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

OPMD的新前沿：眼咽肌营养不良症的干细胞理论

• 批准号: 7938594
• 负责人: ANITA H. CORBETT
• 金额: $ 50万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938594
• 关键词: Address; Adult; Affect; Age; Alanine; Area; Binding; Binding Proteins; Biogenesis; Biological Assay; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Characteristics; Coupled; Cytomegalovirus Infections; Defect; Deglutition; Deterioration; Disease; Eye; Eyelid structure; Fibroblasts; Future; Gene Transfer; Goals; Head and Neck Muscle; Immunoprecipitation; In Vitro; Knowledge; Lead; Length; Limb structure; Link; Messenger RNA; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Mutation; N-terminal; Nuclear; Nuclear Export; Nuclear Inclusion; Oculopharyngeal Muscular Dystrophy; Pathogenesis; Pathology; Pathway interactions; Phenocopy; Physiological; Poly A; Poly(A) Tail; Proteins; RNA; RNA Binding; Rare Diseases; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Skeletal Muscle; Small Interfering RNA; Specificity; Stem cells; Therapeutic Intervention; Time; Transcript; Transgenic Mice; Translational Research; Variant; crosslink; design; frontier; information gathering; late disease onset; lentiviral-mediated; mouse model; mutant; myogenesis; next generation; novel; novel therapeutics; pharynx muscle; polyalanine; research study; stem cell population; theories

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.

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体挑战主题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遗传病，发病晚，目前尚无治疗方法。它的特点是眼皮下垂，吞咽困难和四肢近端肌肉无力。虽然PABPN1是一种普遍存在的mRNA结合蛋白，但PABPN1中的聚丙氨酸扩张导致了OPMD，但PABPN1在骨骼肌中的功能和突变的PABPN1如何在特定肌肉中导致肌肉病理尚不清楚。有待解决的科学知识差距：PABPN1中扩大的聚丙氨酸链导致突变蛋白在骨骼肌内核包涵体中聚集。突变的PABPN1可能通过将特定的mRNA转录物或蛋白质(如野生型PABPN1)隔离在聚集体中而导致病理。我们假设头部和颈部肌肉中的肌肉干细胞是受丙氨酸扩张的PABPN1影响的关键细胞，并负责OPMD中观察到的肌肉特异性病理。方法：为了分析突变的PABPN1在肌肉干细胞中的作用，建议进行实验以鉴定肌肉干细胞中与丙氨酸扩展的PABPN1特异相关的mRNA转录本(特定目标1)，分析与丙氨酸扩展的PABPN1的表达或野生型PABPN1的缺失有关的mRNA生物发生中的分子缺陷(特定目标2)，以及确定在肌肉干细胞中特异表达的丙氨酸扩展的PABPN1是否导致新型转基因小鼠的肌肉病理(特定目标3)。重要的是，这些特定的目的是为了比较PABPN1的作用和受OPMD影响的肌肉中丙氨酸扩大的PABPN1表达的功能后果。意义：针对肌肉干细胞的研究可能导致我们对OPMD病理理解的范式转变，并提供新的治疗策略，针对受影响肌肉中改变的适当分子途径。此外，这项建议中收集的信息还可以扩展到突变蛋白形成聚集体的其他核包涵体疾病。7.项目说明这些研究的目标是了解为什么PABPN1蛋白突变的人会患上一种称为眼咽肌营养不良症(OMPD)的疾病，眼皮和咽部肌肉主要受到影响。我们的实验将研究PABPN1在疾病中受影响的肌肉细胞中的作用。了解PABPN1在这些肌肉细胞中的具体作用将有助于更好地理解OPMD的发病机制，以及可能的新的治疗策略。