Studying guinea pig development to discover how natural collateral arteries form

项目总结 冠状动脉疾病(CAD)是世界范围内导致死亡的主要原因，对人类健康和健康构成重要影响。 医疗保健和患者生活质量的负担。它是由冠状动脉的病理引起的 阻断流向心室肌的血液。现有的血管重建治疗，如冠状动脉 动脉搭桥术(CABG)或经皮冠状动脉介入治疗并不是所有患者的选择 并且有很高的失败率。另一种方法是诱导侧支动脉， 这是一种罕见的动脉子集，连接了两个常规动脉并提供了另一条途径 用于血液流动(即自然搭桥)。一小部分人类患者会形成侧支动脉， 而侧支血流量的增加会增加人类的存活率。因此，刺激侧支动脉 可能是治疗冠心病的有效方法，但它们的发育机制和生物学 人们对其功能知之甚少。 我们实验室将利用豚鼠心脏的正常生物学来探索心脏的作用机制。 侧支动脉发育。豚鼠对永久性冠状动脉完全耐受 闭塞是由于大量的侧支动脉引起的，包括小鼠在内的大多数哺乳动物都没有侧支动脉。在……里面 初步资料显示，本实验室发现豚鼠胚胎期间侧支动脉发育。 开发，这一功能将极大地促进发现。我们建议使用比较生物学 通过比较豚鼠揭示侧支动脉发育机制的方法 和小鼠胚胎心脏。(Aim1)我们将采用整体免疫组织化学和单细胞免疫组织化学 细胞RNA测序对发育中的豚鼠和正常豚鼠细胞分辨率的比较 老鼠的心。与侧支动脉(即豚鼠心脏)相关的基因和途径将 被认为是其发展的候选驱动力。(AIM2)接下来我们将对这些功能进行测试 通过将它们引入新生小鼠的心脏并评估它们是否诱导 侧支动脉发育。 在完成这些目标后，我们将完全建立豚鼠作为援助的模型 侧支动脉学对侧支动脉的研究这包括编制一份豚鼠心脏细胞图谱，确定 豚鼠心脏与小鼠比较，测试筛选出候选侧支诱导剂。成功将会 推动一个对CAD有翻译影响的较长期项目。

PROJECT SUMMARY Coronary artery disease (CAD) is the leading cause of death worldwide and poses a significant burden on healthcare and patient quality of life. It is caused by pathology of the coronary arteries that occludes blood flow to ventricular heart muscle. Existing revascularization treatments, such as coronary artery bypass grafts (CABG) or percutaneous coronary interventions, are not an option for all patients and have significant failure rates. One alternative approach could be induction of collateral arteries, which are a rare subset of arteries that bridge two conventional arteries and provide an alternative route for blood flow (i.e., natural bypasses). A small subset of human patients develops collateral arteries, and elevated collateral blood flow increases survival in humans. Thus, stimulating collateral arteries could be a useful treatment for CAD, yet their developmental mechanisms and biological functions are poorly understood. Our laboratory will utilize the normal biology of guinea pig hearts to discover mechanisms of collateral artery development. Guinea pigs are completely resistant to permanent coronary artery occlusion due to numerous collateral arteries, which are absent in most mammals including mice. In preliminary data, our laboratory discovered that guinea pig collateral arteries develop during embryonic development, a feature that will greatly facilitate discovery. We propose to use a comparative biology approach that uncovers collateral artery developmental mechanisms by comparing guinea pig and mouse embryonic hearts. (Aim1) We will use whole mount immunohistochemistry and single cell RNA sequencing to perform cellular resolution comparisons between developing guinea pig and mouse hearts. Genes and pathways correlating with collateral arteries (i.e. guinea pig hearts) will be considered candidate drivers of their development. (Aim2) We will next functionally test these candidates by introducing them into neonatal mouse hearts and assessing whether they induce collateral artery development. Upon completion of these aims, we will have fully established the guinea pig as a model to aid the study of collateral arteries. This includes compiling a guinea pig heart cell atlas, identifying how the guinea pig heart compares with mouse, and testing select candidate collateral inducers. Success will motivate a longer-term project with translational implications for CAD.