Transcription Factors Involved in Heart Development

描述（由申请人提供）：先天性心脏病占人类出生缺陷的最高频率，影响1/1000活产。为了更好地了解人群中的先天性心脏病，本研究的目标是使用脊椎动物模型来定义控制心脏细胞特化和分化的分子机制。这些分子网络的破坏是先天性心脏病的最终原因，了解控制心脏发生的转录因子将有助于开发更好的筛查和治疗方法。到目前为止，没有心脏特异性转录因子已被确定，这意味着心脏特异性转录调控发生通过多蛋白复合物，从而了解转录因子如何调节其蛋白质-蛋白质相互作用是需要了解心脏特异性转录。HAND类bHLH转录因子HAND 1和HAND 2在不同物种心脏形成的最早阶段表达。HAND基因的基因破坏实验表明，这两个基因对心脏的正常发育都是必不可少的。最近，我们已经表明，HAND 1和HAND 2表现出混杂的二聚化特征，允许形成HAND同源和异源二聚体以及与A类和B类bHLH蛋白的异源二聚体。从我们最近的努力，我们是在一个独特的位置，专注于了解如何手蛋白选择他们的bHLH合作伙伴的机制，并手二聚体是需要实施心脏转录程序的建议。具体地，我们将定义在心脏表达的bHLH因子中进行后修饰的残基。我们将研究HAND蛋白二聚化的机制以及所鉴定的蛋白质修饰如何影响二聚化。最后，我们将定义这些翻译后修饰在心脏特异性转录调控中的作用。这项研究的完成将导致相关的bHLH复合物介导的cardiogensis的鉴定和增加的分子控制，驱动bHLH二聚化的选择的理解。综上所述，这些实验的结果将提供心脏中bHLH因子的功能和调节的全面图片。这些信息将增加对控制心脏发生的分子途径是如何组织的理解，从而提供对控制心脏形成的分子机制的更好理解。这种理解对于人类中存在的多种形式的先天性心脏病的遗传筛查和治疗的发展至关重要。

DESCRIPTION (provided by applicant): Congenital heart diseases account for the highest frequency of human birth defects, affecting 1 in 1000 live births. In an effort to gain a better understanding of congenital heart diseases in the human population, the goals of this study are to define the molecular mechanisms controlling cardiac cell specification and differentiation using vertebrate models. The break down in these molecular networks are the ultimate cause of congenital heart diseases and gaining an understanding of the transcription factors controlling cardiogenesis will facilitate the development of better screens and treatments. To date, no heart-specific transcription factors have been identified, implying that cardiac-specific transcriptional regulation occurs via multiprotein complexes and thus understanding how transcription factors regulate their protein-protein interactions is required for understanding cardiac specific transcription. The HAND class of bHLH transcription factors, HAND1 and HAND2, are expressed at the earliest stages of heart formation across species. Gene disruption experiments of the HAND genes show that both of these genes are essential for proper cardiac development. Recently, we have shown that HAND1 and HAND2 exhibit promiscuous dimerization characteristics allowing for the formation of HAND homo and heterodimers as well as heterodimers with both class A and class B bHLH proteins. From our recent efforts, we are in a unique position to focus this proposal on understanding the mechanism of how HAND proteins choose their bHLH partners and which HAND dimers are required for implementing the cardiac transcriptional program. Specifically, we will define the residues that are post translationally modified in cardiac expressed bHLH factors. We will investigate the mechanism of HAND protein dimerization and how the identified protein modifications affect dimerization. Finally, we will define the role of these posttranslational modifications in cardiac-specific transcriptional regulation. The completion of this study will result in the identification of the relevant bHLH complexes mediating cardiogensis and an increased understanding of the molecular controls that drive bHLH dimerization choices. Taken together, the results of these experiments will provide a comprehensive picture of the function and regulation of the bHLH factors in the heart. This information will increase the understanding of how the molecular pathways that control cardiogenesis are organized, thereby providing a greater understanding of the molecular mechanisms controlling heart formation. This understanding is essential for the development of genetic screens and treatments for the many forms of congenital heart disease present in the human population.