Analysis of a Novel Homeobox gene in CV Development

描述（由申请人提供）：这是一项竞争性更新申请，旨在研究在心脏中表达的称为Hopx的非典型同源结构域蛋白的作用。我的实验室大约在10年前发现了Hopx，我们已经证明，它的功能，至少在一定程度上，是通过将组蛋白去乙酰化酶（hdac）招募到转录复合物上。这项工作，由该基金资助，导致了许多备受瞩目的出版物，专利申请，并促使我们努力与私营部门合作，将研究结果转化为临床心力衰竭的新疗法。我们的机制研究表明Hopx不直接与DNA结合，但它是心脏抑制复合物的一个组成部分。Hopx在小鼠胚胎发生的早期时间点，即Nkx2-5之后，在~E8.0时由心脏祖细胞表达，Hopx的失活导致部分渗透性胚胎致死性和薄心肌。表达Nkx2-5的心脏祖细胞是多能的，可以产生心肌、平滑肌或内皮细胞谱系。然而，表达hopx的祖细胞致力于心肌谱系。我们的数据表明心脏前体细胞的命运决定受到Hopx剂量和活性的影响。我们假设Hopx是一个非常早的（可能是最早的）心肌细胞标记物，并且Hopx通过募集hdac和其他转录辅助因子来抑制交替命运和多能状态的关键介质，从而加强心肌谱系选择。了解心肌命运决定是如何执行和加强的，将使我们有能力加强再生治疗，指导干细胞和祖细胞产生功能性心肌。

DESCRIPTION (provided by applicant): This is a competitive renewal application to study the role an atypical homeodomain protein called Hopx that is expressed in the heart. My laboratory discovered Hopx about 10 years ago, and we have shown that it functions, at least in part, by recruiting histone deacetylases (HDACs) to transcription complexes. This work, funded by this grant, led to numerous high-profile publications, patent applications, and it has spurred our efforts in collaboration with the private sector to translate the findings and bring new therapies for heart failure to the clinic. Our mechanistic studies have shown that Hopx does not bind directly to DNA, but that it is a component of cardiac repressor complexes. Hopx is expressed by cardiac progenitor cells at early time-points of murine embryogenesis, just after Nkx2-5, at ~E8.0, and inactivation of Hopx leads to partially penetrant embryonic lethality and thin myocardium. Cardiac progenitors that express Nkx2-5 are multipotent and can produce myocardial, smooth muscle or endothelial lineages. However, Hopx-expressing progenitors are committed to the myocardial lineage. Our data suggest that fate decisions of cardiac precursor cells are biased by Hopx dose and activity. We hypothesize that Hopx is an extremely early (perhaps the earliest) marker of committed myocardial cells and that Hopx functions to reinforce the myocardial lineage choice by recruiting HDACs and other transcription cofactors to repress critical mediators of alternate fates and of the multipotent state. Understanding how myocardial fate decisions are executed and reinforced will inform our ability to enhance regenerative therapies and instruct stem and progenitor cells to produce functional myocardium.