Regulation of Angiogenesis During Wound Healing

伤口愈合过程中血管生成的调节

• 批准号: 6616469
• 负责人: ERIC W HOWARD
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616469
• 关键词: angiogenesis; angiopoietins; basement membrane; blood vessels; cell migration; cell proliferation; crosslink; gel mobility shift assay; gene expression; gene targeting; genetic regulation; genetic regulatory element; genetically modified animals; homeostasis; in situ hybridization; laboratory mouse; messenger RNA; microinjections; posttranscriptional RNA processing; protein tyrosine kinase; reporter genes; tissue /cell culture; transcription factor; vascular endothelium; vascular smooth muscle; wound healing

Description (provided by applicant): Wound healing requires the formation of new vasculature in a complex process that is dependent on stabilization and destabilization signals. The endothelial cell-specific receptor tyrosine kinase, Tie2, when stimulated by its primary ligand, angiopoietin-1 (Ang1), promotes blood vessel stability by stimulating cell viability, basement membrane integrity, and perivascular cell recruitment. Ang2, an antagonist of the Tie2 receptor, blocks these signals by competing for Ang1 binding, and is necessary for the locaiized vessel instability associated with angiogenesis. Thus, the ratio of Ang1 to Ang2 is a critical factor in the regulation of neovascularization; altering Ang1 or Ang2 expression can lead to profound vascular defects. This study focuses on evidence that Ang2 expression is regulated post-transcriptionally; endothelial and smooth muscle cell culture models demonstrate profound changes in Ang2 mRNA half-life in response to certain growth factors. This induced change in message stability is dependent on new transcription, presumably of factors associated with regulated mRNA turnover. It is hypothesized that such post-traiascriptional regulation is critical for the maintenance of appropriate Ang2 levels during tissue repair. To test this, the putative mRNA control elements within the human, mouse, and rat Ang2 MRNAs that regulate induced message stability/instability or translation will be identified and characterized. Their role in regulating Ang2 expression will then be tested in vivo by introducing these elements into reporter constructs; which will then be used to develop transgenic mice. The biological roles of these mRNA control elements will be further analyzed in mice in which these elements are ablated by conditional homologous recombination. These mouse models will be used to test the effects of dysfunctional Ang2 post-transcriptional regulation on wound healing. These studies will indicate the relative importance of post-transcriptional regulation of Ang2, and whether eliminating the ability of cells to regulate Ang2 mRNA stability or translation impacts vessel structure during the wound healing process.

描述（由申请人提供）：伤口愈合需要形成 在复杂过程中的新脉管系统取决于稳定和 不稳定信号。内皮细胞特异性受体酪氨酸 激酶，TIE2，当由其主要配体刺激Angiopoietin-1（Ang1）时， 通过刺激细胞活力，地下室来促进血管稳定性 膜完整性和血管周细胞募集。 Ang2，对立者 TIE2受体，通过竞争ANG1结合来阻止这些信号，并且是 与血管生成相关的局部血管不稳定性所必需的。 因此，ANG1与Ang2的比率是调节的关键因素 新血管化；改变Ang1或Ang2表达会导致深刻 血管缺陷。这项研究重点是ANG2表达的证据 转录后受到监管；内皮和平滑肌细胞培养 模型显示出Ang2 mRNA半衰期的深刻变化。 某些增长因素。这种诱导的消息稳定性变化取决于 关于新的转录，大概是与受调节mRNA相关的因素 周转。假设这种三口后调节是 在组织修复过程中维持适当的ANG2水平至关重要。 为了测试这一点，人，小鼠和 调节诱导消息稳定/不稳定性或 翻译将被识别和表征。它们在调节Ang2中的作用 然后，将通过将这些元素引入到体内测试 记者构造；然后将用于开发转基因小鼠。这 这些mRNA对照元件的生物学作用将进一步分析 这些元素通过条件同源烧毁的小鼠 重组。这些鼠标模型将用于测试 ANG2功能障碍后的转录后调节伤口愈合。这些 研究将表明转录后的相对重要性 ANG2的调节，以及是否消除了细胞调节的能力 Ang2 mRNA稳定性或翻译会影响伤口期间的血管结构 康复过程。