Pathogenesis of the Neuromuscular Synapse in Pompe Disease

描述（由申请人提供）：本K 01奖申请的目标是提高候选人的学术和科学发展，博士。在巴里伯恩博士、露西娅·诺特佩克博士、大卫富勒博士和斯科特·里夫纳博士的指导下，候选人将研究呼吸功能不全与庞贝氏症中轴突、神经肌肉接头和骨骼肌的病理适应之间的联系。庞贝氏症是一种进行性疾病，其中缺乏或不存在酸性α-葡糖苷酶（GAA），导致严重的肌无力和经常因呼吸肌衰竭而过早死亡。唯一FDA批准的庞贝氏症治疗是酶替代疗法（ERT）。虽然ERT改善了结果，但患者仍然患有肺泡通气不足，最终需要辅助治疗。我们的长期目标是确定导致该患者人群呼吸肌衰竭的机制。为了使庞贝氏症患者的护理管理发生重大转变，我们开发了一种系统的方法来确定直接影响骨骼肌激活和调节的关键机制。这将使用庞贝氏症的转基因模型和重组腺相关病毒（AAV）载体来实现。最近，我们观察到突然的形态学变化发生在神经肌肉接头，可能是阐明呼吸功能障碍背后的主要机制的关键。该申请将重点关注神经肌肉接头（NMJ）的作用和潜在的治疗方法，以恢复庞贝氏症中骨骼肌的激活和功能。我们将通过以下方式实现这一目标：1）确定CNS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产生是否主要由于庞贝氏症小鼠中神经元和神经肌肉接头的病理适应而受损，和3）直接比较现有的和新的治疗方法，以减少关键组织中的糖原沉积，并最终恢复呼吸和运动功能，庞贝氏症患者。在这方面，具体目标旨在解决几个潜在的机制，以提高我们对庞贝氏症发病机制的整体理解，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。

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.