Studying guinea pig development to discover how natural collateral arteries form

研究豚鼠的发育以发现自然侧支动脉是如何形成的

• 批准号: 10195510
• 负责人: Mary Red-Horse
• 金额: $ 23.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195510
• 关键词: Adult; Arteries; Atlases; Biological Process; Biology; Blood; Blood flow; Bypass; CXCL12 gene; Cardiac; Cause of Death; Cavia; Cells; Comparative Biology; Coronary; Coronary Arteriosclerosis; Coronary Artery Bypass; Coronary artery; Data; Development; Disease; Embryonic Development; Embryonic Heart; Exogenous Factors; Failure; Future; Gene Expression Profile; Genes; Health; Healthcare; Heart; Heart Diseases; Heart Injuries; Human; Hypoxia; Image; Immunohistochemistry; Individual; Intervention; Knowledge; Laboratories; Lead; Life; Mammals; Mediating; Methods; Modeling; Molecular; Mus; Myocardial Infarction; Myocardium; Pathology; Pathway interactions; Patients; Property; Quality of life; Refractory; Resistance; Resolution; Route; Survival Rate; Testing; Tissues; Ventricular; cell type; comparative; coronary artery occlusion; design; differential expression; heart cell; improved; neonatal mice; novel; percutaneous coronary intervention; postnatal development; repaired; response; single-cell RNA sequencing; success; transcriptomics

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.

项目摘要 冠状动脉疾病（CAD）是世界范围内死亡的主要原因， 对医疗保健和患者生活质量造成负担。它是由冠状动脉病变引起的， 阻断流向心室心肌的血流。现有的血运重建治疗，如冠状动脉 动脉旁路移植术（CABG）或经皮冠状动脉介入治疗并不是所有患者的选择 并且具有显著的失败率。一种替代方法可以是诱导侧支动脉， 这是一种罕见的动脉子集，它桥接两条传统动脉并提供另一条路线， 对于血流（即，自然旁路）。一小部分人类患者会形成侧支动脉， 侧支血流量的增加增加了人类的存活率。因此，刺激侧支动脉 可能是一种有用的治疗CAD，但他们的发展机制和生物学 功能了解不多。 我们的实验室将利用豚鼠心脏的正常生物学来发现 侧支动脉发育豚鼠对永久性冠状动脉完全有抵抗力 由于许多侧支动脉导致的闭塞，这在包括小鼠在内的大多数哺乳动物中是不存在的。在 初步资料，我们实验室发现豚鼠侧支动脉在胚胎期发育， 开发，这将极大地促进发现的功能。我们建议使用比较生物学 一种通过比较豚鼠的侧支动脉发育机制来揭示侧支动脉发育机制的方法 和小鼠胚胎心脏。（目的1）我们将使用整体安装免疫组化和单 细胞RNA测序，以比较发育中的豚鼠和 老鼠心脏与侧支动脉（即豚鼠心脏）相关的基因和途径将被 被认为是其发展的候选驱动力。（目标2）我们接下来将对这些功能进行测试 通过将它们引入新生小鼠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式， 对侧支动脉的研究。这包括编制豚鼠心脏细胞图谱，确定 豚鼠心脏与小鼠比较，并测试选择候选的侧枝诱导剂。成功将 激励一个长期的项目，对CAD的翻译影响。