Muscle-Specific Basis of OPMD

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晚发性疾病，目前尚无治愈方法。其主要特征是眼睑下垂和吞咽困难，并伴有肢体近端肌肉无力。虽然普遍表达的PABPN1（一种mRNA结合蛋白）的突变可导致OPMD，但关于突变的PABPN1导致肌肉特异性病理的机制仍不清楚。在常染色体显性OPMD中，一个突变的PABPN1等位基因取代了一个正常的PABPN1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者的结合。由于PABPN1似乎在RNA代谢中起着至关重要的作用，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，肌肉组织中PABPN1蛋白的水平明显较低。我们推测，骨骼肌中较低的PABPN1含量可能使该组织对突变型PABPN1的有害作用敏感。本研究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生物发生和肌肉发生。因此，我们将分析在肌肉细胞中表达突变PABPN1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PABPN1的表达敏感（目的2）。最后，我们将确定肌肉细胞中由于PABPN1功能水平下降而发生改变的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，Specific Aims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针对OPMD患者肌肉中改变的适当分子途径的新治疗策略。

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.