This application addresses broad Challenge Area (15) Translational Science and Specific Challenge Topic 15-OD (ORDR)-101. The Challenge: Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disease of late onset for which no cure exists. It is characterized by eyelid drooping, difficulties in swallowing and weakness in proximal limb muscles. Although polyalanine expansion in PABPN1, a ubiquitous mRNA binding protein, causes OPMD neither the function of PABPN1 in skeletal muscle nor how expression of mutant PABPN1 leads to muscle pathology in specific muscles is known. Scientific Gap in Knowledge to be addressed: The expanded polyalanine tract in PABPN1 leads to aggregation of the mutant protein in intranuclear inclusions in skeletal muscle. Mutant PABPN1 may lead to pathology by sequestering either specific mRNA transcripts or proteins such as wildtype PABPN1 in aggregates. We hypothesize that the muscle stem cells in the head and neck muscles are the key cells affected by alanine-expanded PABPN1 and are responsible for the muscle-specific pathology observed in OPMD. The Approach: To analyze the role of mutant PABPN1 in muscle stem cells, experiments are proposed to identify mRNA transcripts associated specifically with alanine-expanded PABPN1 in muscle stem cells (Specific Aim 1), to analyze molecular defects in mRNA biogenesis linked to expression of alanine-expanded PABPN1 or depletion of wildtype PABPN1 (Specific Aim 2), and to determine whether alanine-expanded PABPN1 expressed specifically in muscle stem cells results in muscle pathology in novel transgenic mouse models (Specific Aim 3). Importantly, the Specific Aims are designed to compare the role of PABPN1 and the functional consequences of alanine-expanded PABPN1 expression in muscles affected in OPMD. Significance: Studies targeting muscle stem cells may lead to a paradigm shift in our understanding of the pathology of OPMD and afford new therapeutic strategies that target the appropriate molecular pathways altered in affected muscles. In addition, the information gathered in this proposal could also extend to other nuclear inclusion diseases in which a mutant protein forms aggregates. 7. PROJECT NARRATIVE The goal of these studies is to understand why people with mutations in the PABPN1 protein develop a disease called oculopharyngeal muscular dystrophy (OMPD) where eyelid and pharyngeal muscles are primarily affected. Our experiments will study the role of PABPN1 in the muscle cells that are affected in the disease. Understanding the role of PABPN1 specifically in these muscle cells will lead to a greater understanding of the pathogenesis of OPMD as well as possible new therapeutic strategies for this disease.
The goal of these studies is to understand why people with mutations in the PABPN1 protein develop a disease called oculopharyngeal muscular dystrophy (OMPD) where eyelid and pharyngeal muscles are primarily affected. Our experiments will study the role of PABPN1 in the muscle cells that are affected in the disease. Understanding the role of PABPN1 specifically in these muscle cells will lead to a greater understanding of the pathogenesis of OPMD as well as possible new therapeutic strategies for this disease.
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