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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

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.

项目总结/文摘