Roles of Cypher in Cardiac Muscle

Cypher 在心肌中的作用

• 批准号: 7440118
• 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/7440118
• 关键词: Actinin; Adult; Affect; Affinity; Binding; Biochemical; Biological Process; Birth; Cardiac; Cardiomyopathies; Class; 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; Localized; Mediating; Modeling; Molecular; Mus; Muscle function; Mutation; Myocardium; Myopathy; N-terminal; Numbers; Patients; Phenotype; Physiological; Play; Process; Protein Binding; Protein Isoforms; Protein Kinase C; Proteins; Purpose; RNA Splicing; Role; Sarcomeres; Siblings; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skeletal Muscle; Skeletal system; Striated Muscles; Structure; Symptoms; Tamoxifen; Testing; Texas; Variant; Ventricular; Yeasts; base; day; falls; improved; insight; mouse model; mutant; nebulette; proband; 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）：本五年计划的目的是检验Cypher是一种关键连接蛋白的假设，其通过与α-辅肌动蛋白2、PKC、PKA和潜在的其他Z线蛋白的相互作用来介导Z线的结构完整性和信号通路。每种Cypher亚型具有不同的作用，Cypher的D 626 N突变通过增加Cypher对PKC的亲和力而导致扩张型心肌病（DCM）。该提案的总体目标是了解Cypher及其亚型在心脏功能中的作用，并深入了解突变D 626 N导致DCM的机制。我们将通过对现有的几种基因操作小鼠品系以及正在制造的小鼠品系的心脏表型进行全面的组织学、生物化学和生理学分析来实现这些目标。因此，具体目标是：1。了解Cypher在心脏中的功能作用。我们将通过分析两个小鼠品系来研究Cypher在心脏中的功能，其中Cypher在发育或成年心脏中被选择性消融。2.确定长和短的密码子剪接异构体，密码子1和密码子2，分别的生物学功能。我们将通过详细分析两个小鼠品系来研究长和短Cypher亚型的功能，其中每个亚型都被选择性消融。3.了解Cypher与PKC相互作用在DCM中的作用。这些研究将有助于我们从分子、细胞和生理水平了解Cypher及其亚型的生物学功能。此外，我们将深入了解Cypher突变导致DCM的机制，从而提高我们对DCM的总体理解。此外，小鼠系将可用作潜在疗法的测试模型。