New Frontiers in OPMD: Stem Cell Theory of Oculopharyngeal Muscular Dystrophy

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定挑战主题15- od (ORDR)-101。挑战：眼咽肌营养不良症（OPMD）是一种罕见的常染色体显性迟发性疾病，目前尚无治愈方法。它的特点是眼睑下垂，吞咽困难和肢体近端肌肉无力。虽然聚丙氨酸在PABPN1（一种普遍存在的mRNA结合蛋白）中的扩增导致OPMD，但我们既不知道PABPN1在骨骼肌中的功能，也不知道突变PABPN1的表达如何导致特定肌肉的肌肉病理。有待解决的科学知识缺口：PABPN1中扩大的聚丙氨酸束导致骨骼肌核内内含物中突变蛋白聚集。突变型PABPN1可能通过分离特异性mRNA转录物或蛋白质（如野生型PABPN1）而导致病理。我们假设头颈部肌肉中的肌肉干细胞是受丙氨酸扩增型PABPN1影响的关键细胞，并负责OPMD中观察到的肌肉特异性病理。的方法:为了分析突变型PABPN1在肌肉干细胞中的作用，我们提出了在肌肉干细胞中鉴定与丙氨酸扩增型PABPN1特异性相关的mRNA转录本（Specific Aim 1），以分析与丙氨酸扩增型PABPN1表达或野生型PABPN1缺失相关的mRNA生物发生中的分子缺陷（Specific Aim 2）。并确定在新型转基因小鼠模型中，丙氨酸扩增的PABPN1在肌肉干细胞中特异性表达是否会导致肌肉病理（Specific Aim 3）。重要的是，Specific Aims旨在比较PABPN1的作用和丙氨酸扩展的PABPN1在OPMD受影响肌肉中的功能后果。意义：针对肌肉干细胞的研究可能会导致我们对OPMD病理理解的范式转变，并提供针对受影响肌肉中改变的适当分子通路的新治疗策略。此外，本提案中收集的信息也可以扩展到其他突变蛋白形成聚集体的核包涵性疾病。7. 这些研究的目的是了解为什么携带PABPN1蛋白突变的人会患上眼咽肌营养不良症（OMPD），其中眼睑和咽肌主要受到影响。我们的实验将研究PABPN1在受该病影响的肌肉细胞中的作用。了解PABPN1在这些肌肉细胞中的作用将有助于更好地了解OPMD的发病机制，并可能找到新的治疗策略。

DESCRIPTION (provided by applicant): 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.