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: 6705337
• 负责人: Jim Jung-Ching Lin
• 金额: $ 33.19万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6705337
• 关键词: DNA binding protein; biological signal transduction; cardiogenesis; cell adhesion; gene deletion mutation; gene expression; genetically modified animals; heart function; in situ hybridization; laboratory mouse; molecular cloning; northern blottings; phenotype; proline; protein protein interaction; ventricular hypertrophy; western blottings

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一种新型心脏蛋白Xin在发育和心脏功能中的作用。Xin编码一种富含脯氨酸的蛋白质，这种蛋白质位于成人心脏嵌入盘的粘附连接处。鸡胚Xin反义寡核苷酸处理导致心脏形态发生的破坏。Xin蛋白与N-cadherin/ β -catenin复合物共定位，表明Xin是心肌粘附连接的一个组成部分，可能在心脏发育和功能过程中对N-cadherin信号传导起重要作用。已经产生了一个小鼠敲除以删除第一个Xin （mXinalpha）基因。基因敲除小鼠似乎发育正常。然而，进一步的分析表明，成年mXinalpha -/-小鼠的心脏似乎是肥大的。mXinalpha -/-心脏的心室心肌偶尔会出现纤维化和血栓。此外，以压力过载形式引入mxina -/-小鼠的病理生理应激会导致肥大的加速。我们还发现了第二个mXinbeta基因（mXinbeta），它在mXinalpha基因敲除的心脏中表达上调。这一发现支持了mXinbeta可能在发育过程中部分补偿mXinalpha基因缺失的观点。我们的工作假设是mXina和mXina对正常心脏发育和功能至关重要，并可能通过整合粘附和信号传导起作用。具体目的是：(1)通过引入病理生理应激和生理运动进一步表征mXinalpha基因敲除小鼠；(2)克隆和鉴定mXinalpha相互作用蛋白；(3)克隆并鉴定mXinbeta第二基因；(4)生成mXinbeta敲除小鼠和mXinalpha/mXinbeta双敲除小鼠。这些研究有助于了解mXin蛋白在正常心脏发育和功能中的作用。只有了解正常的发育和心脏功能，才能制定干预策略来减轻心脏缺陷。