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

研究 APJ、缺氧和 SOX17 在冠状血管发育中的作用

• 批准号: 10291709
• 负责人: Bikram Sharma
• 金额: $ 42.9万
• 依托单位: BALL STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291709
• 关键词: APLN gene; Academic Research Enhancement Awards; Address; Adult; Blood Vessels; Cause of Death; Cell Culture Techniques; Cellular biology; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Cues; Data; Defect; Development; Disease; Embryo; Embryonic Heart; Endocardium; Endothelial Cells; Endothelium; Epicardium; Fetal Diseases; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Goals; Growth; Heart; Heart failure; Hypoxia; Hypoxia Inducible Factor; In Vitro; Knock-out; Knowledge; Laboratories; Ligands; Mediating; Modeling; Modernization; Molecular; Molecular Biology; Molecular Biology Techniques; Mus; Myocardial Infarction; Myocardium; Natural regeneration; Pathogenesis; Pathway interactions; Peptides; Population; Procedures; Process; Receptor Activation; Receptor Signaling; Regulation; Research; Research Training; Role; SOX17 gene; Science; Signal Transduction; Source; Structure of sinus venosus of fetus; Students; System; Therapeutic; Time; Training; Transgenic Mice; Trees; Universities; VEGFC gene; Vascular Endothelial Growth Factors; Work; angiogenesis; career; cell behavior; clinically significant; design; effective therapy; experience; experimental study; gain of function; graduate student; high school; in vivo; innovation; loss of function; migration; mouse model; myocardial hypoxia; prevent; progenitor; receptor; repaired; research and development; response; stem cell population; stem cells; tissue culture; transcription factor; undergraduate student; venous sinus

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.

项目摘要 该提案使用转基因小鼠模型和现代细胞和分子生物学方法来表征 APJ、缺氧和SOX 17在冠状动脉血管形成调节中的作用。冠状动脉疾病是 这是世界范围内的主要死因之一，目前仍缺乏有效的治疗方法。因此，了解如何 这些血管在胚胎中首次形成，解剖它们的细胞和分子机制， 在设计适当的治疗方法方面很有价值。从对小鼠的研究中，已知冠状动脉血管是 由多个内皮祖细胞即心外膜、静脉窦和内皮细胞形成。虽然 对于冠状动脉血管形成的起源祖细胞的确定，知识明显缺乏 存在于什么线索引导这些祖细胞形成冠状血管树。在这方面，我们确定了 选择性影响静脉窦和内膜冠状动脉生长的分子途径。Apelin 受体（通常称为APJ），一种G蛋白偶联受体，被发现对窦静脉 而心肌缺氧被发现是潜在的重要的内皮细胞 冠状动脉血管形成的衍生祖细胞途径。此外，还发现了转录因子SOX 17 由激活的内皮祖细胞表达，表明SOX 17在冠状动脉粥样硬化过程中的作用。 血管生成在这一点上，我们对APJ，缺氧诱导因子-1 α（HIF-1 α）， SOX 17调节冠状动脉血管生成。APJ由两种肽配体ELABELA（别名：APELA， TODDLER）和APELIN，它们都在胚胎心脏中表达。目前尚不清楚APJ如何从 这两种配体协调静脉窦祖细胞形成冠状血管的进程 通路该提案旨在揭示APJ、缺氧和SOX 17介导的未知因素 冠状血管形成的调节。在目标1中，我们假设ELABELA/APJ和APELIN/APJ 通过信号传导引发静脉窦来源的冠状动脉祖细胞对血管生成线索如VEGFC作出反应 (in心外膜）和VEGF-A（心肌中）。在目标2中，我们假设 心肌缺氧激活内皮祖细胞中SOX 17的表达，SOX 17促进冠状动脉粥样硬化。 血管生成本研究提出的实验非常适合高中、本科、 这些学生将参与项目的每个阶段，使他们能够 通过创新方法获得真实的研究经验，包括转基因小鼠模型（gain- 功能和功能丧失模型）、细胞和组织培养系统以及现代细胞和分子生物学系统。 生物技术

项目成果

APJ+ cells in the SHF contribute to the cells of aorta and pulmonary trunk through APJ signaling.

• DOI: 10.1016/j.ydbio.2023.04.003
• 发表时间: 2023-04
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: K. Baral;Gaetano D'Amato;Bryce Kuschel;Frank Bogan;Brendan W. Jones;Colton L. Large;Jeffery D. Whatley;K. Red-Horse;B. Sharma