Elucidating the mechanisms of venous reprogramming during coronary development

项目总结/摘要 冠状动脉心脏病是世界范围内每年导致数百万人死亡的主要原因 而数千万人通过药物或手术治疗这种疾病 干预措施。这种疾病是由冠状动脉病变引起的，但尽管 它对全球医疗保健的影响，令人惊讶的是，人们对冠状动脉知之甚少 这可能会阻碍改善现有临床治疗的努力。的 我研究的长期目标是以高分辨率描述所有的细胞分化 以及从其祖细胞产生冠状动脉的形态发生步骤 在胚胎发育过程中。我最近确定了这些祖先的位置， 并描述了导致成熟冠状动脉的发育途径。 路径中的每一步都发生在固定的位置，这表明位置- 特定的线索触发特定的细胞分化事件。冠状血管开始为 静脉窦的静脉芽，当它们迁移到 侵入心脏随后，血管分化成动脉、毛细血管或血管。 静脉取决于它们在心脏内的位置。在这份提案中，我们将调查 初始步骤，发芽和静脉重编程，通过执行以下步骤 目的：（1）通过使用 微阵列，以表征位于这些位置的细胞的转录谱， 事件发生。(2)通过测试确定诱导内皮去分化的因素 在体外功能测定中从这些细胞分离的蛋白质。(3)测试候选人从 目的1和2通过评估敲除中的冠状血管发育来确定其在体内的作用 动物或用功能阻断抗体或药物治疗的那些。的初始部分 这项计划将在斯坦福大学马克·克拉斯诺博士的实验室进行， 环境，支持了许多创新的研究项目，导致 富有成效的独立职业。在这里，我将实现我的短期目标，找到一个任期- 跟踪位置，以完成建议的目标。在结束时，我们将有 确定了冠状动脉发育的第一步的机制， 提供了对这些新过程的深入了解，并提供了实验模型， 用于描述路径的其余部分。我们也将更进一步， 了解如何异位诱导冠状血管，这应该是有价值的 进一步推动临床发展的信息。

Project Summary/Abstract Coronary heart disease is the leading cause of death worldwide killing millions per year while tens of millions manage the disease medically or by undergoing surgical interventions. The disease results from pathology of the coronary arteries, but despite its impact on worldwide healthcare, surprisingly little is known about coronary artery development, which likely hampers efforts to improve available clinical treatments. The long-term goal of my research is to describe, at high resolution, all the cell differentiation and morphogenesis steps that produce coronary arteries from their progenitor cells during embryogenesis. I have recently identified the location of these progenitors in mice and described the developmental pathway leading to mature coronary arteries. Each step in the pathway occurred at stereotyped locations suggesting that position- specific cues trigger specific cell differentiation events. Coronary vessels begin as venous sprouts of the sinus venosus that de-differentiate as they migrate onto and invade the heart. Subsequently, the vessels differentiate into arteries, capillaries, or veins depending on their location within the heart. In this proposal, we will investigate the initial steps, sprouting and venous reprogramming, by carrying out the following aims: (1) Identify candidate sprouting and de-differentiation inducers by using microarrays to characterize the transcriptional profiles of cells located where these events occur. (2) Identify factors that induce endothelial de-differentiation by testing proteins isolated from these cells in an in vitro functional assay. (3) Test candidates from aims 1 and 2 for their role in vivo by assessing coronary vessel development in knockout animals or those treated with function-blocking antibodies or drugs. The initial part of the proposal will be carried out at Stanford University in Dr. Mark Krasnow's lab, an environment that has supported many innovative research projects that have led to fruitful independent careers. Here, I will carry out my immediate goal of finding a tenure- track position in which to complete the proposal's aims. At the conclusion, we will have identified the mechanisms underlying the first steps of coronary artery development providing insight into these novel processes as well as providing an experimental model for describing the remaining portions of the pathway. We will also be a step closer in understanding how to ectopically induce coronary vessels, which should be valuable information in furthering clinical developments.