Pathogenesis of Muscular Dystrophies

描述(由申请人提供)：我们研究的目标是(I)确定发病机制和(Ii)确定一组严重肌营养不良症的新治疗策略。我们已经发现，由促死亡蛋白Bax及其胞浆结合伙伴Ku70介导的细胞死亡的异常激活似乎是至少三种人类肌营养不良症的致病机制：先天性肌营养不良1A型(MDC1A，层粘连蛋白-α2突变)；四肢带状肌营养不良2D型(LGMD2D，α-肌聚糖突变)；以及LGMD2C(伽马-肌聚糖突变)。对于这些肌营养不良症中的每一个，发病机制中的一个关键步骤似乎是异常地增加Ku70的乙酰化，这反过来导致Bax介导的细胞死亡。我们现在建议确定这种疾病诱导的Ku70/Bax途径调节失调的机制。一组实验将确定调节Ku70功能的脱乙酰酶和乙酰转移酶机制。第二组实验将确定恢复正常的Ku70乙酰化是否会改善疾病模型的病理。这些研究将分析小鼠疾病模型和我们广泛的人类患者肌源性细胞库中的细胞。患者细胞为研究发病机制提供了一个特别有利的系统，因为我们发现，在培养的人MDC1A、LGMD2C和LGM2D患者成肌细胞中形成的肌管，而不是正常的成肌细胞，会自发发生细胞死亡。在特定目标1下，我们将确定正常和疾病肌肉细胞中Ku70脱乙酰酶和乙酰转移酶的机制。这些研究将检验我们的假设，即Ku70脱乙酰酶和/或乙酰转移酶的异常功能导致肌肉病理。在特定的目标2下，我们将确定恢复正常的Ku70乙酰化是否可以改善病理。这些研究将检验我们的假设，即恢复健康的低水平Ku70乙酰化将抑制细胞数据，并减轻疾病模型中的病理。我们的研究旨在确定多发性肌营养不良症常见的致病机制。根据我们的结果，我们希望确定可能对多种疾病有效的潜在治疗策略。

DESCRIPTION (provided by applicant): The goals of our studies are to (i) determine pathogenetic mechanisms and (ii) identify new therapeutic strategies for a group of severe muscular dystrophies. We have found that aberrant activation of cell death - mediated by the pro-death protein Bax and its cytosolic binding partner Ku70 - appears to be a pathogenetic mechanism in at least three human muscular dystrophies: Congenital Muscular Dystrophy Type 1A (MDC1A, mutations of laminin- alpha2); Limb-girdle Muscular Dystrophy Type 2D (LGMD2D, mutations of alpha-sarcoglycan); and LGMD2C (mutations of gamma-sarcoglycan). For each of these muscular dystrophies, a key step in pathogenesis appears to be aberrantly increased acetylation of Ku70, which in turn leads to induction of Bax-mediated cell death. We now propose to identify the mechanisms that underlie this disease-induced dysregulation of the Ku70/Bax pathway. One set of experiments will identify the deacetylase and acetyltransferase mechanisms that regulate Ku70 function. A second set of experiments will determine if restoring normal Ku70 acetylation will ameliorate pathology in disease models. The studies will analyze both mouse disease models and cells from our extensive library of myogenic cells from human patients. The patient cells provide a particularly favorable system to study mechanisms of pathogenesis, because we find that myotubes formed in culture from human MDC1A, LGMD2C, and LGM2D patient myoblasts, but not normal myoblasts, spontaneously undergo cell death. Under Specific Aim 1, we will identify Ku70 deacetylase and acetyltransferase mechanisms in normal and diseased muscle cells. These studies will test our hypothesis that aberrant function of Ku70 deacetylases and/or acetyltransferases causes muscle pathology. Under Specific Aim 2, we will determine if restoring normal Ku70 acetylation ameliorates pathology. These studies will test our hypothesis that restoring a healthy low level of Ku70 acetylation will inhibit cell dath and lessen pathology in disease models. Our studies are designed to identify pathogenetic mechanisms that are common to multiple muscular dystrophies. From our results, we expect to identify potential therapeutic strategies that could be effective for multiple diseases.