Transcriptional Control of Cardiac Conduction System Function by T-box Genes

描述（由申请人提供）：尽管心脏传导系统（CCS）疾病具有显著的临床后果，但控制CCS功能的分子机制尚不清楚。该建议结合了新的创新与最新进展，实验解剖心室传导系统（VCF）功能的转录控制，一个具有重要临床意义的问题。我们已经开发了一种新的VCS特异性诱导型Cre转基因小鼠系（minKCreERT 2），并利用它从成熟的大肠杆菌中去除Tbx 5（Tbx 5 MinK：CreERT 2）。在Tbx 5 MinK：CreERT 2小鼠中，正常快速传导的ESTA在功能上变得缓慢，伴随着ESTA基因表达的分子改变。重要的是，Tbx 3，所需的慢传导节点表型得到维持。这些观察结果和最近的文献合并在总体假设：Tbx 5/Tbx 3 T盒代码确定成熟心室心脏传导系统的功能和分子区域表型。我们预测，Tbx 5确定的功能和分子的身份和Tbx 3所需的潜在的结电位的Tbx 5的情况下，发现的Tbx 5。我们提出（1）检验Tbx 5促进功能性和分子性突触表型的假设;（2）检验Tbx 5直接调节突触中SCN 5A表达以控制突触功能所需的分子等级的假设;（3）检验Tbx 3足以在突触中建立节点表型的假设;（4）检验Tbx 5和Tbx 3协同促进特化CCS表型的假设。一组领先的专家在分子分析的CCS已组装调查的转录控制成熟的转录功能。一个全面的实验集将建立特定的作用Tbx 5和Tbx 3在CCS区域特异性的转录控制。这些研究将为未来的工作建立一个平台，以详细说明控制CCS功能的转录网络，帮助知识渊博的临床CCS疗法和干预措施的发展。

DESCRIPTION (provided by applicant): Despite the significant clinical consequences of cardiac conduction system (CCS) disease, the molecular mechanisms that control CCS function are unknown. This proposal combines novel innovations with recent progress to experimentally dissect the transcriptional control of ventricular conduction system (VCS) function, a problem of great clinical significance. We have developed a novel VCS-specific inducible Cre transgenic mouse line (minKCreERT2) and utilized it to remove Tbx5 from the mature VCS (Tbx5MinK: CreERT2). The normally fast conducting VCS became functionally slow in Tbx5MinK:CreERT2 mice, with concomitant molecular alterations of VCS gene expression. Importantly, Tbx3, required for slow-conducting nodal phenotype was maintained. These observations and recent literature coalesce in the Overall Hypothesis: A Tbx5 / Tbx3 T-box code determines the functional and molecular regional phenotype of the mature Ventricular Cardiac Conduction System. We predict that Tbx5 determines VCS functional and molecular identity and that Tbx3 is required for underlying nodal potential of the VCS, uncovered in the absence of Tbx5. We propose to (1) Test the hypothesis that Tbx5 promotes functional and molecular VCS phenotype; (2) Test the hypothesis that Tbx5 directly regulates SCN5A expression in the VCS to control a molecular hierarchy required for VCS function; (3) Test the hypothesis that Tbx3 is sufficient for establishing a nodal phenotype in the VCS; and (4) Test the hypothesis that Tbx5 and Tbx3 cooperatively promote specialized CCS phenotype. A group of the leading experts in molecular analysis of the CCS have been assembled to investigate the transcriptional control of mature VCS function. A comprehensive experimental set will establish the specific roles of Tbx5 and Tbx3 in the transcriptional control of CCS regional specificity. These investigations will establish a platform for future efforts to detail transcriptional networks governing CCS function, aiding knowledgeable development of clinical CCS therapies and interventions.