Muscular Dystrophy Specialized Research Center

整体总结

OVERALL SUMMARY The overall goal of the University of Iowa Wellstone Muscular Dystrophy Specialized Research Center (MDSRC) is to perform research on the various muscular dystrophies that arise from abnormal processing of the dystroglycan protein (dystroglycanopathies). The Center will achieve this overall goal by conducting basic and translational research in dystroglycanopathy patients, patient-derived biosamples, and mouse models. Our MDSRC application is composed of two projects and three cores, all of which are directed by investigators with a proven track record of excellence and collaboration in basic, translational and clinical research. Project 1 (Campbell) will investigate the cellular and molecular mechanisms that underly dystroglycanopathies by evaluating the relationship between α-dystroglycan (α-DG) matriglycan length and its laminin-binding properties in control and dystroglycanopathy patient fibroblasts and muscle biopsies. Additional studies will define the requirements for matriglycan synthesis as regulated by protein-protein and protein-sugar interactions. A dystroglycanopathy mouse model will be utilized to identify novel pathophysiologic mechanisms and determine the structure and laminin binding properties required to improve muscle function. Project 2 (Mathews) will refine the natural history of FKRP-related dystroglycanopathy derived from an established, unique cohort of patients by expanding the number of clinical sites evaluating patients and by extending the natural history study to patients with more advanced clinical severity. Extended follow up of non-FKRP genotypes will identify cohorts that share similar rates of motor progression who might be studied together in gene non-specific clinical trials. Candidate proteomic biomarkers in blood or urine for the full spectrum of dystroglycanopathy genotypes will be validated and related to disease status. Core A (Campbell and Moore) is an administrative core that will coordinate the activities within and outside the Center, as a means to promote an interactive and collaborative research environment, and to engage patients in muscular dystrophy research. Core B (Moore), a Muscle-Tissue/Cell-Culture/Diagnostics Core, will support Projects 1 and 2, serve as a national tissue and cell-culture resource for research, provide specialized diagnostic testing for a wide range of muscular dystrophies, and maintain the infrastructure needed to evaluate muscle biopsies in support of clinical trials. Finally, Core C (Mathews and Campbell) will coordinate our Training initiatives. Among the support this Core provides will be fellowships enabling two medical students per year to perform research in the Center and to participate in the care of patients alongside Dr. Mathews, with basic science training opportunities also provided to a postdoctoral fellow and an undergraduate research fellow. The highly integrated cores and projects of this Center will accelerate the tempo of discovery in preclinical translational research, and also establish the clinical-trial readiness of a cohort of dystroglycanopathy patients.