Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy

项目总结/摘要 脊髓性肌萎缩症（SMA）是婴儿最常见的遗传性死亡原因之一 和年幼的孩子。SMA是由运动神经元1的存活缺失或突变引起的 （SMN 1）基因，导致普遍表达的SMN蛋白的缺陷。最近 批准的疗法增加SMN蛋白并部分纠正运动神经元损失， 肌肉退化是这种疾病的标志。然而，SMA患者需要关键的 由于心肺损伤和机会性感染而需要护理。这一观察， 加上广泛的新的初步数据，使我们假设，SMN缺乏症， 损害心肌细胞功能，代表了以前未被认识到的贡献， 心血管系统对SMA疾病病理的影响。为了验证这个假设，我们将使用primary 来自该疾病的小鼠模型的心肌细胞和来自 SMA患者诱导多能干细胞（iPSC），以确定SMN的后果 缺乏收缩功能（目的1），导致受损的分子机制， 收缩（目的2），并表征SMN恢复后的心血管缺陷， SMA小鼠（Aim 3）。使用我们独特方法的初步结果已经提供了 对SMA疾病过程的一个知之甚少的方面的新机制见解， 在设计临床治疗策略时可能至关重要。

PROJECT SUMMARY/ABSTRACT Spinal muscular atrophy (SMA) is one of the most common inherited cause of death in infants and young children. SMA is caused by the deletion or mutation in the survival of motor neuron 1 (SMN1) gene, leading to a deficiency of the ubiquitously expressed SMN protein. Recent approved therapies increase SMN protein and partially correct the motor neuron loss and muscle degeneration that are hallmarks of the disease. However, SMA patients require critical care as a result of cardiopulmonary impairment and opportunistic infections. This observation, together with extensive new preliminary data, leads us to hypothesize that SMN-deficiency impairs cardiomyocyte function, representing a previously unrecognized contribution of the cardiovascular system on SMA disease pathology. To test this hypothesis, we will use primary cardiomyocytes from a mouse model of the disease and human cardiomyocytes derived from SMA patient induced pluripotent stem cells (iPSC) to determine the consequences of SMN deficiency on contractile function (Aim 1), the molecular mechanisms leading to impaired contraction (Aim 2), and characterize cardiovascular deficiencies following SMN restoration in SMA mice (Aim 3). The preliminary results using our unique approach are already providing novel mechanistic insight into a poorly understood aspect of the SMA disease process which could be critically important when designing strategies to manage the disease clinically.