Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy

脊髓性肌萎缩症中的钙失调和细胞功能

• 批准号: 10623012
• 负责人: Barrington G Burnett
• 金额: $ 2.86万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10623012
• 关键词: ATP2A2; Affect; Age; Alternative Splicing; Autonomic Dysfunction; Biology; Calcium; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiology; Cardiopulmonary; Cardiovascular system; Caring; Cause of Death; Cell physiology; Cells; Child; Clinical; Congenital Heart Defects; Coupling; Critical Care; Data; Defect; Development; Disease; Disease Management; Disease model; Functional disorder; Gene Expression; Genes; Genetic; Goals; Heart; Heart Abnormalities; Homeostasis; Hospitalization; Impairment; Infant; Infant Mortality; Inherited; Kinetics; Live Birth; Longevity; Messenger RNA; Molecular; Morphology; Motor; Motor Neurons; Mus; Muscle; Mutation; Myocardium; Neuraxis; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Opportunistic Infections; Outcome; Pathologic; Pathology; Patients; Performance; Process; Pulmonary Heart Disease; RNA Splicing; Regulator Genes; Relaxation; Reporting; Resolution; Role; SMN deficiency; SMN protein (spinal muscular atrophy); SMN1 gene; Spinal Muscular Atrophy; Spliceosomes; Testing; Therapeutic; Time; Tissues; United States; Ursidae Family; axion; base; care systems; deep sequencing; design; experience; gene therapy; heart function; human model; imaging approach; improved outcome; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; infant death; insight; interdisciplinary approach; motor function improvement; mouse model; muscle degeneration; neuromuscular; neuron loss; novel; restoration; skeletal muscle wasting; success

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.

项目概要/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 和幼儿。 SMA是由运动神经元1的存活缺失或突变引起的 (SMN1) 基因，导致普遍表达的 SMN 蛋白缺乏。最近的 批准的疗法可增加 SMN 蛋白并部分纠正运动神经元损失和 肌肉退化是该疾病的标志。然而，SMA 患者需要关键 心肺损伤和机会性感染引起的护理。这一观察， 结合大量新的初步数据，我们推测 SMN 缺陷 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 疾病病理学的影响。为了检验这个假设，我们将使用初级 来自该疾病小鼠模型的心肌细胞和源自该疾病的人类心肌细胞 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），导致收缩功能受损的分子机制 收缩（目标 2），并表征 SMN 恢复后的心血管缺陷 SMA 小鼠（目标 3）。使用我们独特方法的初步结果已经提供 对 SMA 疾病过程中一个鲜为人知的方面提出了新的机制见解 在设计临床治疗疾病的策略时可能至关重要。