Pathogenesis of Muscular Dystrophies

描述（由申请人提供）：我们研究的目的是（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。我们发现，细胞死亡的异常激活-由促死亡蛋白Bax及其胞质结合伴侣Ku 70介导-似乎是至少三种人类肌营养不良症的发病机制：先天性肌营养不良1A型（MDC 1A，层粘连蛋白-α 2突变）;肢带型肌营养不良2D型（LGMD 2D，α-肌聚糖的突变）;和LGMD 2C（γ-肌聚糖的突变）。对于这些肌营养不良症中的每一种，发病机制中的关键步骤似乎是Ku 70的乙酰化异常增加，这反过来又导致诱导Ku-介导的细胞死亡。我们现在建议确定这种疾病引起的Ku 70/Bax通路失调的机制。一组实验将确定调节Ku 70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Ku 70乙酰化是否会改善疾病模型中的病理学。这些研究将分析小鼠疾病模型和来自我们广泛的人类患者肌源性细胞库的细胞。患者细胞提供了一个特别有利的系统来研究发病机制，因为我们发现，在培养中形成的人MDC 1A，LGMD 2C和LGM 2D患者成肌细胞，但不是正常的成肌细胞，肌管自发地经历细胞死亡。在特定目标1下，我们将确定Ku 70脱乙酰酶和乙酰转移酶在正常和患病肌肉细胞中的机制。这些研究将验证我们的假设，即Ku 70脱乙酰酶和/或乙酰转移酶的异常功能导致肌肉病理学。在特定目标2下，我们将确定恢复正常Ku 70乙酰化是否改善病理。这些研究将验证我们的假设，即恢复健康的低水平Ku 70乙酰化将抑制细胞dath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发病机制。从我们的研究结果中，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.