E2F1 in Cardiac Neovascularization

E2F1 在心脏新生血管中的作用

• 批准号: 8235046
• 负责人: Gangjian Qin
• 金额: $ 37.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-09 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235046
• 关键词: Acute myocardial infarction; Angiogenesis Inhibitors; Binding; Biological; Blood Vessels; Blood flow; Bone Marrow; Cardiac; Cardiovascular system; Cause of Death; Cell Cycle Regulation; Cell Survival; Cell physiology; Cells; Complex; Development; Disease; E2F transcription factors; E2F1 gene; Elements; Event; Gene Expression; Genetic Transcription; Goals; Growth; Half-Life; Health; Heart; Hindlimb; Histocompatibility Testing; Hypoxia; Investigation; Ischemia; Mediating; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; Oncogenes; Pathogenesis; Pathway interactions; Physiological; Play; Preventive; Production; Proliferating; Recovery; Recovery of Function; Regulation; Reporting; Role; Series; Stem cells; Testing; Tissue Preservation; Transcription Coactivator; Transcriptional Regulation; Transplantation; Ubiquitin; VEGFA gene; Vascular Endothelial Growth Factors; Vascular blood supply; Wild Type Mouse; Work; angiogenesis; cell growth; domain mapping; follow-up; functional outcomes; heart function; improved; in vivo; neovascularization; novel; novel strategies; overexpression; promoter; public health relevance; research study; response; therapeutic target; tissue regeneration; vasculogenesis

DESCRIPTION (provided by applicant): Insufficient neovascularization, characterized by poor vessel growth, is a major contributor to the pathogenesis of ischemic heart disease and limits the capacity of cardiac tissue preservation and regeneration. The E2F transcription factors are key regulators of cell growth and survival. Specifically, E2F1 is a transcriptional activator that, when overexpressed, induces quiescent cells to proliferate. However, accumulating evidence also indicates that, beyond cell cycle regulation, E2F1 has diverse physiological functions that are specific to tissue type and biological context. We have recently reported the following: A) Loss of E2F1 enhances angiogenesis in surgically induced hindlimb ischemia and accelerates the recovery of blood flow, indicating that E2F1 is an angiogenic inhibitor; B) The primary cause of the enhanced angiogenesis observed in E2F1-deficient mice appears to be the overproduction of vascular endothelial growth factor (VEGF), and E2F1 suppresses the transcription of VEGF; C) Oncogene p53 may also play a role in this E2F1- mediated hypoxic regulation of VEGF expression and resulting modulation of angiogenesis. However, neither the molecular mechanisms governing E2F1-mediated VEGF suppression nor the contributions of the intracellular association and crosstalk between E2F1 and p53 in VEGF-induced angiogenesis have been elucidated. In addition, our follow-up preliminary studies indicate that loss of E2F1 not only leads to an increase in VEGF expression but also significantly enhances the migratory capacity of bone marrow-derived endothelial progenitor cells (BM EPCs) under hypoxic conditions. It is our central hypothesis that E2F1 regulates neovascularization by modulating both p53-dependent VEGF gene expression and EPC activity, and thereby impacts the functional outcome of myocardial infarction. This hypothesis will be tested by the following specific aims: 1) to investigate molecular mechanisms of E2F1-mediated p53-dependent regulation of VEGF transcription; 2) to elucidate the role of E2F1-regulated neovascularization in the recovery of heart function after myocardial infarction; 3) to define the role of E2F1 in BM EPC-mediated vasculogenesis in the ischemic myocardium. We anticipate that the experiments proposed in this project will provide a critical framework for understanding the mechanisms that underlie E2F1-mediated regulation of neovascularization and the functional significance of E2F1 in ischemic heart disease, which could potentially aid the development of novel therapies for ischemic diseases. PUBLIC HEALTH RELEVANCE: Ischemic heart disease, the leading cause of death nationally, occurs when vessels are unable to deliver a sufficient supply of blood to the heart, which also limits the capacity of the heart to regenerate tissues damaged by a cardiovascular event or disease. This proposal describes a series of experiments that will help to unravel the mechanisms of blood vessel growth and thereby identify potential novel strategies for treating this critical health problem.

描述（由申请方提供）：新生血管形成不足，特征为血管生长不良，是缺血性心脏病发病机制的主要因素，并限制了心脏组织保存和再生的能力。E2 F转录因子是细胞生长和存活的关键调节因子。具体而言，E2 F1是一种转录激活因子，当过表达时，诱导静止细胞增殖。然而，越来越多的证据也表明，除了细胞周期调控，E2 F1具有多种生理功能，这些功能对组织类型和生物学环境具有特异性。我们最近报道了以下结果：A）E2 F1的缺失增强了手术诱导的后肢缺血中的血管生成并加速了血流的恢复，表明E2 F1是血管生成抑制剂：B）在E2 F1缺失小鼠中观察到的增强的血管生成的主要原因似乎是血管内皮生长因子（VEGF）的过度产生，并且E2 F1抑制VEGF的转录; C）癌基因p53也可能在E2 F1介导的VEGF表达的低氧调节和导致的血管生成调节中起作用。然而，无论是E2 F1介导的VEGF抑制的分子机制，也没有在VEGF诱导的血管生成的E2 F1和p53之间的细胞内协会和串扰的贡献已被阐明。此外，我们的后续初步研究表明，E2 F1的损失不仅导致VEGF表达的增加，而且还显着增强骨髓来源的内皮祖细胞（BM EPCs）在缺氧条件下的迁移能力。我们的中心假设是E2 F1通过调节p53依赖的VEGF基因表达和EPC活性来调节新生血管形成，从而影响心肌梗死的功能结局。这一假设将通过以下具体目标进行验证：1）研究E2 F1介导的p53依赖性VEGF转录调节的分子机制; 2）阐明E2 F1调节的新生血管在心肌梗死后心脏功能恢复中的作用; 3）确定E2 F1在缺血心肌BM EPC介导的血管发生中的作用。我们预计，在这个项目中提出的实验将提供一个重要的框架，了解E2 F1介导的新生血管的调节机制和E2 F1在缺血性心脏病中的功能意义，这可能有助于开发缺血性疾病的新疗法。 公共卫生相关性：缺血性心脏病是全国死亡的主要原因，当血管无法向心脏提供足够的血液供应时就会发生，这也限制了心脏再生心血管事件或疾病损伤组织的能力。该提案描述了一系列实验，这些实验将有助于揭示血管生长的机制，从而确定治疗这一关键健康问题的潜在新策略。