Nuclear membrane protein interaction in heart and muscle disease

心脏和肌肉疾病中核膜蛋白的相互作用

• 批准号: 8071234
• 负责人: Elizabeth M McNally
• 金额: $ 38.46万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071234
• 关键词: Actins; Adenine; Affect; Amino Acids; Binding; Biological Assay; Cardiac Myocytes; Cardiomyopathies; Cell Nucleus; Cells; Complex; Cultured Cells; Cytoplasm; Cytoskeleton; DNA Methylation; Data; Defect; Development; Dilated Cardiomyopathy; Dimerization; Disease; Dominant-Negative Mutation; Emery-Dreifuss Muscular Dystrophy; Epigenetic Process; Familial partial lipodystrophy; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Glutathione S-Transferase; Golgi Apparatus; Green Fluorescent Proteins; Heart; Heart Diseases; Heterochromatin; High Pressure Liquid Chromatography; Higher Order Chromatin Structure; In Vitro; Inherited; Intermediate Filament Proteins; Laboratories; Lamin Type A; Lamins; Lead; Length; Link; Lipodystrophy; MM form creatine kinase; Mechanics; Mediator of activation protein; Membrane Proteins; Messenger RNA; Methyltransferase; Modeling; Mus; Muscle Cells; Muscle Development; Muscle Fibers; Muscle Proteins; Muscular Dystrophies; Mutation; Myocardium; Myopathy; Myosin Heavy Chains; Natural regeneration; Neuromuscular Diseases; Neuromuscular Junction; Neurons; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Outer Membrane; Nuclear Pore Complex; Pattern; Positioning Attribute; Protein Binding; Proteins; RNA Splicing; Retinoblastoma; Role; Skeletal Muscle; Spectrin; Striated Muscles; System; Transmembrane Domain; Ventricular Cardiac alpha-Myosin; cell type; chromatin immunoprecipitation; in vivo; interest; lamin C; mutant; periplasm; research study; response; skeletal

DESCRIPTION (provided by applicant): Defects of the nuclear membrane have emerged as an important mediator of cardiac and neuromuscular disease. Mutations in the gene encoding the intermediate filament proteins lamins A and C occur as one of the more common forms of dominantly inherited muscle disease leading to cardiomyopathy as well as muscular dystrophy. Lamins A and C are more highly expressed in terminally differentiated cell types including cardiomyocytes, skeletal myofibers and neurons. The majority of genetic mutations associated with striated muscle disease are inherited in an autosomal dominant manner where dominant negative or haploinsufficient genetic mechanisms may occur and lead to disease. Loss of lamins A and C produces cells that have impaired mechanical nuclear function. We hypothesize that the protein composition of the nuclear membrane may be specialized in cardiomyocytes and skeletal muscle, and that protein interactions within the nuclear membrane of striated muscle cells may be perturbed in response to lamin A and C gene mutations. To this end, we have characterized nesprin-11, a smaller protein generated from the nesprin-1 locus. Nesprins are nuclear membrane- associated spectrin repeat-containing proteins. In their full length form, nesprins are giant proteins that can bind to the outer nuclear membrane where they may participate in localizing the nucleus within the cell. Nesprin-11 is a smaller product that contains six spectrin repeats and is localized at the inner nuclear membrane. Nesprin-11 mRNA and protein are both highly expressed in cardiac and skeletal muscle. Moreover, nesprin-11 directly binds to lamin A in vitro, and nesprin-11 requires lamin A or lamin C for proper localization within cells. This proposal outlines experiments to elucidate protein interactions in the striated muscle nuclear membrane and the role of these interactions in cardiac and skeletal muscle disease. RELEVENCE: Mutations in genes that encode proteins of the nuclear membrane are a common cause of cardiomyopathy that affects the electrical system of the heart and muscular dystrophy. My laboratory is interesting in determining how changing the nuclear membrane leads to muscle disease.

描述（由申请人提供）：核膜缺陷已成为心脏和神经肌肉疾病的重要介质。编码中间丝蛋白核纤层蛋白 A 和 C 的基因突变是导致心肌病和肌营养不良的显性遗传性肌肉疾病的更常见形式之一。核纤层蛋白 A 和 C 在终末分化细胞类型中表达更高，包括心肌细胞、骨骼肌纤维和神经元。与横纹肌疾病相关的大多数基因突变以常染色体显性方式遗传，其中显性失活或单倍体不足的遗传机制可能发生并导致疾病。核纤层蛋白 A 和 C 的缺失会产生机械核功能受损的细胞。我们假设核膜的蛋白质组成可能专门存在于心肌细胞和骨骼肌中，并且横纹肌细胞核膜内的蛋白质相互作用可能会因核纤层蛋白 A 和 C 基因突变而受到干扰。为此，我们对 Nesprin-11 进行了表征，这是一种由 Nesprin-1 位点产生的较小蛋白质。 Nesprin 是核膜相关的血影蛋白重复序列​​蛋白质。全长形式的 Nesprin 是一种巨大的蛋白质，可以与外核膜结合，在外核膜上它们可以参与细胞核的定位。 Nesprin-11 是一种较小的产品，包含六个血影蛋白重复序列​​，位于内核膜上。 Nesprin-11 mRNA 和蛋白质在心肌和骨骼肌中均高表达。此外，nesprin-11 在体外直接与核纤层蛋白 A 结合，并且 nesprin-11 需要核纤层蛋白 A 或核纤层蛋白 C 才能在细胞内正确定位。该提案概述了阐明横纹肌核膜中蛋白质相互作用以及这些相互作用在心脏和骨骼肌疾病中的作用的实验。相关性：编码核膜蛋白质的基因突变是影响心脏电系统和肌营养不良症的心肌病的常见原因。我的实验室致力于确定核膜的变化如何导致肌肉疾病。

项目成果

Nesprins, but not sun proteins, switch isoforms at the nuclear envelope during muscle development.

• DOI: 10.1002/dvdy.22229
• 发表时间: 2010-03
• 期刊: DEVELOPMENTAL DYNAMICS
• 影响因子: 2.5
• 作者: Randles, K. Natalie;Lam, Le Thanh;Sewry, Caroline A.;Puckelwartz, Megan;Furling, Denis;Wehnert, Manfred;McNally, Elizabeth M.;Morris, Glenn E.
• 通讯作者: Morris, Glenn E.