Pathogenesis of Muscular Dystrophies

肌营养不良症的发病机制

• 批准号: 8603664
• 负责人: Jeffrey Boone Miller
• 金额: $ 17.84万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603664
• 关键词: Pathogenesis; Muscular; Dystrophies

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. Our early studies suggest that SIRT1 and SIRT3 are two deacetylases that interact with Ku70 or the Ku70/Bax complex in muscle. 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 death 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.

描述（由申请人提供）：我们的研究目标是（i）确定致病机制，（ii）为一组严重的肌肉发育不全确定新的治疗策略。我们已经发现，在至少三个人类的三种人肌营养不良症中，在促甲蛋白Bax及其胞质结合伴侣KU70介导的细胞死亡的异常激活似乎是一种致病机制：先天性肌肉营养不良1A型（MDC1A）（MDC1A，MDC1A，MDC1A，MDC1A，Laminin -alpha2的突变）；肢体束肌营养不良型2D（LGMD2D，α-Sarcoglycan的突变）；和lgmd2c（伽马 - 萨尔科利果糖的突变）。对于这些肌肉营养不良的每一个，发病机理的关键步骤似乎异常增加了Ku70的乙酰化，这又导致了Bax介导的细胞死亡。现在，我们建议确定这种疾病诱导的KU70/BAX途径失调的机制。一组实验将确定调节KU70功能的脱乙酰基酶和乙酰转移酶机制。我们的早期研究表明，SIRT1和SIRT3是两个与Ku70相互作用或肌肉中KU70/BAX复合物相互作用的脱乙酰基酶。第二组实验将确定在疾病模型中恢复正常的KU70乙酰化是否会改善病理。这些研究将分析来自人类患者的大量肌原细胞库的小鼠疾病模型和细胞。患者细胞为研究发病机理提供了一个特别有利的系统，因为我们发现在人MDC1A，LGMD2C和LGM2D患者肌细胞中形成的肌管中形成的肌管，但不是正常的成肌细胞，但并非正常的肌细胞，自发地发生细胞死亡。在特定的目标1下，我们将在正常肌肉细胞和患病的肌肉细胞中鉴定KU70脱乙酰基酶和乙酰基转移酶机制。这些研究将检验我们的假设，即KU70脱乙酰基酶和/或乙酰基转移酶的异常功能会导致肌肉病理学。在特定目标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乙酰化将抑制细胞死亡并减少疾病模型的病理学。我们的研究旨在鉴定多发性肌营养不良的致病机制。从我们的结果来看，我们希望确定可能对多种疾病有效的潜在治疗策略。