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Nesprin 1 and 2 in cardiac structure, function, and disease

Nesprin 1 和 2 在心脏结构、功能和疾病中的作用

基本信息

批准号：
8207842
负责人：
Ju Chen
金额：
$ 38.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207842
关键词：
Ablation Address Adult Age-Months Alleles Animals Binding Biological Process Body Weight C-terminal Cardiac Cardiac Myocytes Cardiomyopathies Cell Nucleus Cells Data Defect Desmin Dilated Cardiomyopathy Disease Emery-Dreifuss Muscular Dystrophy Exercise Family Gene Deletion Goals Heart Intermediate Filaments Investigation Knock-out Knockout Mice Lamin Type A Membrane Membrane Proteins Microfilaments Molecular Mus Muscle Muscle Fibers Muscle function Mutant Strains Mice Mutation Myocardium N-terminal Nuclear Nuclear Envelope Nuclear Outer Membrane Nuclear Structure Organism Pathogenesis Peptides Perinatal Phenotype Physiological Positioning Attribute Protamines Proteins Relative (related person)Role Sampling Shapes Skeletal Muscle Spectrin Stretching Structure Survivors Synapses Tamoxifen Testing Up-Regulation calponin improved insight loss of function member muscular structure mutant novel papillary muscle research study response retinal rods

项目摘要

Summary Mutations in the outer nuclear membrane proteins Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes, including cardiomyopathy and dilated cardiomyopathy (DCM). Nesprins belong to a newly discovered family of spectrin-repeat proteins, composed of four members. Nesprin 1 and 2 are believed to anchor nuclei to actin filaments, and are ubiquitously expressed. To investigate functions of Nesprin 1 and 2, we have generated floxed and global knockout mice of both Nesprin 1 and 2. Our studies reveal that Nesprin 2 global knockout mice are viable and have no obvious basal phenotype, whereas over half of Nesprin 1 global knockout (Nesprin 1-/-) mice die perinatally. Remaining Nesprin 1-/- survivors have reduced body weight before three months of age and compromised exercise capacity. Consistent with data from others, we have found 100% perinatal lethality in double knockout mice for Nesprin 1 and 2. Histological analyses of skeletal muscle in Nesprin 1-/- mice and Nesprin 1 and 2 double knockout mice revealed abnormal positioning of non-synaptic nuclei and the disappearance of clusters of synaptic nuclei. We also observed that Nesprin 1-/- mice display abnormal shape and positioning of cardiomyocyte nuclei. In addition, we observed upregulation of protein levels of SUN1, a Nesprin 1 binding partner and an inner nuclear membrane protein, in Nesprin 1-/- heart samples. This 5 year proposal is to investigate the role of Nesprin 1 and 2 in cardiac nuclear position, nuclear membrane structure, and cardiac function by analysis of mutant mice and cells derived from them. Our unique ability to genetically ablate Nesprins in mouse cardiomyocytes, combined with the ability to test molecular and physiological functions in the whole animal, isolated papillary muscles, and cultured cardiomyocytes, will provide novel information as to the function of Nesprins in cardiac structure, function and disease.

总结