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

病理生理学

• 批准号: 7418633
• 负责人: Katherine Dianne Mathews
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7418633
• 关键词: Address; Age; Behavioral; Binding; Biochemical; Biochemical Genetics; Biochemistry; Biopsy; Blood; Cardiac; Cardiomyopathies; Caregivers; Clinical; Clinical Data; Clinical assessments; Complex; Correlation Studies; Cultured Cells; Daily; Development; Disease; Disease Progression; Dystroglycan; Dystrophin; Environmental Risk Factor; Event; Extracellular Matrix; Functional disorder; Future; Gene Delivery; Gene Transfer; Genetic; Genetic Determinism; Glycoproteins; Goals; Heterogeneity; Histology; Human; Individual; Interview; Investigation; Life Style; Limb-Girdle Muscular Dystrophies; Link; Measures; Mediating; Medical History; Modeling; Molecular; Motor; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Dystrophies; Mutation; Myocardium; Pathogenesis; Pathology; Patients; Pharmacology; Phenotype; Physiological; Physiology; Proteins; Range; Recommendation; Reporting; Sarcolemma; Skeletal Muscle; Skeletal system; Skin; Steroids; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Studies; Therapy Clinical Trials; Viral; Viral Proteins; Western Blotting; Work; alpha Dystroglycan; base; clinical phenotype; cohort; experience; functional loss; glycosylation; glycosyltransferase; improved; member; mouse model; muscle strength; prednisolone; protein expression; research clinical testing; respiratory

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(LGMD2I)患者存在Fukutin相关蛋白(FKRP)突变，并呈现异常广泛的临床表型。由于这种临床变异的基础尚不完全清楚，我们提出了一个合作项目，包括患者和补充的小鼠模型研究，以评估LGMD2I的发病机制和治疗策略。我们将定义LGMD2I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估，包括标准化的骨骼肌或运动发育测试、心脏和呼吸评估以及病史回顾。这些患者还将为α-肌营养不良症患者提供肌肉活检。 糖基化分析，皮肤活检和血液突变确认，细胞培养和 未来的调查。在小鼠研究中，我们将敲除FKRP Leu276到LLE突变，这是在LGMD2I患者中发现的最常见的突变。将通过对FKRP(L2761/L2761)小鼠的行为、生化和组织学分析来评估该模型的特点。我们将验证一种假设，即成熟骨骼肌和心肌中的FKRP突变会导致FKRP表达或活性的丧失，从而削弱α-肌营养不良蛋白聚糖与细胞外基质的相互作用。我们还将评估FKRP病毒介导的基因转移在FKRP(L276I/L2761)小鼠中的治疗潜力。最后，基于初步的临床数据表明力量的改善，我们将测试类固醇治疗缓解FKRP(L276I/L2761)小鼠肌肉无力和病理的假设。这些研究将推动我们的 LGMD2I临床表型与FKRP肌病分子发病机制的认识 营养不良。此外，这项工作将使未来的治疗研究成为可能，因为：(A)患者分析可能建议用于治疗干预的协变量，(B)可能使用小鼠模型评估潜在治疗药物的生存能力，以及(C)我们特征良好的患者队列可能形成未来治疗试验的基础。