Epsilon-sarcoglycan in LGMD Type 2D

LGMD 2D 型中的 ε-肌聚糖

基本信息

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
项目类别：
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&apos -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

项目摘要

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）：父母项目的长期目标是探索上调5-核糖水平的治疗潜力，以治疗肢体束肌营养不良2D（LGMD2D）。 1-核糖基因的突变引起LGMD2D，并导致进行性肌肉纤维坏死和无力。我们发现5-核糖能够挽救1-肌酸酯缺乏症，并防止LGMD-2D小鼠模型中的肌肉营养不良。尽管表现出正常的肌肉功能，但这些“救出”小鼠由于缺乏肌膜NNOS信号传导而导致轻度运动的疲劳反应。因此，像我们的救援小鼠一样，我们发现这种特定形式的疲劳可能会在没有肌肉病理学的小鼠模型中发生，这表明缺乏肌肉症状的NNOS信号可能是人类这种疲劳形式的原因。值得注意的是，我们发现用PDE5A抑制剂的药理学治疗通过增强活性肌肉的一氧化氮信号传导来缓解这种疲劳。此外，我们发现这种治疗方法还可以提高运动耐受性，并减少营养不良小鼠锻炼诱导的肌肉水肿。这种竞争性的修订重点是探索涉及运动中涉及的途径的药理治疗策略，以防止这种形式的疲劳以及在我们的小鼠模型中防止运动引起的肌肉水肿。第一个目的假设长期的PDE5A抑制剂治疗将改善小鼠模型的日常活动。用PDE5A抑制剂长期衍生物处理的营养不良和救援小鼠模型的纵向表征将检验该假设。第二个目的假设绕过一氧化氮依赖性途径是增加运动诱导的信号传导的替代方法。分析用一氧化氮依赖性的鸟苷酸环化酶活化剂处理的小鼠模型以及可溶性鸟烯酸甲酯环化酶和PDE5A的遗传缺失将检验该假设。最终目的假设抗炎治疗将减少营养不良小鼠模型的病理，但也会增加活性并减少运动引起的肌肉水肿。分析用各种抗炎药处理的小鼠模型将检验该假设。这些实验的总体结果将有助于作为基因疗法的协同治疗，并提供对健康个体中运动诱发的疲劳和水肿的见解。公共卫生相关性：这项研究将有助于NIAMS的使命，以解决肌肉的生物医学研究，以解决运动引起的疲劳和肌肉水肿。这项拟议的研究还将为ARRA的使命做出贡献，以改善人类生活的质量，同时通过为项目提供招聘机会，并为我们的科学家提供更多的培训，以提高科学家的培训，以提高他们作为独立生物医学研究人员的销售能力，这些研究人员将开始自己的实验室。