Transcription Factors Involved in Heart Development

描述(申请人提供)：先天性心脏病是人类出生缺陷发生率最高的疾病，每1000名活产儿中就有一名受到影响。为了更好地了解人类人群中的先天性心脏病，本研究的目的是利用脊椎动物模型来确定控制心肌细胞特化和分化的分子机制。这些分子网络的崩溃是先天性心脏病的最终原因，了解控制心脏生成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，还没有发现心脏特异的转录因子，这意味着心脏特异的转录调控是通过多蛋白复合体发生的，因此了解转录因子如何调节它们的蛋白质-蛋白质相互作用是理解心脏特异转录的必要条件。HAND类转录因子HAND1和HAND2在不同物种心脏形成的最早阶段表达。手部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，我们发现HAND1和HAND2表现出混杂的二聚化特征，允许形成手性同源和异源二聚体，以及与A类和B类bHLH蛋白形成的异源二聚体。从我们最近的努力中，我们处于一个独特的位置，可以将这一提议的重点放在理解手蛋白如何选择其bHLH伙伴的机制上，以及哪些手二聚体是实施心脏转录计划所必需的。具体地说，我们将定义在心脏表达的bHLH因子中被翻译后修饰的残基。我们将研究手蛋白二聚化的机制以及已识别的蛋白质修饰如何影响二聚化。最后，我们将确定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确定相关的bHLH复合体介导心脏发生，并增加对驱动bHLH二聚化选择的分子控制的了解。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景。这些信息将增加对控制心脏形成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多理解。这一认识对于开发人类人口中存在的多种形式的先天性心脏病的基因筛查和治疗至关重要。

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.