Epsilon-sarcoglycan in LGMD Type 2D

LGMD 2D 型中的 ε-肌聚糖

• 批准号: 7836793
• 负责人: KEVIN P. CAMPBELL
• 金额: $ 48.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2010-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7836793
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Alternative Therapies; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Articular Range of Motion; Biology; Biomedical Research; Blood; Blood flow; Bypass; Cyclic GMP; Disease; Edema; Exercise; Exercise Tolerance; Faculty; Fatigue; Feedback; Funding; GLUT4 gene; Genes; Genetic; Goals; Grant; Guanylate Cyclase; Human; Human Resources; Individual; Inflammation; Laboratories; Letters; Life; Limb-Girdle Muscular Dystrophies; Long-Term Effects; Longitudinal Studies; Manuscripts; Massage; Membrane; Mission; Moderate Exercise; Molecular; Mus; Muscle; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Dystrophies; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nature; Necrosis; Neuromuscular Diseases; Nitric Oxide; Nitric Oxide Pathway; Pathology; Pathway interactions; Patients; Pharmacological Treatment; Phosphodiesterase Inhibitors; Phosphorylation; Play; Publications; Rattus; Research; Research Personnel; Research Proposals; Sarcoglycans; Sarcolemma; Scientist; Seminal; Signal Transduction; Soluble Guanylate Cyclase; Swelling; Testing; Therapeutic; Training; Writing; base; epsilon Sarcoglycan; experience; gene therapy; glucose uptake; improved; inhibitor/antagonist; insight; mouse model; muscular dystrophy mouse model; parent grant; parent project; phosphoric diester hydrolase; prevent; public health relevance; public health research; research study; response; treatment strategy

DESCRIPTION (provided by applicant): The parent project long-term goal is to explore the therapeutic potential of up-regulating 5-sarcoglycan levels for the treatment of limb-girdle muscular dystrophy type 2D (LGMD2D). Mutations in the 1-sarcoglycan gene cause LGMD2D, and leads to progressive muscle fiber necrosis and weakness. We found that 5-sarcoglycan is able to rescue 1- sarcoglycan deficiency and prevent the muscular dystrophy in a mouse model for LGMD-2D. Despite displaying normal muscle function, these "rescued" mice experienced an exaggerated fatigue response to mild exercise due to deficient sarcolemmal nNOS signaling. Thus, like our rescue mouse, we found that this specific form of fatigue can occur in mouse models that do not have muscle pathology suggesting that deficient sarcolemmal nNOS signaling could be the cause of this form of fatigue in humans that do not have a somatic disease. Significantly, we found that pharmacological treatment with PDE5A inhibitors relieves this form of fatigue by enhancing the nitric oxide signaling from active muscle. In addition, we found that this treatment also improves exercise tolerance and reduces exercised-induced muscle edema in our dystrophic mice. This Competitive Revision focuses on exploring pharmacological treatment strategies encompassing pathways involved in exercise to prevent this form of fatigue as well as prevent exercise-induced muscle edema in our mouse models. The first aim hypothesizes that long-term PDE5A inhibitor treatment will improve the daily activity of our mouse models. Longitudinal characterization of dystrophic and rescue mouse models treated with long-term derivatives of PDE5A inhibitors will test this hypothesis. The second aim hypothesizes that bypassing the nitric oxide dependent pathway is an alternative to increasing exercise-induced signaling. Analysis of mouse models treated with nitric oxide-independent guanylate cyclase activators as well as genetic deletion of soluble guanylate cyclase and PDE5A will test this hypothesis. The final aim hypothesizes that anti-inflammatory treatment will decrease pathology in dystrophic mouse models but also increase activity and reduce exercise-induced muscle edema. Analysis of mouse models treated with various anti-inflammatories will test this hypothesis. The overall results of these experiments will help develop as a synergistic treatment with gene therapy as well as provide insights into exercise-induced fatigue and edema in healthy individuals. PUBLIC HEALTH RELEVANCE: This research will contribute to the mission of NIAMS for biomedical research affecting muscles in terms of addressing exercise-induced fatigue and muscle edema. This proposed research will also contribute to the mission of the ARRA in improving the quality of human life while stimulating the economy by providing hiring opportunities for the project as well as providing increased training for our scientists to improve their marketability as independent biomedical researchers who will start their own laboratories.

描述（由申请人提供）：母项目的长期目标是探索上调 5-肌聚糖水平治疗 2D 型肢带型肌营养不良症 (LGMD2D) 的治疗潜力。 1-肌聚糖基因突变会导致 LGMD2D，并导致进行性肌纤维坏死和无力。我们发现 5-肌聚糖能够挽救 LGMD-2D 小鼠模型中的 1-肌聚糖缺陷并预防肌营养不良症。尽管表现出正常的肌肉功能，但由于肌膜 nNOS 信号传导缺陷，这些“获救”的小鼠对轻度运动产生了过度的疲劳反应。因此，与我们的救援小鼠一样，我们发现这种特定形式的疲劳可能发生在没有肌肉病理学的小鼠模型中，这表明肌膜 nNOS 信号传导缺陷可能是没有躯体疾病的人类出现这种形式疲劳的原因。值得注意的是，我们发现 PDE5A 抑制剂的药物治疗可以通过增强活跃肌肉的一氧化氮信号来缓解这种形式的疲劳。此外，我们发现这种治疗还可以提高营养不良小鼠的运动耐量并减少运动引起的肌肉水肿。本次竞争性修订的重点是探索包含运动相关途径的药物治疗策略，以防止这种形式的疲劳，并在我们的小鼠模型中预防运动引起的肌肉水肿。第一个目标假设长期 PDE5A 抑制剂治疗将改善小鼠模型的日常活动。用 PDE5A 抑制剂长期衍生物治疗的营养不良和救援小鼠模型的纵向特征将检验这一假设。第二个目标假设绕过一氧化氮依赖性途径是增加运动诱发信号传导的替代方案。对用不依赖一氧化氮的鸟苷酸环化酶激活剂以及可溶性鸟苷酸环化酶和 PDE5A 基因删除的小鼠模型进行的分析将检验这一假设。最终目标假设抗炎治疗将减少营养不良小鼠模型的病理，同时增加活动并减少运动引起的肌肉水肿。对用各种抗炎药治疗的小鼠模型的分析将检验这一假设。这些实验的总体结果将有助于开发与基因疗法的协同治疗方法，并为健康个体运动引起的疲劳和水肿提供见解。 公共健康相关性：这项研究将有助于 NIAMS 的使命，即影响肌肉的生物医学研究，解决运动引起的疲劳和肌肉水肿问题。这项拟议的研究还将有助于实现 ARRA 的使命，即通过为该项目提供招聘机会，同时刺激经济，提高人类生活质量，并为我们的科学家提供更多的培训，以提高他们作为独立生物医学研究人员的市场竞争力，并建立自己的实验室。