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: 7827825
• 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/7827825
• 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）转化科学和特定挑战主题15-OD（ORR）-101。挑战：眼咽肌营养不良症（OPMD）是一种罕见的晚发性常染色体显性遗传疾病，目前尚无治愈方法。其特征是眼睑下垂，吞咽困难和近端肢体肌肉无力。尽管PABPN 1（一种普遍存在的mRNA结合蛋白）中的多聚丙氨酸扩增导致OPMD，但PABPN 1在骨骼肌中的功能以及突变型PABPN 1的表达如何导致特定肌肉中的肌肉病理学都是未知的。有待解决的科学知识差距：PABPN 1中扩展的聚丙氨酸束导致突变蛋白在骨骼肌核内包涵体中聚集。突变型PABPN 1可通过在聚集体中隔离特定mRNA转录物或蛋白质（如野生型PABPN 1）而导致病理学。我们假设，头部和颈部肌肉中的肌肉干细胞是受丙氨酸扩增的PABPN 1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：为了分析突变型PABPN 1在肌肉干细胞中的作用，提出了在肌肉干细胞中鉴定与丙氨酸扩增的PABPN 1特异性相关的mRNA转录物的实验（具体目的1），分析与丙氨酸扩增的PABPN 1的表达或野生型PABPN 1的消耗相关的mRNA生物发生中的分子缺陷（特异性目的2），并确定在肌肉干细胞中特异性表达的丙氨酸扩增的PABPN 1是否导致新型转基因小鼠模型中的肌肉病理学（特异性目的3）。重要的是，特定目的旨在比较PABPN 1的作用和丙氨酸扩增的PABPN 1表达在OPMD受影响的肌肉中的功能后果。重要性：针对肌肉干细胞的研究可能会导致我们对OPMD病理学的理解发生范式转变，并提供新的治疗策略，靶向受影响肌肉中改变的适当分子途径。此外，该提案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内含物疾病。7.这些研究的目的是了解为什么PABPN 1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，这种疾病主要影响眼睑和咽肌。我们的实验将研究PABPN 1在受疾病影响的肌肉细胞中的作用。了解PABPN 1在这些肌肉细胞中的作用将有助于更好地了解OPMD的发病机制以及这种疾病可能的新治疗策略。