Mechanisms of ER71/ETV2-regulated Vascularization

ER71/ETV2 调节血管化的机制

• 批准号: 8706229
• 负责人: Changwon Park
• 金额: $ 34.1万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706229
• 关键词: Address; Adult; Binding; Biology; Blood Cells; Blood Vessels; Blood flow; Cardiovascular Diseases; Cells; Data; Development; Disease; Embryo; Embryonic Development; Fibroblast Growth Factor 2; Gene Expression; Generations; Genes; Genetic; Genetic Models; Goals; Hematopoiesis; Injury; KDR gene; Kinetics; Knock-out; Knockout Mice; Lead; Limb structure; MAP Kinase Gene; Mediating; Mesoderm; MicroRNAs; Modeling; Molecular; Mus; Outcome; Pathologic Neovascularization; Pathway interactions; Pattern Formation; Play; Process; Proteins; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Staging; Structure; System; TEK gene; Testing; Tissues; Treatment Efficacy; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascularization; Zinc Fingers; angiogenesis; arm; early embryonic stage; embryonic stem cell; insight; member; neovascularization; novel therapeutics; overexpression; postnatal; programs; public health relevance; receptor; research study; response to injury; stem cell differentiation; tissue regeneration; tissue repair; transcription factor

DESCRIPTION (provided by applicant): FLK1 (VEGFR2), a receptor tyrosine kinase, is a critical component for blood cell and vessel formation as evidenced by knockout studies. FLK1 continues to play an important role in postnatal and pathological angiogenesis. Therefore, understanding molecular mechanisms of Flk1 expression is essential for delineating the pathways involved in vessel formation as well as postnatal angiogenesis. We have demonstrated that the transcription factor ER71 (also known as ETV2) is a critical regulator of FLK1 and thereby it is essential for generation of vascular endothelial cells. Deficiency in Er71 leads to embryonic lethality with a complete absence of vascular structures and blood cells. We also showed that ER71 functions to directly regulate Flk1, indicating the important role of the ER71-FLK1 axis in pathophysiological angiogenesis. However, the mechanisms by which ER71 regulates Flk1 expression and neovascularization remain largely unexplored. Our preliminary studies provide compelling evidence showing its potent and unexpected functions in the mechanism of vascular endothelial cell generation and revascularization in the adult. With our new data, we hypothesize that the interaction between ER71 and OVOL2 is essential for optimal FLK1+ cell generation and revascularization. Additionally, we will test the hypothesis that ER71 regulates FLK1+ cell generation through miR126-Spread1-MAPK signaling. Finally, we will test the hypothesis that reactivation of ER71 following ischemic injury promotes neovascularization through Flk1 expression and thus activates the VEGF-FLK1 signaling pathway. Upon completed, our findings will provide a new and detailed insight into the role of ER71 in vascular endothelial cell generation and revascularization in the adult, which can lead to the development of new therapeutic strategies for cardiovascular diseases.

描述（由申请人提供）： FLK1 (VEGFR2) 是一种受体酪氨酸激酶，敲除研究证明它是血细胞和血管形成的关键成分。 FLK1 在出生后和病理性血管生成中继续发挥重要作用。因此，了解 Flk1 表达的分子机制对于描绘血管形成以及出生后血管生成所涉及的途径至关重要。我们已经证明转录因子 ER71（也称为 ETV2）是 FLK1 的关键调节因子，因此它对于血管内皮细胞的生成至关重要。 Er71 缺乏会导致胚胎死亡，血管结构和血细胞完全缺失。我们还发现 ER71 具有直接调节 Flk1 的功能，表明 ER71-FLK1 轴在病理生理血管生成中的重要作用。然而，ER71 调节 Flk1 表达和新生血管形成的机制在很大程度上仍未被探索。我们的初步研究提供了令人信服的证据，表明其在成人血管内皮细胞生成和血运重建机制中具有强大且意想不到的功能。根据我们的新数据，我们假设 ER71 和 OVOL2 之间的相互作用对于最佳 FLK1+ 细胞生成和血运重建至关重要。此外，我们将测试 ER71 通过 miR126-Spread1-MAPK 信号传导调节 FLK1+ 细胞生成的假设。最后，我们将检验以下假设：缺血性损伤后 ER71 的重新激活通过 Flk1 表达促进新生血管形成，从而激活 VEGF-FLK1 信号通路。完成后，我们的研究结果将为 ER71 在成人血管内皮细胞生成和血运重建中的作用提供新的、详细的见解，这可能导致心血管疾病新治疗策略的开发。