Mechanotransduction and transcriptional regulation during artery development

摘要 由冠状动脉病理引起的缺血性心脏病是导致心脏病的主要原因。 死亡一种潜在的治疗方法可能是医学刺激动脉再生， 心，但这仍然是一个遥远的目标。进展的一个障碍是， 冠状动脉的发展在很大程度上仍然是未知的。这项提案使用了一种新的干细胞- 内皮细胞分化方案，使新的和更精确的方法，以发现 动脉化因素我们以前的研究确定转录因子Dach 1是一个关键的 冠状动脉分化和形态发生的组成部分。1项未完成的后续行动 本研究的问题是Dach 1诱导的影响动脉内皮细胞的基因是什么 细胞分化由于缺乏足够的内皮细胞， 细胞培养模型，可用于快速询问多个基因。我们的同事，在 与我们的实验室合作，最近发表了一个高效，易于执行的干 细胞到动脉内皮细胞的分化，重演了人类早期发育的步骤 我们将使用这个模型：1。探讨Dach 1诱导动脉粥样硬化的机制 差异化，2。探讨切应力对动脉内皮细胞的影响 分化这些数据将从机制上阐明Dach 1如何诱导动脉分化。 此外，我们将整合剪切应力对人类细胞的能力的影响， 分化为动脉和静脉细胞。了解这些信号通路可以识别 旨在增强患病心脏血管重建的新治疗靶点， 扩张动脉网络

ABSTRACT Ischemic heart disease resulting from pathology of the coronary arteries is the leading cause of death. One potential therapy could be medically stimulating artery regeneration in diseased hearts, yet this remains a distant goal. One roadblock to progress is that the mechanisms of coronary artery development are still largely unknown. This proposal uses a novel stem cell-to- endothelial cell differentiation protocol that enables new and more precise approaches to discover arterialization factors. Our previous research identified the transcription factor Dach1 as a critical component of coronary artery differentiation and morphogenesis. One outstanding follow-up question to this research is what are the genes induced by Dach1 that influence artery endothelial cell differentiation. Identifying these has been slow and difficult owning to inadequate endothelial cell culture models that can be used to quickly interrogate multiple genes. Our colleagues, in collaboration with our lab, have recently published a highly efficient and easy to execute stem cell-to-artery endothelial cell differentiation that recapitulates steps in early human development We will use this model to: 1. Investigate the mechanisms underlying Dach1-induced artery differentiation and 2. Investigate whether shear stress influences artery endothelial cell differentiation. This data will illuminate mechanistically how Dach1 induces arterial differentiation. Additionally, we will integrate the effects of shear stress on the ability of human cells to differentiate into artery and veins cells. Understanding these signaling pathways could identify novel therapeutic targets aimed at enhancing revascularization of diseased hearts through expanding artery networks.