Roles of Cypher in Cardiac Muscle

Cypher 在心肌中的作用

• 批准号: 7884370
• 负责人: Ju Chen
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884370
• 关键词: Actinin; Adult; Affect; Affinity; Binding; Biochemical; Biological Process; Birth; Cardiac; Collaborations; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Dilated Cardiomyopathy; Doctor of Philosophy; Exons; Failure; Family Study; Goals; Heart; Human; In Vitro; Japan; Japanese Population; Knockout Mice; LIM Domain; LIM Domain Protein; Left; Left Ventricular Dysfunction; Link; Mediating; Modeling; Molecular; Mus; Muscle function; Mutation; Myocardium; Myopathy; N-terminal; Patients; Phenotype; Physiological; Play; Process; Protein Binding; Protein Isoforms; Protein Kinase C; Proteins; RNA Splicing; Role; Sarcomeres; Siblings; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skeletal Muscle; Striated Muscles; Structure; Symptoms; Tamoxifen; Testing; Texas; Variant; Ventricular; Yeasts; base; falls; improved; insight; mouse model; muscular structure; mutant; nebulette; proband; skeletal; yeast two hybrid system

DESCRIPTION (provided by applicant): The aim of this five-year proposal is to test the hypothesis that Cypher is a critical linker protein, which serves to mediate structural integrity and signaling pathways at the Z-line via its interactions with a-actinin 2, PKC, PKA, and potentially other Z-line proteins. Each Cypher isoform has distinct role and the D626N mutation of Cypher results in dilated cardiomyopathy (DCM) through increased affinity of Cypher for PKC. The overall goals of this proposal are to understand the role of Cypher and its isoforms in cardiac function and to gain insight into the mechanisms by which the mutation D626N causes DCM. We will achieve these goals by comprehensive histological, biochemical, and physiological analyses of the cardiac phenotypes of several existing genetically manipulated mouse lines as well as mouse lines in the process of being made. Accordingly, the Specific Aims are: 1. To understand the functional role of Cypher in heart. We will investigate the function of Cypher in heart by analyzing two mouse lines in which Cypher is selectively ablated in developing or adult heart. 2. To determine the biological function of long and short Cypher splice isoforms, Cypher1 and Cypher2, respectively. We will investigate the function of long and short Cypher isoforms by analyzing in detail two mouse lines in which each isoform is selectively ablated. 3. To understand the role of Cypher's interaction with PKC in DCM. The proposed studies will help us to understand the biological function of Cypher and its isoforms at molecular, cellular, and physiological levels. Furthermore, we will gain insight into the mechanisms by which mutations in Cypher causes DCM, thereby improving our general understanding of DCM. In addition, the mouse lines will be useful as test models for potential therapies.

描述（由申请人提供）：该五年提案的目的是检验Cypher是一种关键的接头蛋白的假设，该假说通过与A-肌动蛋白2，PKC，PKA以及潜在的Z系线蛋白的相互作用，可通过其与A-肌动蛋白2，PKC，PKC，PKA进行相互作用来介导结构完整性和信号通路。每个Cypher同工型都具有明显的作用，并且通过Cypher对PKC的亲和力增加，Cypher的D626N突变导致心肌病（DCM）的扩张。该提案的总体目标是了解Cypher及其同工型在心脏功能中的作用，并深入了解突变D626N引起DCM的机制。我们将通过对几种现有遗传操纵小鼠系的心脏表型以及在制造过程中的小鼠系的心脏表型以及小鼠系的心脏表型的全面组织学，生化和生理分析来实现这些目标。因此，具体目的是：1。了解Cypher在心脏中的功能作用。我们将通过分析两种小鼠系在发育或成人心脏中选择性地消融的两种小鼠线来研究Cypher在心脏中的功能。 2。分别确定长的和短的Cypher剪接同工型的生物学功能，分别是Cypher1和cypher2。我们将通过详细分析两种小鼠系有选择性地消融的两种小鼠线条，研究长的和短的密码型的功能。 3。了解Cypher与PKC在DCM中的相互作用的作用。拟议的研究将帮助我们了解分子，细胞和生理水平上的Cypher及其同工型的生物学功能。此外，我们将深入了解Cypher中突变导致DCM的机制，从而提高我们对DCM的一般理解。此外，小鼠系将作为潜在疗法的测试模型有用。