GENE TARGETS OF THE CARDIAC SPECIFIC HOMEOBOX (CSX) GENE

描述 （改编自申请人的摘要）本项目的目标将是 促进对指导心脏病的遗传控制的理解， 结构发展。 识别和表征相关基因 在这一过程中可能是了解 先天性心脏病和确定新的治疗策略。 为 在许多组织中，同源异型盒蛋白已被证明是至关重要的， 通过精确调控靶基因， 空间和时间模式。 心脏特异性同源异型盒蛋白Csx， 是正常心脏发育所必需的;缺乏这种基因的小鼠会死于 子宫内有一个非常原始的心管，还没有完成第一个 结构发育阶段心脏循环 因此， 该基因可以指导心脏的生长和发育，当突变时， 会导致先天性心脏缺陷 此外，由于Csx基因继续 在成人心脏中表达，它的靶基因也可能起作用 心脏对高血压或局部缺血的反应。 然而，到目前为止，没有 Csx的直接靶基因已被鉴定。 本研究 候选人将使用染色质沉淀技术和酵母一个 杂交系统来鉴定Csx蛋白的靶基因。 一旦目标 已经鉴定了基因并且在体外证实了Csx对它们的调节， 该调节的体内意义将使用 转基因小鼠模型。 基于这些研究， 这些对心脏发育至关重要的靶基因将被鉴定。 在 未来的研究，这些基因在人类先天性 心脏病将被检查。 作为一名儿科心脏病专家， 调查员有兴趣从事独立的调查职业 研究心肌发育的遗传控制， 这一过程的紊乱如何导致先天性心脏缺陷。 的 该项目的赞助商，Seigo Izumo博士，心脏病学主任， 密歇根大学，因其在信号方面的工作而广受认可 在心肌细胞中的转导和转录调节。 他 实验室将为高级培训提供良好的环境， 分子生物学 密歇根大学，已经是一个活跃的中心， 分子生物学研究，正在建立一个器官发生中心， 核心实验室将促进发育生物学研究。 此外，儿科心脏病学分部正在创建一个储存库， 复杂先天性心脏病患者的细胞系。 在这 环境，主要研究人员预计将获得必要的 研究技能，以促进对心脏生长的理解， 结构发展。 (End摘要）

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)