GENE TARGETS OF THE CARDIAC SPECIFIC HOMEOBOX (CSX) GENE

描述 (改编自申请者的摘要)这个项目的目标是 促进对指导心脏疾病的遗传控制的理解 结构性发展。识别和表征涉及的基因 在这一过程中可能是理解 先天心脏缺陷和确定新的治疗策略。为 许多组织，同源盒蛋白已被证明是关键的 通过精确调控靶基因实现正常生长发育 空间和时间模式。心脏特有的同源异型盒蛋白CSX， 是心脏正常发育所必需的；缺乏该基因的小鼠会死于 子宫有一个非常原始的心管，还没有完成第一次 结构发展阶段，心脏循环。因此，其目标是 该基因可能指导心脏的生长和发育，当突变时，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，它的目标基因可能也有一定的作用 在心脏对高血压或缺血的反应中。然而，到目前为止，没有 目前已鉴定出CSX的直接靶基因。在这项研究中， 应聘者将使用染色质沉淀技术和酵母技术 利用杂交系统识别CSX蛋白的靶基因。一次目标 在体外，基因已经被确定，并被CSX证实了它们的调控。 这一调节的体内意义将被用来检验 转基因小鼠模型。基于这些研究，人类的同源物 那些对心脏发育至关重要的靶基因将被识别出来。在……里面 未来的研究，这些基因在人类先天性心脏病发生中的作用 将对心脏病进行检查。作为一名儿科心脏病专家，校长 调查员对追求独立的调查事业感兴趣 研究心肌发育的遗传控制及其特征 这一过程的扰动如何导致先天性心脏缺陷。这个 该项目的发起人、世界卫生组织心脏病科主任出云医生 密歇根大学，因其在信号方面的工作而广为人知 心肌细胞中的转导和转录调节。他的 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 分子生物学研究，正在建立一个器官发生中心 将促进发育生物学研究的核心实验室。 此外，儿科心脏病学分部正在创建一个资料库 来自复杂先天性心脏病患者的细胞系。在这 环境，首席调查员预计将获得必要的 有助于理解心脏生长和心脏发育的研究技能 结构性发展。(摘要结束)

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)