Mechanotransduction and transcriptional regulation during artery development

项目摘要 心脏病是最常见的死亡原因，通常是由于心脏血流受阻而引起的。 肌肉.血流首先通过冠状动脉到达心脏，然后进入毛细血管网， 发生氧交换。治疗心脏病的一种方法是扩大毛细血管网络， 但取得的成功有限。在这里，我们建议扩大冠状动脉网络， 促进侧支动脉的发育，侧支动脉是动脉的一种亚型，具有形成天然血管的潜力。 旁路。在上一个资助期，我们的实验室发现了细胞和分子机制， 发育中胚胎的冠状动脉形成，包括转录因子Dach 1如何支持 动脉生长通过调节血流刺激细胞行为（Chang，2017，Genes and Dev）。我们也 描述了趋化因子CXCL12如何在受损心脏中触发侧支动脉形成， 新生儿生长期（Das，2019，Cell）。我们假设这些发育途径可以被利用 刺激成人冠状动脉再生并在心脏损伤期间提供有益的结果， 疾病在成人中激活Dach 1或CXCl 12的初步研究显示了增强恢复的迹象 实验性心肌梗死后我们将使用以下目标，以进一步探讨其修复性 潜力Aim 1将使用组织清除、整个器官成像技术和计算建模， 定义损伤、Dach 1过表达和CXCL 12给药如何改变动脉结构并影响血液 流动参数目的2将使用心脏损伤模型深入研究Dach 1和CXCL 12如何诱导 动脉生长和侧支发展增强心肌梗塞后的恢复。Aim 3将深入研究 Dach 1刺激动脉内皮细胞分化和形态发生的机制。 这项工作是有意义的，因为描绘发育信号如何刺激冠状动脉 再生最终可能有助于心脏病的治疗干预。作品具有创新性 因为它采用了一种新的血管重建方法-靶向动脉分化，而不仅仅是 微脉管系统它还进一步发展了尖端的实验技术，如成人整个器官 成像和一种新的体外内皮细胞分化模型，这可能最终有利于 心血管研究领域的专家最后，确保成功完成目标的是 斯坦福大学的跨学科环境和这群 研究者（Kristy Red-Horse、凯尔洛、Alison Marsden和丹尼尔伯恩斯坦博士）。拟议工作 将通过阐明心血管的生物学， 迄今为止神秘的侧支动脉，以及转录调节因子如DACH1如何决定 动脉的命运

PROJECT SUMMARY Heart disease, the most common cause of death, frequently arises from blocking blood flow to cardiac muscle. Blood flow travels to the heart first through coronary arteries and then into a capillary network where oxygen exchange occurs. One approach to treating heart disease has been to expand the capillary network, but this has achieved limited success. Here, we propose to instead expand coronary artery networks and promote the development of collateral arteries, which are a subtype of artery with the potential to form a natural bypass. In the previous funding period, our laboratory discovered cellular and molecular mechanisms driving coronary artery formation in the developing embryo, including how the transcription factor Dach1 supports artery growth through regulating blood flow stimulated cell behaviors (Chang, 2017, Genes and Dev). We also described how the chemokine CXCL12 triggers collateral artery formation in the injured heart during the neonatal growth period (Das, 2019, Cell). We hypothesize that these developmental pathways can be utilized to stimulate adult coronary artery regeneration and provide beneficial outcomes during cardiac injury and disease. Preliminary studies activating Dach1 or CXCl12 in adults shows indications of enhanced recovery following experimental myocardial infarction. We will use the following Aims to further explore their reparative potential. Aim 1 will use tissue clearing, whole organ imaging technology, and computational modeling to define how injury, Dach1 overexpression, and CXCL12 administration alter artery structure and affect blood flow parameters. Aim 2 will use cardiac injury models to intensively study how Dach1- and CXCL12-induced artery growth and collateral development enhance recovery post-myocardial infarction. Aim 3 will delve into the mechanisms by which Dach1 stimulates artery endothelial cell differentiation and morphogenesis. This work is significant because delineating how developmental signals stimulate coronary artery regeneration could ultimately contribute to therapeutic interventions for heart disease. The work is innovative because it takes a new approach to revascularization—targeting artery differentiation rather than just the microvasculature. It also further develops cutting edge experimental techniques such as adult whole organ imaging and a novel in vitro endothelial cell differentiation model, which could ultimately benefit the cardiovascular research community at large. Finally, successful completion of the Aims is ensured by the interdisciplinary environment at Stanford University and collaborative track record between this group of investigators (Drs. Kristy Red-Horse, Kyle Loh, Alison Marsden, and Daniel Bernstein). The proposed work will enhance our knowledge on cardiovascular development and regeneration by illuminating the biology of the hitherto-enigmatic collateral arteries, as well as how transcriptional regulators such as DACH1 determine artery fate.