Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy

项目摘要/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。运动神经元存活中的缺失或突变引起的SMA (SMN1)基因，导致普遍表达的SMN蛋白缺失。近期 批准的治疗方法增加SMN蛋白并部分纠正运动神经元丢失和 肌肉退化是这种疾病的特征。然而，SMA患者需要危重的 由于心肺功能受损和机会性感染而导致的护理。这一观察结果， 结合大量新的初步数据，我们提出了SMN缺乏的假设 损害心肌细胞功能，这是以前未被认识到的 心血管系统对SMA病的病理影响。为了验证这一假设，我们将使用主 来自疾病的小鼠模型的心肌细胞和来源于 SMA患者诱导多能干细胞(IPSC)以确定SMN的后果 收缩功能缺陷(目标1)，导致功能受损的分子机制 收缩(目标2)，并表征SMN修复后的心血管缺陷 SMA小鼠(目标3)。使用我们独特的方法的初步结果已经提供了 对SMA疾病过程中一个鲜为人知的方面的新的机械洞察力 在设计临床管理疾病的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.