Pitx2 Function in Cardiac Development

描述（由申请人提供）：节点介导的左右不对称通路对心血管发展的多个方面至关重要。Pitx2c是淋巴结通路的下游效应物，已被证明是正常流出和流入通道发育所必需的。此外，Pitx2c调节心脏分隔和心室生长。Pitx2c被认为与人类疾病有关，因为它被确定为Rieger综合征i的突变基因。重要的是，Pitx2c最近被认为是4号染色体q25上发现的心房颤动（AF）位点的一个强有力的候选者。Pitx2c在心脏发育中的作用及其与房颤的关系尚缺乏明确的认识。本研究项目将通过条件基因失活研究和转基因分析直接研究Pitx2c在心脏器官发生中的功能。我们建议通过使用cre重组酶转基因方法来精确灭活Pitx2c，剖析Pitx2c在发育中的时间和组织特异性需求，以深入了解Pitx2c在人类疾病中的作用。Pitx2c与人类遗传和获得性疾病有关，包括Rieger综合征和心房颤动（AF）。最近的人类遗传学研究表明，Pitx2附近的序列变异与房颤有关。这项研究揭示了Pitx2c在人类心脏传导系统的发育或稳态中的作用。该研究项目将在脊椎动物发育过程中对Pitx2c进行深入研究，从而深入了解Pitx2c的功能，并为人类患者发现治疗途径。公共卫生相关性：在本研究项目中，我们建议研究Pitx2c介导的左右不对称通路，这对心脏发育至关重要。最近的研究表明Pitx2c是人类心房颤动的候选因子。在心脏流入道，我们将确定Pitx2c在确定左房型中的作用。此外，在流出道中，我们将研究Pitx2c在OFT生长和重塑中的阶段特异性功能。最后，我们将使用Pitx2c转基因来研究调节Pitx2c转录的信号通路。总之，这些实验将提供Pitx2c在心脏发育中的机制洞察。

DESCRIPTION (provided by applicant): Nodal mediated left right asymmetry pathways are critical for multiple aspects of cardiovascular development. Pitx2c, a downstream effector of the Nodal pathways, has been shown to be required for normal outflow and inflow tract development. Moreover, Pitx2c regulates cardiac septation and ventricular growth. Pitx2c is known to be involved in human diseases since it was identified as the gene mutated in Rieger Syndrome I. Importantly, Pitx2c has recently been implicated as a strong candidate for the atrial fibrillation (AF) locus identified on chromosome 4 q25. A firm understanding about the role of Pitx2c in cardiac development and its relationship to AF is lacking. This research program will directly investigate Pitx2c function in cardiac organogenesis using conditional gene inactivation studies and transgenic analysis. We propose to dissect the temporal and tissue specific requirements for Pitx2c in the developing heart by using cre recombinase transgenic methods to precisely inactivate Pitx2c to gain insight into the role of Pitx2c in human disease. Pitx2c has been implicated in human inherited and acquired disorders including Rieger Syndrome and atrial fibrillation (AF). Recent human genetic studies revealed that sequence variations in close proximity to Pitx2 were associated with AF. This study uncovered a role for Pitx2c in the development or homeostasis of the human cardiac conduction system. This research program will perform in depth investigation of Pitx2c during vertebrate development and will therefore provide insight into Pitx2c function with the long-term goal of uncovering therapeutic avenues for human patients. PUBLIC HEALTH RELEVANCE: In this research program, we propose to study the Pitx2c mediated left right asymmetry pathway that is critically important for heart development. Recent work has implicated Pitx2c as a candidate factor for atrial fibrillation in human patients. In the cardiac inflow tract, we will determine the function of Pitx2c in specifying the left atrial pattern. Moreover, in the outflow tract we will investigate the stage-specific function for Pitx2c in OFT growth and remodeling. Lastly, we will use Pitx2c transgenes to investigate the signaling pathways that regulate Pitx2c transcription. Together, these experiments will provide mechanistic insight into Pitx2c in heart development.