Novel Xin Protein in Cardiac Development and Function

心脏发育和功能中的新型 Xin 蛋白

• 批准号: 7160538
• 负责人: Jim Jung-Ching Lin
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160538
• 关键词: A Mouse; Adherens Junction; Adhesions; Adult; Antibody Formation; Antisense Oligonucleotides; Candidate Disease Gene; Cardiac; Chick Embryo; Co-Immunoprecipitations; Complex; Condition; Congenital Heart Defects; Coupled; Development; Disruption; Embryonic Development; Embryonic Heart; Exercise; Fibrosis; Financial compensation; Gene Deletion; Genes; Genomics; Goals; H-Cadherin; Heart; Heart Hypertrophy; Hypertrophy; In Situ Hybridization; Intercalated disc; Intervention; Knock-out; Knockout Mice; Length; Localized; Modeling; Morphogenesis; Mus; Myocardium; N-Cadherin; Northern Blotting; Pattern; Phenotype; Physiological; Play; Proteins; Rate; Recombinant Proteins; Role; Signal Transduction; Stress; Thrombus; Ventricular; Western Blotting; Work; Yeasts; beta catenin; cardiogenesis; design; loss of function; mRNA Differential Displays; mouse model; novel; pressure; proline-rich proteins; protein function; vector; yeast two hybrid system; A Mouse; Adherens Junction; Adhesions; Adult; Antibody Formation; Antisense Oligonucleotides; Candidate Disease Gene; Cardiac; Chick Embryo; Co-Immunoprecipitations; Complex; Condition; Congenital Heart Defects; Coupled; Development; Disruption; Embryonic Development; Embryonic Heart; Exercise; Fibrosis; Financial compensation; Gene Deletion; Genes; Genomics; Goals; H-Cadherin; Heart; Heart Hypertrophy; Hypertrophy; In Situ Hybridization; Intercalated disc; Intervention; Knock-out; Knockout Mice; Length; Localized; Modeling; Morphogenesis; Mus; Myocardium; N-Cadherin; Northern Blotting; Pattern; Phenotype; Physiological; Play; Proteins; Rate; Recombinant Proteins; Role; Signal Transduction; Stress; Thrombus; Ventricular; Western Blotting; Work; Yeasts; beta catenin; cardiogenesis; design; loss of function; mRNA Differential Displays; mouse model; novel; pressure; proline-rich proteins; protein function; vector; yeast two hybrid system

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the role of a novel cardiac protein, Xin, in development and cardiac function. Xin encodes a proline-rich protein located in adherens junctions of the intercalated discs of adult hearts. Xin antisense oligonucleotide treatment of chick embryos results in disruption of cardiac morphogenesis. Xin protein is co-localized and associated with the N-cadherin/beta-catenin complex suggesting that Xin is a component of adherens junctions of cardiac muscle and may play a vital role in the N-cadherin signaling during cardiac development and function. A mouse knockout to delete the first Xin (mXinalpha) gene has been generated. The knockout mice appear to develop normally. However, further analysis reveals that hearts from adult mXinalpha -/- mice appear to be hypertrophied. Fibrosis and thrombi are occasionally found within the ventricular myocardium of the mXinalpha -/- heart. Furthermore, introduction of pathophysiological stress in a form of pressure-overload to the mXinaalpha -/- mice results in an accelerated rate of hypertrophy. We have also discovered a second mXinbeta gene (mXinbeta, which is upregulated in the mXinalpha knockout hearts. This finding supports the idea that mXinbeta may partially compensate for loss of the mXinalpha gene during development. Our working hypothesis is that mXina and mXina are essential for normal heart development and function and may act by integrating adhesion and signaling. The specific aims are: (1) To further characterize the mXinalpha knockout mice by introducing pathophysiological stress and physiological exercise; (2) To clone and characterize mXinalpha interacting proteins; (3) To clone and characterize the second mXinbeta gene; and (4) To generate and characterize mXinbeta knockout and mXinalpha/mXinbeta double knockout mice. These studies should help provide the basic understanding of mXin protein function in normal cardiac development and function. Only through understanding normal development and cardiac function can intervention strategies be developed to alleviate cardiac defects.

描述（由申请人提供）：该项目的长期目标是了解新型心脏蛋白（XIN）在发育和心脏功能中的作用。 XIN编码成人心脏插入式椎间盘的粘附连接中的富含脯氨酸的蛋白质。 XIN反义寡核苷酸对雏鸡胚胎的处理导致心脏形态发生破坏。 XIN蛋白是共定位的，并与N-钙粘蛋白/β-catenin复合物相关联，这表明XIN是心脏肌肉粘附连接的组成部分，并且在心脏发育和功能过程中可能在N-钙粘蛋白信号传导中起着至关重要的作用。已经生成了删除第一个XIN（MXinalpha）基因的小鼠敲除。淘汰小鼠似乎正常发展。然而，进一步的分析表明，成年mxinalpha - / - 小鼠的心脏似乎被肥大。纤维化和血栓有时会在mxinalpha - / - 心脏的心室心肌内发现。此外，以压力超负荷形式的病理生理压力引入mxinaalpha - / - 小鼠会导致肥大的加速速率。我们还发现了第二个mxinbeta基因（Mxinbeta，它在Mxinalpha敲除心脏中被上调。这一发现支持Mxinbeta可能部分补偿发育过程中Mxinalpha基因的损失的想法。我们的工作假设是MXINA和MXINA对正常心脏的发展和正常功能的作用，可以通过正常的攻击和指示：（1）是对（1）的指示：1（1）是对AD的指示。通过引入病理生理压力和生理运动来表征MXinalpha敲除小鼠；正常的心脏发育和功能中的蛋白质功能只能通过理解正常发育和心脏功能来减轻心脏缺陷。