Mechanotransduction and transcriptional regulation during artery development

项目总结 心脏病是最常见的死亡原因，通常是由于流向心脏的血流受阻引起的。 肌肉。血流首先通过冠状动脉进入心脏，然后进入毛细血管网络，在那里 就会发生氧气交换。治疗心脏病的一种方法是扩大毛细血管网络， 但这一举措取得的成功有限。在这里，我们建议改为扩大冠状动脉网络和 促进侧支动脉的发育，侧支动脉是动脉的一个亚型，具有形成自然动脉的潜力 旁路。在之前的资助期间，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Dach1如何支持 通过调节血流促进动脉生长刺激细胞行为(Chang，2017，gene and Dev)。我们也 描述了趋化因子CXCL12如何在损伤的心脏中触发侧支动脉的形成 新生儿生长期(Das，2019年，细胞)。我们假设这些发育途径可以被利用 在心脏损伤期间刺激成人冠状动脉再生并提供有益的结果 疾病。在成人中激活Dach1或CXCL12的初步研究显示有增强恢复的迹象 在实验性心肌梗死后。我们将利用以下目标来进一步探索它们的修复 潜力。目标1将使用组织清除、整体器官成像技术和计算建模来 明确损伤、Dach1过度表达和CXCL12应用如何改变动脉结构和影响血液 流动参数。Aim 2将使用心脏损伤模型来深入研究Dach1和CXCL12是如何诱导 动脉生长和侧支发育可促进心肌梗死后的恢复。《目标3》将深入研究 Dach1刺激动脉内皮细胞分化和形态发生的机制。 这项工作很有意义，因为描绘了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。这项工作具有创新性 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 微血管系统。它还进一步发展了尖端的实验技术，如成人整体器官 成像和一种新的体外内皮细胞分化模型，最终可能有利于 心血管研究社区的广泛关注。最后，目标的成功完成是由 斯坦福大学的跨学科环境和这组学生之间的合作记录 调查人员(Kristy Red-Horse博士、Kyle Loh博士、Alison Marsden博士和Daniel Bernstein博士)。拟议中的工作 将加强我们对心血管发育和再生的知识，通过阐明 迄今未解之谜的侧支动脉，以及转录调控因子如DACH1如何决定 大动脉的命运。

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.