuously improve our training program, and our database and tracking plan highlights the achievements and career outcomes of our trainees.

NIH Research Projects · FY 2025 · 2010-05

Project Summary The Case Western Reserve University (CWRU) School of Medicine (SOM) is a leader in immunology research and education, with a rich history of seminal contributions to the field over many decades, including the discovery of the alternative pathway of complement. The Immunology Training Program Leadership Track (ITP-LT) is a training program within the broader Immunology PhD Program that is built to capitalize on the numerous strengths of the institution and our affiliates, which includes multiple departments at CWRU SOM, University Hospitals Cleveland Medical Center (UHCMC), the Cleveland Clinic Foundation (CCF; including the Lerner Research Institute) and the Louis Stokes VA Medical Center (VAMC), to prepare PhD and MD/PhD scientists for outstanding careers in immunology-related research. The Leadership Track places extra emphasis on developing the next generation of investigative group leaders for academia and industry (pharmaceuticals and biotechnology) as a central goal. Participating mentors provide a rich confluence of basic science, clinical activities and resources, and career development workshops to enrich the training of PhD students as they engage in basic and/or translational research ranging from innate immunity and signaling, T cell biology, antigen processing and presentation, complement, antibody structure and function, and mucosal immunity to research in clinically relevant models of infectious diseases (e.g. tuberculosis, HIV, malaria), immunopathology, transplantation and autoimmunity. Moreover, CWRU SOM has a newly developed Center for Systems Immunology (CSI) and has built a rare reputation for strength in glycoimmunology, or the role of glycans and their binding partners in the immune response. The ITP-LT draws upon these strengths and enjoys the explicit co-sponsorship by the CWRU Department of Pathology, CCF Department of Inflammation and Immunity, CWRU/UHCMC Division of Infectious Diseases, and the CWRU Center for Global Health and Disease. These unique research opportunities are central to the ongoing and future success of the ITP-LT. Training for the PhD degree in the program includes course work, research rotations, formal and informal seminars, a Thesis Proposal Defense/Qualifying Examination, research experience resulting in scholarly publications, career development activities, a PhD dissertation, and a variety of opportunities to come together to share and celebrate the accomplishments of the program's diverse population of trainees.

NIH Research Projects · FY 2025 · 2007-09

The Interdisciplinary Biomedical Imaging Training Program will prepare predoctoral trainees to become leaders in organism-level biomedical imaging technology and application research. Multi-disciplinary teams of engineers, physicists, biologists, and clinicians are required to advance biomedical imaging, especially with the advent of in vivo cellular and molecular imaging. We will create the next generation of interdisciplinary biomedical imaging scientists and engineers who will contribute to and lead such teams. Our training program will build upon continuing, significant institutional, state, federal, and commercial investment in faculty and imaging infrastructure. A training grant award will place students squarely in the center of ongoing interdisciplinary/multi-disciplinary research programs. Trainees will use imaging facilities in the Case Center for Imaging Research, which includes state-of-the-art clinical and preclinical imaging systems, along with labs of mentoring faculty. Predoctoral trainees will be from the highly-rated departments of Biomedical Engineering and Physics, both of which have a long history of training in biomedical imaging. Trainees will conduct research projects combining enabling technologies in imaging with biomedical research. Each trainee will have two or more mentors representing both imaging technology and biological/clinical applications of imaging. Our educational program includes a portfolio of imaging courses, including ones focusing on imaging physics, image analysis, and reconstruction, as well as nanomedicine. We will promote a culture of interdisciplinary research during a designated Imaging Hour. In general, our T32 has helped make graduate students cost-effective as compared to postdocs and ensured training of domestic PhDs in this area of critical need. In less than nine years, our T32 program has already successfully trained several graduates, all of whom have exemplary training records and a trajectory towards success. Other trainees are moving through the program, focusing on exciting interdisciplinary imaging research, and with excellent research productivity.

NIH Research Projects · FY 2026 · 2007-08

The Centers for Disease Control and Prevention (CDC) designated Carbapenem-Resistant Acinetobacter baumannii (CRAb) an “urgent threat pathogen” for which novel therapies are desperately needed. The current COVID-19 pandemic has only accelerated the emergence of CRAb in medical intensive care units and hospitals, creating a parallel health care crisis in the US. The combination of β-lactamase production and cell penetration challenge every drug class used to treat CRAb. By applying novel chemistry to design more potent “cross-class” boronic acid transition state inhibitors (BATSIs) that are effective β-lactamase inactivators, and developing a deeper understanding of the genetic diversity of β-lactamases present in CRAb, we propose to extend our efforts to also target class B metallo-β-lactamases (MBLs; specifically IMP-1, -14, and NDM-1, as they are the most prevalent MBLs in Ab), and develop drugs that penetrate Ab more readily. We will build upon the efficacy of two potent BATSIs (MB076 and CR167 that were iteratively designed in our current funding cycle) to also interact with Zn2+ ions in the active site of MBLs, as well as penetrate CRAb more effectively. Concurrently, we discovered that OXA β-lactamase overexpression in Ab drives significant collateral changes in bacteria consistent with increased amidase activity. As a result, peptidoglycan integrity is impacted, and new cellular vulnerabilities were revealed. Further studies have also shown that at least five genes become conditionally essential in OXA expressing Ab. As a result, we propose a multidisciplinary approach to overcome CRAb using the following strategies. Firstly, we propose that structural and mechanistic similarities in class B, C, and D β-lactamases can be exploited to permit the design of “cross-class” inhibitors by the addition of novel functional groups (e.g., Zinc Binding groups, ZBGs). In addition, we will design novel cyclic boronates that demonstrate interactions in the active site that inhibit MBLs as well as serine β-lactamases. Secondly, we hypothesize that the penetration of BATSIs into Ab can be improved and overcome by modifications of the R1/R2 side chains to enhance steric and electronic interactions that facilitate passage through porins, specifically CarO. In addition, we will synthesize novel BATSIs that use Fe3+ mediated transport that penetrate CRAb readily and resist efflux. We will perform molecular modeling and structural analyses of CarO to give us insight on how to overcome this major porin conferring imipenem resistance. Studying the mechanistic/structural features inherent to CarO and the imipenem scaffold will facilitate our first two goals. Thirdly, we discovered that OXA β-lactamase expression in CRAb creates new cellular vulnerabilities and that certain gene products become essential for viability, but only in OXA- overexpressing isolates. We propose that these gene products represent novel bacterial targets that can be inhibited by small molecules to selectively kill OXA expressing bacteria. We will use high-throughput screening to identify compounds that selectively kill OXA expressing Ab and identify the cellular target of these inhibitors.

NIH Research Projects · FY 2026 · 2007-02

ABSTRACT The Case Clinical Trials Unit (CTU) comprises three highly productive clinical research sites: Case/UHC in Cleveland, the University of Cincinnati, and the Joint Clinical Research Center in Kampala. Each of these three sites is a top performing ACTG treatment trial site with excellent accruals, outstanding performance evaluations and major roles in the leadership of the network and it is scientific productivity. A key theme of this CTU is the close link of our clinical research portfolio with our basic and translational research programs. Thus, the three CRS sites of the Case CTU bring a comprehensive research plan to the enterprise. Led by faculty who are national and international leaders in their fields, these units are poised to make substantive contributions to each of the priority areas targeted by the ACTG: Inflammation/End Organ Disease, Antiretroviral Medications, HIV Eradication and Cure, Tuberculosis, and Hepatitis. The Case/UHC CRS has also been a productive member of the HVTN. The Case/UHC CRS has been a high- performing site in this network, having enrolled participants, including some from difficult-to-reach segments of the population, into multiple HVTN trials during this funding cycle. In some cases, enrollment has substantially exceeded expectations from the site. Additionally, Case CTU investigators are highly accomplished researchers who have extensive experience in the monitoring of immune responses form immunization, in evaluating diverse immunization strategies to enhance vaccine responsiveness, and in the use of vaccine responsiveness as a readout of immune competence. The University of Cincinnati CRS is a highly efficient, well-managed CRS that has been conducting clinical and translational research for the ACTG since 1987, and is the number 1 site by number of participants enrolled in the US. In addition to their extraordinary performance on enrollments, the site has extensive accumulated expertise in the metabolic complications of HIV, and is additionally a high-performing protocol-specific HPTN site. The JCRC is one of the top-performing international sites in the ACTG, and is the critical component in the contributions of the Case CTU to the tuberculosis agenda. It is also the site of the first hepatitis C treatment clinical trial in Africa, the ACTG A5360 protocol. The JCRC CRS has also previously demonstrated its ability to access large numbers of subjects in well-defined populations at high risk for HIV infection, having been the site of the first HIV vaccine trial in Africa, and can begin contributing to the HIV prevention networks immediately as well if selected as a site. Thus, the three CRS that comprise this CTU are positioned to provide sustained leadership and contribution to the treatment and prevention agenda of the NIAID Networks.

NIH Research Projects · FY 2024 · 2006-08

The US population is becoming increasingly diverse, but that is not reflected in the current biomedical research workforce. The National Institutes of Health is concerned by this lack of diversity and has established a variety of supportive mechanisms to ensure that workforce diversity is representative of the diversity in American society. One important NIH diversity initiative is the Postbaccalaureate Research Education Program or PREP. The overall goal of PREP is to develop recent baccalaureate science graduates from diverse backgrounds under-represented in biomedical sciences so that they have the necessary knowledge and skills to pursue PhD or MD-PhD degrees in these fields. Case Western Reserve University was awarded PREP funding beginning in 2007. The program, termed CasePREP, has been notably successful, matriculating 54 Scholars into upper-tier PhD or MD/PhD programs across the nation. The current proposal seeks to continue this program by funding eight Case PREP Scholars each year for an additional 5 years. The key components of CasePREP involve individually tailored graduate coursework, professional credentials enhancement, well-crafted experiential skill development, immersion in the PhD student experience, and extensive exposure to biomedical research. Indeed, Case PREP Scholars complete a one-year apprenticeship in CWRU School of Medicine faculty laboratories located throughout many of our 14 PhD-granting programs. PREP mentor laboratories are well funded, dynamic, and led by experienced mentors with substantial minority training experience. In addition, Case PREP Scholars will complete graduate level coursework, GRE preparation experiences, professional skills development, and other enrichment activities. These core developmental experiences are designed to further strengthen a student's scholarly potential and improve their research skills, ultimately leading to their matriculation into and completion of rigorous biomedical doctoral degree programs across the nation. Important outcome assessments will show improved graduate school application credentials, enhanced research and presentation skills, improved attitudes about research careers, and greater than 75% success rates in PREP Scholar matriculation into PhD programs and completion of the PhD degree, respectively. Importantly, one of the main outcomes is for Case PREP to continue improving diversity in the biomedical PhD programs at CWRU and across the nation.

NIH Research Projects · FY 2025 · 2005-08

Over 30M people in the U.S. suffer from diabetes; one-third have CKD and almost half of incident ESRD is due to diabetic kidney disease (DKD). Albuminuria and decreased GFR reflect glomerular dysfunction, and are risks for DKD progression. However, tubular atrophy is superior to glomerular pathology as a predictor of DKD progression. The mechanisms for loss of tubular epithelial cells have not been established. Non-esterified fatty acids (NEFA) circulate bound to albumin, or as triglycerides. Neither is filtered due to their size. Low concentrations of filtered NEFA are reabsorbed by apical scavenger transporters in the proximal tubule. This segment normally uses NEFA as metabolic substrates that are taken up across the basolateral membrane. In DKD, injured glomeruli permit filtration of albumin-bound NEFA in large quantities, which are then reabsorbed by apical proximal tubule transporters, causing accumulation of NEFA, long-chain acyl-CoAs, and apoptosis. Apical NEFA uptake is mediated primarily by fatty acid transport protein-2 (FATP2), and at NEFA concentrations that mimic DKD in vitro, is cytotoxic. Basolateral NEFA uptake is FATP2-independent and not cytotoxic. We showed that global FATP2 deletion in genetic and inducible mouse models of DKD improves GFR, tubular atrophy and plasma glucose, but the mechanisms are not understood. First, FATP2 deletion does not completely block AP proximal tubule NEFA uptake. Second, how FATP2 deletion account for the enhanced synthesis and decreased degradation of NEFA associated with DKD, has not been reconciled. In DKD proximal tubules accumulate lipid droplets (LD), which store excess NEFA to prevent lipotoxicity. Perilipin (Plin) proteins facilitate LD assembly and maintenance. Plin5 augments LD docking with mitochondria, thereby enhancing autophagy, reducing ER stress and apoptosis, and shifts metabolism from -oxidation to lipid storage and glucose utilization. Our data show that proximal tubule Plin5 expression is blunted in DKD, and increased with FATP2 deletion. Plin5 overexpression inhibited, and Plin5 loss of function exacerbated lipoapoptosis. These data suggest that the beneficial effect of FATP2 deletion is partly due to enhanced expression of Plin5. We also propose that Plin5 mediates metabolic reprogramming from -oxidation to glycolysis and decreased gluconeogenesis, which would mediate the hypoglycemic effects of FATP2 deletion. Hypothesis: In DKD-associated glomerular injury, constitutive basolateral NEFA transport, combined with apical FATP2-regulated proximal tubule NEFA uptake leads to lipotoxicity, tubular atrophy and progressive DKD. Tubular atrophy can be circumvented by proximal tubule FATP2 deletion or enhanced Plin5-dependent lipid droplet expansion. The hypothesis will be pursued with the following specific aims: 1. To determine whether proximal tubule FATP2 mediates lipotoxicity and DKD progression. 2. To determine the role of Plin5 in proximal tubule metabolism and DKD. 3. To determine the therapeutic utility of FATP2 inhibition in DKD.

NIH Research Projects · FY 2026 · 2002-03

The ability to adapt to environmental challenges is critical for cellular and organismal function. A frequent challenge is dehydration which increases osmotic pressure on the cells causing water loss and cell shrinkage. Cells respond by accumulating organic osmolytes to accommodate decreases in cell volume and ionic strength in a process called osmoadaptation. This cellular stress response is critical for survival of all organisms and tissues. Defects in osmoadaptation induce a pro-inflammatory program that decreases cell survival and has implications for multiple pathologies, including inflammatory bowel disease, diabetes, cancer and dry eye syndrome. Diabetes associated hyperglycemic hyperosmolar syndrome (HHS) is life threatening. It is therefore important to understand the molecular mechanisms of osmoadaptation. Our application focuses on the regulation of protein synthesis during osmoadaptation, a critical process that is poorly understood. The overall goal of this proposal is to develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation that will lead to development of therapeutics of diseases that cause decreased tissue osmotolerance. We will examine the function of key regulators, including the amino transporter SNAT2 for establishing osmoadaptive mRNA translation programs using Human Corneal Epithelial Cells (HCEs). Corneal Epithelial cells are the cells in the eye that develop the pathology of dry eye syndrome in diabetes. To develop a mechanistic, transcriptome-wide understanding of translation regulation during osmoadaptation we characterize the translation landscape during osmoadaptation and define the regulatory RNA features that control the changes in mRNA translation (Aim 1). We then focus on the interplay between translation regulation, amino acid homeostasis and liquid-liquid phase separation (LLPS) of RNA binding proteins (RBPs) during osmoadaptation and delineate how mTOR and SNAT2 activities affect the translation landscape in response to hyperosmotic stress (Aim 2). Finally, we examine the function of RBPs that link LLPS and translation regulation, by determining RNA binding patterns and LLPS for specific RBPs during osmoadaptation (Aim 3).

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY Case Western Reserve University (CWRU) proposes to continue to serve as a clinical center for Phase 5 of the Chronic Renal Insufficiency Cohort (CRIC) Study. Chronic kidney disease (CKD) affects over 37 million Americans who are at risk of progression to end stage kidney disease and development of cardiovascular disease and other comorbidities associated with disability, high costs of care and premature mortality. Since its inception in 2001, the CRIC Study has recruited and followed a racially and ethnically diverse cohort of 5,625 participants with reduced kidney function from 13 recruitment sites at 7 Clinical Centers across the US. The original aim of CRIC was to establish a clinical research laboratory designed to (a) identify novel predictors of CKD progression, and (b) characterize the manifestations of cardiovascular disease and identify its risk factors among individuals with CKD. As the landmark prospective cohort study of CKD, the CRIC Study has accomplished extensive biological, physiological, and social phenotyping, longitudinal follow-up, and ascertainment of clinical and patient-centered outcomes across multiple domains. Findings from the CRIC Study have defined trajectories of CKD progression, catalogued development and evolution of comorbidities in CKD, and identified a diverse array of factors and pathways that explain the progression and complications of CKD in adults. Through its highly productive Ancillary Studies and Opportunity Pool Programs, both the scientific scope of the CRIC Study and the community of kidney disease researchers have been markedly expanded. During the most recent funding cycle (Phase 4: 2018-2023), three innovative sub-protocol studies were implemented to enrich CRIC data with highly granular home-based assessments of kidney function and cardiovascular measures. During the fifth and final phase of the CRIC Study, the major focus will be to (1) ascertain the clinical outcomes for all participants including those enrolled in the Phase 4 sub-protocols, (2) perform analyses linking the sub-protocol measurements to clinical outcomes, (3) integrate data from multiple domains to identify sub-phenotypes underlying the heterogeneity in CKD progression outcomes, (4) conduct final study visits for the full CRIC cohort eligible for Phase 5, (5) create mechanisms for future data collection via linkages with external sources of health data, and (6) generate tools and resources to facilitate ongoing use of CRIC data and biospecimens by a broad group of investigators after the CRIC Study has officially ended. CWRU investigators will work closely with the Scientific and Data Coordinating Center and other CRIC investigators to generate new scientific output and successfully transition the CRIC Study from its active prospective cohort phase to a long-lasting resource for supporting ongoing and future mechanistic, epidemiologic, and translational investigations.

NIH Research Projects · FY 2026 · 2001-04

Obstetric practices and treatments are steeped in tradition, often introduced without rigorous evaluation based on “expert” opinion. Practices are often influenced by the media with societal acceptance then entering common practice without an assessment for risk or benefit. Because obstetrics often impacts two patients it is important to understand the potential consequences for both individuals when a new intervention, medication, or device is introduced into clinical practice. A treatment may benefit the mother but harm the fetus or inversely benefit the fetus but harm the mother. These adverse events have both social and financial implications for both the family and society. In addition, new therapeutic interventions can be associated with increased healthcare expenditures. These social and financial burdens need to be determined to help mold health care policy and practice. Since its inception, the Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units (MFMU) research network has conducted clinical trials and observational studies that have provided new knowledge to our understanding of pregnancy especially in the area of prematurity. Past studies have demonstrated the benefit of 17-OH progesterone caproate to reduce the risk of preterm delivery and antibiotics to prolonged pregnancy after premature preterm rupture of the membranes, among other effective interventions. Other studies have put an end to expensive and ineffective interventions, such as fetal pulse oximetry and fetal heart rate ST segment analysis, both of which failed to change delivery outcomes. MFMU network studies have played a significant role in providing evidence for and against numerous practices over the past 26 years. In this application, we demonstrate that the investigators in the Department of Reproductive Biology at Case Western Reserve University (CASE) have the ability to conduct collaborative research and have successfully participated in the MFMU research network and are qualified to continue as a study center. Our investigators have a diverse background in clinical trials and multi-center studies providing a depth of experience for future as well as on-going studies. Our center has performed well in both recruitment and data quality while maintaining high rates of participant retention. The CASE community (participating institutions and medical school) has been and continues to be highly supportive of the CASE-MFMU study center and our investigators. The CASE study center has provided leadership and participated in the administrative operations that lead to the success of the entire MFMU network. Our use of administrative processes to improve recruitment and hold down costs has been innovative. CASE provides a strong administrative and research infrastructure such as the CASE-Clinical & Translational Science Collaborative to support our study center operations. The CASE study center team is ideally positioned to provide leadership with exceptional performance in the coming MFMU Network cycle.

NIH Research Projects · FY 2026 · 2000-09

The Visual Sciences Training Program (VSTP) at Case Western Reserve University (CWRU) offers multidisciplinary training in fundamental and translational vision science. This training program advances research in the following thematic areas: (a) Retinal Development and Function; (b) Retinal Disorders: Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD); (c) Biochemistry, Cell Biology, Immunology of Eye Diseases; and (d) Genetics, Physiology, and Epidemiology of Eye Diseases. An essential objective is to provide an efficient and vibrant collaborative training environment which integrates basic science with translational and clinical research. Therefore, the VSTP partners with the Core Modules of the Visual Sciences Research Center, University Hospitals Cleveland Medical Center (UHCMC), the Cleveland Clinic Lerner College of Medicine and Cole Eye Institutes (CCLCM), and the Louis Stokes Cleveland VA Medical Research Center. Our interdisciplinary program is built upon and supported by basic and clinical scientists in the Departments of Population and Quantitative Health Sciences, Medicine, Molecular Biology & Microbiology, Ophthalmology & Visual Sciences, Pathology, Pharmacology, Physiology & Biophysics, and Systems Biology & Bioinformatics (CWRU and UHCMC) and Ophthalmology (CCLCM). Our established faculty members work in conjunction with our junior faculty to cultivate a robust mentoring environment and to promote innovative projects in vision science. The 29 faculty of the T32 Institutional Training Grant application seek renewed support for four predoctoral student positions and one postdoctoral position in all years. The goal of the program is to develop professional scientists with the maturity to address novel research questions in vision sciences through innovation and collaboration. Rapid advances in biotechnology and bioengineering coupled to the ever-expanding development of new therapeutics for eye diseases has created a growing need for highly qualified scientists with core training in the principles and practice of visual sciences. Our multifaceted approach incorporates not only basic science, translational research, and didactic coursework but also enrichment opportunities such as the Annual Association for Research in Vision and Ophthalmology Conference, Vision Research Seminar Series, the Vision Science Data Conference, and the Annual VSRC Symposium. These educational experiences will equip trainees with a strong foundation and technical skills to make them competitive candidates for careers in academia, industry, and healthcare.