Pathogenesis of the Neuromuscular Synapse in Pompe Disease

描述(申请人提供)：本次K01奖项申请的目的是促进候选人福尔克博士的学术和科学发展。在Barry Byrne博士、Lucia Notterpek博士、David Fuller博士和Scott Rivkees博士的指导下，候选人将探索呼吸功能不全与庞培病中轴突、神经肌肉接头和骨骼肌的病理适应之间的联系。Pompe病是一种进行性疾病，在这种疾病中，酸性α-葡萄糖苷酶(GAA)的缺乏或缺失会导致严重的肌肉无力和经常因呼吸肌衰竭而过早死亡。FDA批准的唯一治疗庞贝病的方法是酶替代疗法(ERT)。虽然ERT的结果有所改善，但患者仍然存在肺泡通气量不足的问题，最终需要机械辅助。我们的长期目标是确定导致这一患者群体呼吸肌衰竭的机制。为了使庞培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Pompe病的转基因模型和重组腺相关病毒(AAV)载体来实现。最近，我们观察到在神经肌肉连接处发生了突然的形态变化，这可能是阐明呼吸功能障碍的主要机制的关键。这项应用将集中在神经肌肉接头(NMJ)的作用和潜在的治疗方法，以恢复骨骼肌的激活和功能的庞培病。我们将通过以下方式完成这项工作：1)确定中枢神经系统和骨骼肌糖原积聚对神经肌肉接头的负面影响；2)我们将确定骨骼肌力的产生是否主要是由于神经元和神经肌肉接头的病理适应性受损；以及3)我们将直接比较现有和创新的治疗方法，以减少关键组织中糖原的沉积，并最终恢复庞培患者的呼吸和运动功能。在这方面，具体目标寻求解决几个潜在的机制，以提高我们对庞贝病发病机制的整体理解，并为未来的研究和资金提供平台，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.