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: 10405492
• 负责人: Mary Red-Horse
• 金额: $ 19.85万
• 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/10405492
• 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.

项目概要 冠状动脉疾病 (CAD) 是全球范围内死亡的主要原因，并造成重大影响 医疗保健和患者生活质量的负担。它是由冠状动脉病理引起的 阻断流向心室心肌的血流。现有的血运重建治疗，例如冠状动脉 动脉搭桥术 (CABG) 或经皮冠状动脉介入治疗并不适合所有患者 并且故障率很高。一种替代方法是诱导侧支动脉， 这是罕见的动脉子集，桥接两条传统动脉并提供替代路线 用于血流（即自然旁路）。一小部分人类患者会出现侧支动脉， 侧支血流量增加可以提高人类的生存率。因此，刺激侧支动脉 可能是 CAD 的有效治疗方法，但其发育机制和生物学 功能了解甚少。 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具有完全抵抗力 由于大量侧支动脉导致闭塞，而大多数哺乳动物（包括小鼠）均不存在侧支动脉。在 初步数据，我们实验室发现豚鼠的侧支动脉在胚胎时期发育 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。 （目标1）我们将使用整体免疫组织化学和单 细胞 RNA 测序可对发育中的豚鼠和 老鼠的心。与侧支动脉（即豚鼠心脏）相关的基因和通路将被 被认为是其发展的候选驱动力。 （目标2）接下来我们将对这些进行功能测试 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。 完成这些目标后，我们将完全建立豚鼠作为援助模型 侧支动脉的研究。这包括编制豚鼠心脏细胞图谱，确定 豚鼠心脏与小鼠心脏比较，并测试选择候选旁路诱导剂。成功将会 激发对 CAD 具有转化意义的长期项目。