Chordate heart gene networks

描述（由申请人提供）：解读相互连接的转录因子网络如何协调心脏基因表达对于先天性心脏病的诊断和治疗至关重要。我们的长期目标是全面了解脊索动物心脏基因网络以及保守的心脏转录因子Ets如何影响早期心脏形成。脊椎动物胚胎中这一过程的复杂性阻碍了进展。我们已经开始利用简单的玻璃海鞘，一个密切的进化关系的脊椎动物，调查保守的作用Ets在早期心脏发育。我们的具体假设是，Ets与谱系特异性辅因子协同工作，以建立心脏祖细胞身份。这一假设基于三组观察结果。1. Ets活性是心脏祖细胞基因表达的必要条件和充分条件。2. Ets和推定辅因子的配对结合基序是心脏祖细胞基因调控所需的。3.成对Ets+辅因子基序的检测揭示了新的心脏祖细胞调节元件。所提出的具体目标集中在确定Ets在心脏祖细胞基因网络中的精确转录作用。我们的努力将首先集中在确定推定的Ets辅因子。然后我们将开始阐明Ets和这种辅助因子如何直接调节一组确定的主要心脏基因。我们还将专注于开发尖端技术，用于在建立心脏谱系期间全面分析Ets/辅因子结合模式。这些努力将针对性地促进对本科生研究人员在制定和执行独立研究项目方面的强化培训。

DESCRIPTION (provided by applicant): Deciphering how networks of interlinked transcription factors coordinate heart gene expression is essential for the diagnosis and treatment of congenital heart disorders. Our long-term goal is to gain a comprehensive understanding of chordate heart gene networks and how the conserved cardiac transcription factor, Ets, impacts early heart formation. The complexity of this process in vertebrate embryos has hindered progress. We have begun to exploit the simplicity of Ciona intestinalis, a close evolutionary relative of the vertebrates, to investigate a conserved role for Ets in early heart development. Our specific hypothesis is that Ets works in tandem with a lineage specific co-factor to establish heart progenitor identity. This hypothesis is based on three sets of observations. 1. Ets activity is both necessary and sufficient for heart progenitor gene expression. 2. Paired binding motifs for Ets and a presumptive co-factor are required for heart progenitor gene regulation. 3. Detection of paired Ets+co- factor motifs reveals new heart progenitor regulatory elements. The proposed specific aims focus on determining the precise transcriptional role of Ets in the heart progenitor gene network. Our efforts will initially focus on identification of the presumptive Ets co-factor. We will then begin to elucidate how Ets and this co-factor directly regulate a defined set of primary heart genes. We will also focus on developing cutting edge technology for comprehensive analysis of Ets/Co-Factor binding patterns during establishment of the heart lineage. These efforts will be tailored to promote intensive training of undergraduate researchers in the formulation and execution of independent research projects.