Pathophysiology & therapeutics: Fukutin related protein(FKRP) muscular dystrophy

病理生理学

• 批准号: 6960788
• 负责人: Katherine Dianne Mathews
• 金额: $ 25.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960788
• 关键词: biotechnology; cooperative study; disease /disorder model; gene mutation; gene therapy; genetic polymorphism; genetically modified animals; glycosylation; hormone therapy; human subject; laboratory mouse; molecular pathology; muscular dystrophy; musculoskeletal disorder therapy; myocardium; pathologic process; patient oriented research; prednisolone; striated muscles; therapy design /development

Limb girdle muscular dystrophy 21 (LGMD2I) patients have mutations in fukutin- related protein (FKRP) and present with an unusually wide spectrum of clinical phenotypes. Since the basis for such clinical variability is not yet fully understood, we propose a collaborative project involving patient and complimentary mouse model studies to evaluate the pathogenesis and treatment strategies for LGMD2I. We will define the clinical, molecular and biochemical profiles of patients with LGMD2I to better understand the variability in the clinical presentation of this disorder. Patients with FKRP mutations will undergo annual clinical evaluation, including standardized skeletal muscle or motor development testing, cardiac and respiratory assessment and review of medical history. These patients will also provide a muscle biopsy for alpha-dystroglycan glycosylation analysis, and skin biopsy and blood for mutation confirmation, cell culture and future investigations. In mouse studies we will knockin the FKRP Leu276 to lle mutation, the most common mutation identified in LGMD2I patients. The features of this model will be assessed by behavioral, biochemical and histological analysis of FKRP(L2761/L2761) mice. We will test the hypothesis that the FKRP mutation in mature skeletal and cardiac muscle leads to loss of FKRP expression or activity and, consequently, impaired alpha-dystroglycan interaction with the extracellular matrix. We will also assess the therapeutic potential of FKRP viral-mediated gene transfer in FKRP(L276I/L2761) mice. Finally, based on initial clinical data suggesting an improvement in strength, we will test the hypothesis that steroid treatment alleviates muscle weakness and pathology in FKRP(L276I/L2761) mice. These studies will advance our understanding of LGMD2I clinical phenotypes and the molecular pathogenesis of FKRP muscular dystrophy. Furthermore, this work will enable future therapeutic studies as (a) patient analysis may suggest covariates for therapeutic intervention, (b) potential therapeutic agents may be assessed for viability using the mouse model, and (c) our well-characterized cohort of patients may form the basis for future therapeutic trials.

肢带型肌营养不良症21（LGMD 2 I）患者在FKRP相关蛋白（FKRP）中具有突变，并且呈现出异常广谱的临床表型。由于这种临床变异性的基础尚未完全了解，我们提出了一个合作项目，涉及患者和免费的小鼠模型研究，以评估LGMD 2 I的发病机制和治疗策略。我们将确定LGMD 2 I患者的临床、分子和生化特征，以更好地了解这种疾病临床表现的变异性。FKRP突变患者将接受年度临床评价，包括标准化骨骼肌或运动发育测试、心脏和呼吸评估以及病史审查。这些患者还将提供α-肌营养不良蛋白聚糖的肌肉活检 糖基化分析，皮肤活检和血液用于突变确认，细胞培养和 未来的调查。在小鼠研究中，我们将敲入FKRP Leu 276至Ile突变，这是在LGMD 2 I患者中鉴定的最常见突变。将通过FKRP（L2761/L2761）小鼠的行为、生化和组织学分析评估该模型的特征。我们将检验以下假设：成熟骨骼肌和心肌中的FKRP突变导致FKRP表达或活性丧失，从而导致α-肌营养不良蛋白聚糖与细胞外基质的相互作用受损。我们还将评估FKRP病毒介导的基因转移在FKRP（L276 I/L2761）小鼠中的治疗潜力。最后，基于表明力量改善的初始临床数据，我们将检验类固醇治疗加重FKRP（L276 I/L2761）小鼠的肌无力和病理的假设。这些研究将推动我们的 了解LGMD 2 I临床表型和FKRP肌肉的分子发病机制 营养不良此外，这项工作将使未来的治疗研究，因为（a）患者分析可能会建议治疗干预的协变量，（B）潜在的治疗剂可以使用小鼠模型评估生存能力，和（c）我们的良好表征的患者队列可能会形成未来治疗试验的基础。