Regulation of Angiogenesis During Wound Healing

伤口愈合过程中血管生成的调节

• 批准号: 6623765
• 负责人: ERIC W HOWARD
• 金额: $ 34.48万
• 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/6623765
• 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