Pathogenesis of the Neuromuscular Synapse in Pompe Disease

庞贝病神经肌肉突触的发病机制

基本信息

批准号：
9130100
负责人：
Darin J Falk
金额：
$ 11.1万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130100
关键词：
Acetylcholinesterase Inhibitors Acids Address Affect Age Alveolar Animal Experiments Animals Attenuated Automobile Driving Axon Blood - brain barrier anatomy Caring Cellular Morphology Cessation of life Complement Cre-LoxP Defect Dependovirus Deposition Development Disease Elements Environmental air flow Enzymes FDA approved Failure Functional disorder Funding Generations Genes Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Goals Health Human In Situ Knock-out Laboratories Lead Link LoxP-flanked allele MM form creatine kinase Magnetic Resonance Imaging Measurement Measures Mediating Mentored Research Scientist Development Award Metabolism Modeling Motor Neurons Mus Muscle Weakness Muscle function Nerve Neuraxis Neuromuscular Diseases Neuromuscular Junction Neurons Outcome Measure Pathogenesis Pathologic Pathology Patients Production Property Rattus Recombinant adeno-associated virus (rAAV)Recombinants Regulation Respiratory Diaphragm Respiratory Insufficiency Respiratory Muscles Rodent Model Role Skeletal Muscle Synapses Synapsins Testing Therapeutic Therapeutic Intervention Time Tissues Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Treatment Efficacy adeno-associated viral vector base career design enzyme replacement therapy glucosidase improved improved outcome in vivo mouse model muscular system neuromuscular next generation novel novel therapeutics patient population premature promoter research study respiratory restoration tool vector zinc finger nuclease

项目摘要

DESCRIPTION (provided by applicant): The goal of this K01 Award application is to enhance the academic and scientific development of the Candidate, Dr. Falk. Under the guidance of Drs. Barry Byrne, Lucia Notterpek, David Fuller, and Scott Rivkees, the Candidate will pursue the link between respiratory insufficiency and the pathologic adaptations of axons, the neuromuscular junction, and skeletal muscle in Pompe disease. Pompe disease is a progressive disorder in which the deficiency or absence of acid alpha-glucosidase (GAA), leads to severe muscle weakness and often-premature death from respiratory muscle failure. The only FDA approved treatment for Pompe disease is enzyme replacement therapy (ERT). While ERT has improved outcomes, patients still suffer from inadequate alveolar ventilation and eventually require ventilatory assistance. Our long-term goal is to determine the mechanisms, which lead to respiratory muscle failure in this patient population. To make a significant shift in the management of care for Pompe patients, we have developed a systematic approach to identify the key mechanisms, which directly impact skeletal muscle activation and regulation. This will be accomplished using transgenic models of Pompe disease and recombinant adeno-associated virus (AAV) vectors. Recently, we observed that abrupt morphologic changes occur at the neuromuscular junction and may be key in elucidating the primary mechanism behind respiratory dysfunction. This application will focus on the role of the neuromuscular junction (NMJ) and potential therapies to restore skeletal muscle activation and function in Pompe disease. We will accomplish this by: 1) determining the negative impact at the neuromuscular junction as a result of CNS and skeletal muscle glycogen accumulation, 2) we will determine if skeletal muscle force production is primarily impaired due to pathologic adaptations in neurons and the neuromuscular junction in Pompe mice, and 3) directly compare existing and novel therapies to reduce glycogen deposition in critical tissues and ultimately restore respiratory and locomotor function in Pompe patients. In this regard, the specific aims seek to address several potential mechanisms for improving our overall understanding of the pathogenesis of Pompe disease and provide a platform for future research and funding to initiate an independent career centered on neuromuscular disease.

描述（由申请人提供）：本次 K01 奖申请的目标是促进候选人 Falk 博士的学术和科学发展。在博士的指导下。候选人 Barry Byrne、Lucia Notterpek、David Fuller 和 Scott Rivkees 将研究庞贝病中呼吸功能不全与轴突、神经肌肉接头和骨骼肌的病理适应之间的联系。庞贝病是一种进行性疾病，其中酸性 α-葡萄糖苷酶 (GAA) 的缺乏或缺乏会导致严重的肌肉无力，并常常因呼吸肌衰竭而过早死亡。 FDA 批准的唯一治疗庞贝病的疗法是酶替代疗法 (ERT)。虽然 ERT 改善了结果，但患者仍然存在肺泡通气不足的问题，最终需要通气辅助。我们的长期目标是确定导致该患者群体呼吸肌衰竭的机制。为了在庞贝氏症患者的护理管理方面做出重大转变，我们开发了一种系统方法来确定直接影响骨骼肌激活和调节的关键机制。这将使用庞贝病转基因模型和重组腺相关病毒（AAV）载体来完成。最近，我们观察到神经肌肉接头处发生突然的形态变化，这可能是阐明呼吸功能障碍背后的主要机制的关键。该应用将重点关注庞贝病中神经肌肉接头 (NMJ) 的作用以及恢复骨骼肌激活和功能的潜在疗法。我们将通过以下方式实现这一目标：1）确定中枢神经系统和骨骼肌糖原积累对神经肌肉接头的负面影响，2）我们将确定骨骼肌力量的产生是否主要由于神经元和神经肌肉接头的病理适应而受损3）直接比较现有疗法和新疗法，以减少关键组织中的糖原沉积，并最终恢复庞贝氏症患者的呼吸和运动功能。在这方面，具体目标旨在解决几种潜在的机制，以提高我们对庞贝病发病机制的整体了解，并为未来的研究和资助提供一个平台，以启动以神经肌肉疾病为中心的独立职业生涯。