Muscle-Specific Basis of OPMD

OPMD 的肌肉特异性基础

• 批准号: 8530965
• 负责人: ANITA H. CORBETT
• 金额: $ 32.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530965
• 关键词: Adult; Affect; Alanine; Alleles; Binding Proteins; Biogenesis; Cell Nucleus; Cell physiology; Cells; Characteristics; Data; Deglutition; Disease; Dose; Doxycycline; Etiology; Event; Eyelid structure; Gene Expression; Genes; Genetic; Goals; Histocompatibility Testing; Immunoblotting; Impairment; In Vitro; Knockout Mice; Knowledge; Lead; Length; Limb structure; Mediating; Messenger RNA; Metabolism; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Mutation; Myoblasts; N-terminal; Normal tissue morphology; Nuclear; Oculopharyngeal Muscular Dystrophy; Onset of illness; Ontology; Pathogenesis; Pathology; Pathway interactions; Patients; Physiological; Physiology; Play; Poly A; Poly(A) Tail; Proteins; RNA; Reverse Transcriptase Polymerase Chain Reaction; Role; Skeletal Muscle; Small Interfering RNA; Tertiary Protein Structure; Tissues; Transcript; base; cell type; design; in vivo; late disease onset; mouse model; muscle regeneration; mutant; myogenesis; next generation sequencing; novel therapeutics; polyalanine; promoter; response; theories; therapeutic development; therapy development; transcriptome sequencing

DESCRIPTION (provided by applicant): Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disease of late onset for which no cure exists. It is characterized primarily by eyelid drooping and difficulties in swallowing with some weakness in proximal limb muscles. Although mutations in the ubiquitously expressed PABPN1, an mRNA binding protein, cause OPMD, much is still unknown regarding the mechanism by which mutant PABPN1 leads to muscle-specific pathology. In autosomal dominant OPMD one mutant allele of PABPN1 replaces one normal allele of PABPN1. Thus, pathology could be due to the loss of one normal allele, the gain of a mutant allele or the combination of both events. Due to the fact that PABPN1 appears to play an essential role in RNA metabolism, any impairment of its function should, in theory, affect numerous cell and tissue types, but the intrinsic characteristics of skeletal muscle may make this tissue more vulnerable to the effects of mutant PABPN1. Indeed, our preliminary data reveal that muscle tissue shows significantly lower levels of PABPN1 protein as compared to unaffected tissues. We hypothesize that the lower amount of PABPN1 in skeletal muscle could sensitize this tissue to the deleterious effects of mutant PABPN1. The overall goal of this proposal is to examine how both mutant PABPN1 and decreased functional levels of wild type PABPN1 impact RNA biogenesis and myogenesis. Thus, we will analyze the consequences of expressing mutant PABPN1 in muscle cells (Aims 1 and 2). We will exploit a PABPN1 knockout mouse to determine whether a decrease in PABPN1 is sufficient to cause muscle pathology or sensitize cells to the expression of mutant PABPN1 (Aim 2). Finally, we will identify RNAs that are altered in response to decreased functional levels of PABPN1 in muscle cells and consider key muscle functions for these putative PABPN1 targets (Aim 3). Importantly, the Specific Aims are designed to understand the muscle-specific role of PABPN1, which is critical for understanding the pathogenesis of OPMD. The knowledge gained from our studies is likely to afford new therapeutic strategies that target the appropriate molecular pathways altered in the muscles of OPMD patients.

描述（由申请人提供）：眼咽肌营养不良症（OPMD）是一种罕见的常染色体显性遗传疾病，迟发性，目前尚无治愈方法。其主要特征是眼睑下垂和吞咽困难，近端肢体肌肉有些无力。尽管广泛表达的PABPN1（一种mRNA结合蛋白）的突变导致OPMD，但关于突变型PABPN1导致肌肉特异性病理的机制仍有很多未知。在常染色体显性OPMD中，PABPN1的一个突变等位基因取代PABPN1的一个正常等位基因。因此，病理可能是由于一个正常等位基因的丢失，突变等位基因的获得或两种事件的组合。由于PABPN1似乎在RNA代谢中起着重要作用，理论上，其功能的任何损害都应该影响许多细胞和组织类型，但骨骼肌的内在特征可能使该组织更容易受到突变PABPN1的影响。事实上，我们的初步数据显示，与未受影响的组织相比，肌肉组织显示出显著较低的PABPN1蛋白水平。我们假设骨骼肌中PABPN1的较低含量可以使该组织对突变型PABPN1的有害作用敏感。该提案的总体目标是研究突变型PABPN1和野生型PABPN1功能水平降低如何影响RNA生物发生和肌发生。因此，我们将分析在肌肉细胞中表达突变体PABPN 1的后果（目的1和2）。我们将利用PABPN1敲除小鼠来确定PABPN1的减少是否足以引起肌肉病理或使细胞对突变型PABPN1的表达敏感（Aim 2）。最后，我们将鉴定在肌肉细胞中响应PABPN1功能水平降低而改变的RNA，并考虑这些假定的PABPN1靶点的关键肌肉功能（目的3）。重要的是，特定目的旨在了解PABPN1的肌肉特异性作用，这对于了解OPMD的发病机制至关重要。从我们的研究中获得的知识可能提供新的治疗策略，靶向OPMD患者肌肉中改变的适当分子途径。