GENE TARGETS OF THE CARDIAC SPECIFIC HOMEOBOX (CSX) GENE

心脏特异性同源盒 (CSX) 基因的基因靶点

• 批准号: 2900981
• 负责人: Mark W Russell
• 金额: $ 12.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-07 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900981
• 关键词: developmental genetics; genetic techniques; genetically modified animals; heart; histogenesis; homeobox genes; laboratory mouse; myogenesis

DESCRIPTION (Adapted from applicant's abstract) The goal of this project will be to advance the understanding of the genetic controls that guide cardiac structural development. Identifying and characterizing the genes involved in this process may be an important step in understanding the genesis of congenital heart defects and in identifying new treatment strategies. For many tissues, homeobox proteins have been demonstrated to be critical for the normal growth and development by regulating target genes in a precise spatial and temporal pattern. The Cardiac-specific homeobox protein, Csx, is required for normal cardiac development; mice lacking this gene die in utero with a very primitive heart tube that has not completed the first phase of structural development, cardiac looping. Therefore, the targets of this gene may direct cardiac growth and development and, when mutated, may cause congenital heart defects. Furthermore, since the Csx gene continues to be expressed in the adult heart, it's target genes may also have a role in the heart's response to hypertension or ischemia. However, to date, no direct target genes of Csx have been identified. In this study, the candidate will use the chromatin precipitation technique and the yeast one hybrid system to identify target genes of the Csx protein. Once target genes have been identified and their regulation by Csx confirmed in vitro, the in vivo significance of this regulation will be examined using transgenic mouse models. Based on these studies, the human homologues of those target genes vital to cardiac development will be identified. In future studies, the role of these genes in the genesis of human congenital heart disease will be examined. As a pediatric cardiologist, the principal investigator is interested in pursuing an independent investigative career studying the genetic controls of myocardial development and characterizing how perturbations of this process cause congenital cardiac defects. The sponsor for this project, Dr. Seigo Izumo, Chief of Cardiology at the University of Michigan, is widely recognized for his work on signal transduction and transcription regulation in cardiac myocytes. His laboratory will provide an excellent environment for advanced training in molecular biology. The University of Michigan, already an active center for molecular biology research, is establishing an Organogenesis Center with core laboratories that will facilitate developmental biology research. Furthermore, the Division of Pediatric Cardiology is creating a repository of cell lines from patients with complex congenital heart defects. In this environment, the principal investigator anticipates acquiring the necessary research skills to contribute to the understanding of cardiac growth and structural development. (End of Abstract)

描述 （根据申请人的摘要改编）该项目的目标是 促进对引导心脏的遗传控制的理解 结构发展。 识别和表征涉及的基因 在此过程中，可能是理解起源的重要步骤 先天性心脏缺陷并确定新的治疗策略。 为了 许多组织，同源蛋白已被证明对 正常的生长和发育通过确切的调节靶基因来确切地调节靶基因 空间和时间模式。 心脏特异性同源蛋白CSX， 正常心脏发育需要；缺乏这个基因的小鼠死在 子宫带有非常原始的心管，尚未完成第一个 结构发展的阶段，心脏循环。 因此， 该基因可能指导心脏生长和发育，如果突变，可能 导致先天性心脏缺陷。 此外，由于CSX基因继续 要在成人心脏中表达，它的靶基因也可能发挥作用 心中对高血压或缺血的反应。 但是，迄今为止，没有 已经确定了CSX的直接靶基因。 在这项研究中， 候选人将使用染色质沉淀技术和酵母 鉴定CSX蛋白的靶基因的杂种系统。 一次目标 已经鉴定出基因，CSX的调节在体外证实， 该法规的体内意义将使用 转基因小鼠模型。 基于这些研究，人类的同源 将确定那些对心脏发育至关重要的靶基因。 在 未来的研究，这些基因在人类先天性的起源中的作用 将检查心脏病。 作为儿科心脏病专家，校长 调查人员有兴趣从事独立的调查职业 研究心肌发育的遗传控制和表征 该过程的扰动如何导致先天性心脏缺陷。 这 该项目的赞助商Seigo Izumo博士，心脏病学负责人 密歇根大学因信号的工作而受到广泛认可 心肌细胞中的转录和转录调节。 他的 实验室将为高级培训提供一个绝佳的环境 分子生物学。 密歇根大学，已经是活跃的中心 分子生物学研究正在建立一个有机物中心 核心实验室将有助于发展生物学研究。 此外，小儿心脏病学部正在创建一个存储库 来自先天性心脏缺陷患者的细胞系。 在这个 环境，主要研究人员预计将获得必要的 研究技能有助于理解心脏增长和 结构发展。 （抽象的结尾）