The overall goal of our research is to develop therapeutic strategies for treating muscular dystrophy. Our current research focuses on the dystroglycanopathies ? muscular dystrophies in which aberrant post- translational modification of the ?-dystroglycan (?-DG) protein results in a reduction of its glycosylation, and thereby in loss of an essential link between it and its laminin-G domain-containing ligands in the extracellular matrix (ECM). At least eighteen genes encode post-translational enzymes that act on ?-DG, and mutations therein cause congenital/limb-girdle muscular dystrophies, conditions that can be accompanied by brain and eye abnormalities. Although great progress has been made on the identification and characterization of dystroglycanopathy genes, we still do not fully understand how mutations therein lead to the observed abnormalities in dystroglycan glycosylation and to muscular dystrophy. The overarching hypothesis of our research is that a thorough understanding of 1) the structure of an ECM ligand-binding glycan on native dystroglycan, 2) the abnormal glycan structure(s) in dystroglycanopathy patients, and 3) the pathological mechanisms underlying the abnormal glycosylation and receptor function in the dystroglycanopathies, are required to develop rational diagnostic and therapeutic strategies. We will approach our objectives using patient cells and state-of-the-art biological, cell biological and glycobiological analyses.
Specific Aim 1 will establish the in vivo relevance of the LARGE repeats on ?-DG in skeletal muscle. These studies will reveal whether LARGE repeats are present on native ?-DG, and establish their contribution to ligand binding in vivo.
Specific Aim 2 will define the ligand- and antibody-binding properties of LARGE repeats, establish the binding affinity and absolute stoichiometry of the LARGE-dependent glycan for its ECM ligands, and determine the specificity of antibodies that target the dystroglycan glycan.
Specific Aim 3 will establish the post-translational modification status of ?-DG in various dystroglycanopathies. Identifying the molecular defects in ?-DG within different patient populations will improve our understanding of the modifications that will be required for therapeutic treatments. Finally, Specific Aim 4 will identify the mechanistic defects that result in abnormal ?-DG glycosylation. We will analyze the enzymatic activities of several dystroglycanopathy genes (LARGE, POMK, POMGNT2, B3GALNT2, and B4GAT1) and correlate these with functional glycosylation in patient cells and severity of the clinical phenotype. We will also prepare mutant constructs and test the enzymatic activity and sub-cellular localization of the translated proteins. Classification of the mutant enzymes as ?inactive? or ?defective for trafficking? will provide a framework for developing novel therapeutic strategies based on the functional defect. Collectively, these aims will provide a critical understanding of the pathological mechanisms underlying dystroglycanopathies and a rationale for future diagnostic and therapeutic strategies.
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