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

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的心脏蛋白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，位于成人心脏间盘的粘连连接处。XIN反义寡核苷酸处理鸡胚胎会导致心脏形态发生的破坏。Xin蛋白与N-钙粘蛋白/β-连环蛋白复合体共定位，提示Xin是心肌黏附连接的组成部分，在心脏发育和功能过程中可能在N-钙粘附素信号转导中发挥重要作用。已经产生了删除第一个XIN(MXINAlpha)基因的小鼠敲除。基因敲除的小鼠似乎发育正常。然而，进一步的分析显示，成年mSina-/-小鼠的心脏似乎肥大。心肌纤维化和血栓偶尔见于心肌纤维化和血栓形成。此外，以压力超负荷的形式将病理生理应激引入mXinaα/-小鼠，会导致肥大速度加快。我们还发现了第二个mCinbeta基因(MCinbeta)，它在mCinAlpha基因敲除的心脏中上调。这一发现支持这样一种观点，即mCinbeta可能部分补偿了mCinpha基因在发育过程中的丢失。我们的工作假设是，mXINA和MXINA对心脏的正常发育和功能是必不可少的，可能通过整合黏附和信号发挥作用。本研究的具体目的是：(1)通过引入病理生理应激和生理锻炼，进一步研究mSinAlpha基因敲除小鼠的特性；(2)克隆和鉴定mCinAlpha相互作用蛋白；(3)克隆和鉴定第二个mCinbeta基因；(4)建立和鉴定mSinbeta基因敲除小鼠和mCinAlpha/mCinbeta双基因敲除小鼠。这些研究将有助于对mXin蛋白在正常心脏发育和功能中的功能提供基本的了解。只有通过了解正常发育和心脏功能，才能制定干预策略来减轻心脏缺陷。

项目成果

Structure, Expression, and Function of a Novel Intercalated Disc Protein, Xin.

• DOI: 10.1901/jaba.2005.25-215
• 发表时间: 2005-10
• 期刊: Journal of medical sciences
• 作者: Jim Jung-Ching Lin;Elisabeth A. Gustafson-Wagner;Haley W. Sinn;Sunju Choi;Shannon M Jaacks;Da-Zhi Wang;S. Evans;Jenny Li-Chun Lin

Essential roles of an intercalated disc protein, mXinbeta, in postnatal heart growth and survival.

• DOI: 10.1161/circresaha.109.212787
• 发表时间: 2010-05-14
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Wang Q;Lin JL;Reinking BE;Feng HZ;Chan FC;Lin CI;Jin JP;Gustafson-Wagner EA;Scholz TD;Yang B;Lin JJ
• 通讯作者: Lin JJ

Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.

• DOI: 10.2741/e344
• 发表时间: 2011-06-01
• 期刊: Frontiers in bioscience (Elite edition)
• 作者: Chan FC;Cheng CP;Wu KH;Chen YC;Hsu CH;Gustafson-Wagner EA;Lin JL;Wang Q;Lin JJ;Lin CI
• 通讯作者: Lin CI

On the mechanisms of arrhythmias in the myocardium of mXinalpha-deficient murine left atrial-pulmonary veins.

• DOI: 10.1016/j.lfs.2008.06.020
• 发表时间: 2008-08-15
• 期刊: LIFE SCIENCES
• 影响因子: 6.1
• 作者: Lai, Yu-Jun;Huang, Eagle Yi-Kung;Yeh, Hung-I;Chen, Yen-Lin;Lin, Jim Jung-Ching;Lin, Cheng-I
• 通讯作者: Lin, Cheng-I

Xin proteins and intercalated disc maturation, signaling and diseases.

• DOI: 10.2741/4072
• 发表时间: 2012-06-01
• 期刊: Frontiers in bioscience (Landmark edition)
• 作者: Wang Q;Lin JL;Wu KH;Wang DZ;Reiter RS;Sinn HW;Lin CI;Lin CJ
• 通讯作者: Lin CJ