Pitx2 Function in Cardiac Development

描述（由申请人提供）：结介导的左右不对称通路对心血管发育的多个方面至关重要。Pitx2c是结途径的下游效应物，已被证明是正常流出道和流入道发育所需的。此外，Pitx2c调节心脏分隔和心室生长。已知Pitx2c与人类疾病有关，因为它被鉴定为Rieger综合征I中突变的基因。重要的是，Pitx2c最近被认为是在染色体4 q25上鉴定的心房颤动（AF）位点的强有力候选者。对Pitx2c在心脏发育中的作用及其与AF的关系缺乏确切的了解。该研究计划将使用条件性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地表达Pitx2c，以深入了解Pitx2c在人类疾病中的作用，从而解剖发育中心脏对Pitx2c的时间和组织特异性需求。Pitx2c与人类遗传性和获得性疾病有关，包括Rieger综合征和心房颤动（AF）。最近的人类遗传学研究表明，在接近Pitx2的序列变异与AF。这项研究揭示了Pitx2c在人类心脏传导系统的发展或稳态的作用。该研究计划将在脊椎动物发育过程中对Pitx2c进行深入研究，因此将深入了解Pitx2c的功能，其长期目标是揭示人类患者的治疗途径。公共卫生相关性：在这项研究计划中，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是人类患者房颤的候选因素。在心脏流入道中，我们将确定Pitx2c在指定左心房模式中的功能。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，这些实验将为Pitx2c在心脏发育中的作用提供机制性的见解。

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.