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

基本信息

批准号：
10331028
负责人：
Barrington G Burnett
金额：
$ 38.12万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-20 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331028
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

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

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项目摘要

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.

项目摘要/摘要脊柱肌肉萎缩（SMA）是婴儿最常见的遗传死亡原因之一和年幼的孩子。 SMA是由运动神经元生存中的缺失或突变引起的（SMN1）基因，导致普遍表达的SMN蛋白的缺乏。最近的批准的疗法会增加SMN蛋白质，并部分纠正运动神经元丧失和肌肉变性是该疾病的标志。但是，SMA患者需要关键由于心肺损伤和机会性感染而导致的护理。这个观察结果，加上广泛的新初步数据，导致我们假设SMN缺乏效率损害心肌细胞功能，代表先前未认可的贡献 SMA病病理学的心血管系统。为了检验这一假设，我们将使用主要来自疾病的小鼠模型和人类心肌细胞的心肌细胞 SMA患者诱导多能干细胞（IPSC）确定SMN的后果收缩功能缺乏（AIM 1），这是导致受损的分子机制收缩（AIM 2），并在SMN修复后表征心血管缺陷 SMA小鼠（AIM 3）。使用我们独特的方法的初步结果已经在提供对SMA疾病过程中了解不足的方面的新机械洞察力的洞察力在设计临床管理疾病的策略时，可能至关重要。