Investigating the Roles of APJ, Hypoxia, and SOX17 in the Development of Coronary Vessels

项目总结

Project Summary This proposal uses transgenic mouse models and modern cell and molecular biology approaches to characterize the roles of APJ, hypoxia, and SOX17 in the regulation of coronary vessel formation. Coronary artery disease is one of the leading causes of death worldwide and still lacks effective treatment. Therefore, understanding how these vessels form for the first time in the embryos and dissecting their cellular and molecular mechanisms can be valuable in designing appropriate therapeutics. From studies in mice, it is known that coronary vessels are formed from multiple endothelial progenitors namely proepicardium, sinus venosus, and endocardium. Although the progenitor stem cells for the origin of coronary vessel formation is identified, a significant lack of knowledge exist on what cues guide these progenitors to form coronary vascular tree. In this context, we have identified molecular pathways that selectively impact coronary growth from sinus venosus and endocardium. Apelin receptor (commonly known as APJ), a G-protein coupled receptor, is found to be important for the sinus venous derived progenitor pathway whereas myocardial hypoxia is found to be potentially important for the endocardium derived progenitor pathway of coronary vessel formation. Furthermore, a transcription factor SOX17 is also found to be expressed by activated endocardial progenitors, suggesting a role for SOX17 during coronary angiogenesis. At this point, we know very little on how APJ, hypoxia inducible factor-1alpha (HIF-1alpha), and SOX17 regulate coronary angiogenesis. APJ is activated by two peptide ligands, ELABELA (aliases: APELA, TODDLER) and APELIN, which are both expressed in embryonic hearts. It is not clear how APJ signaling from these two ligands coordinate the progression of coronary vessel formation from sinus venosus progenitor pathway. This proposal is aimed at unraveling the unknowns of APJ, Hypoxia, and SOX17 mediated regulation of coronary vessel formation. In Aim 1, we hypothesize that ELABELA/APJ and APELIN/APJ signaling primes sinus venosus derived coronary progenitors to respond to angiogenic cues such as VEGFC (in the epicardium) and VEGF-A (in the myocardium) respectively. In Aim 2, we hypothesize that myocardial hypoxia activates SOX17 expression in endocardial progenitors, and SOX17 promotes coronary angiogenesis. The experiments proposed in this study are highly appropriate for high school, undergraduate, and graduate students and these students will be engaged in every stage of the project, allowing them to obtain authentic research experience with innovative approaches including transgenic mouse models (gain- of-function and loss-of-function models), cell and tissue culture systems, and modern cell and molecular biology techniques.