Mechanisms of MMP-2 transcription in hindlimb ischemia

后肢缺血中MMP-2转录的机制

• 批准号: 7032907
• 负责人: RAJABRATA SARKAR
• 金额: $ 41.25万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032907
• 关键词: amputation; angiogenesis; cardiovascular surgery; collagenase; enzyme activity; gene expression; genetic promoter element; genetic regulatory element; genetically modified animals; hypoxia; inflammation; introns; ischemia; laboratory mouse; leg; molecular genetics; molecular site; postoperative complications; striated muscles; transcription factor; vascular endothelium

DESCRIPTION (provided by applicant): Critical ischemia of the lower limbs remains a serious problem in vascular surgery with a substantial fraction of patients undergoing eventual amputation despite surgical bypass and catheter-directed therapies. The cellular and molecular mechanisms that drive in vivo transcription of genes essential for correction of ischemia remain largely undefined, and are a potential area for the development of therapeutic regimens for tissue ischemia. Matrix metalloproteinases are enzymes critical for angiogenesis and arteriogenesis induced by tissue ischemia. Matrix metalloproteinase 2 (MMP-2) is transcriptionally induced in tissue ischemia and is a critical enzyme for angiogenesis and arterial enlargement. The molecular mechanisms for transcriptional induction of MMP-2 and the significance of MMP-2 upregulation in ischemia in vivo remain unknown. Therefore, we propose to test the central hypotheses of this proposal: Tissue ischemia induces MMP-2 transcription via specific cis- and trans-acting regulatory elements and MMP-2 expression plays a critical role in the angiogenesis and arteriogenesis induced by ischemia. This hypothesis will be tested with the following Specific Aims: 1) To determine the regions within the MMP-2 promoter that are critical for in vivo transcriptional activation by ischemia, 2) To identify the transcription factors responsible for ischemia-induced MMP-2 transcription in vivo and characterize their activation by specific mediators in vivo, 3) To determine if MMP-2 is critical to the revascularization response after ischemia and to examine the effect of cell type-specific overexpression of MMP-2 on ischemia-induced angiogenesis and arteriogenesis in vivo. Defining the cellular and molecular mechanisms that induce MMP-2 expression in vivo will increase our knowledge of transcriptional activation of critical genes by tissue ischemia, and form the foundation for the development of molecular therapy for critical limb ischemia in patients.

描述（由申请人提供）：下肢严重缺血仍然是血管手术中的一个严重问题，尽管进行了外科搭桥手术和导管导向治疗，仍有相当一部分患者最终接受截肢。驱动纠正缺血所必需的基因体内转录的细胞和分子机制在很大程度上仍不清楚，并且是开发组织缺血治疗方案的潜在领域。基质金属蛋白酶是对组织缺血诱导的血管生成和动脉生成至关重要的酶。基质金属蛋白酶 2 (MMP-2) 在组织缺血中被转录诱导，是血管生成和动脉扩张的关键酶。 MMP-2 转录诱导的分子机制以及 MMP-2 上调在体内缺血中的意义仍不清楚。因此，我们建议测试该提议的中心假设：组织缺血通过特定的顺式和反式作用调节元件诱导MMP-2转录，并且MMP-2表达在缺血诱导的血管生成和动脉生成中发挥关键作用。该假设将通过以下具体目标进行测试：1) 确定 MMP-2 启动子内对缺血引起的体内转录激活至关重要的区域，2) 鉴定负责体内缺血诱导的 MMP-2 转录的转录因子，并表征其在体内通过特定介质的激活，3) 确定 MMP-2 是否对缺血后的血运重建反应至关重要，并检查 细胞类型特异性 MMP-2 过度表达对体内缺血诱导的血管生成和动脉生成的影响。明确体内诱导 MMP-2 表达的细胞和分子机制将增加我们对组织缺血引起的关键基因转录激活的认识，并为开发针对患者严重肢体缺血的分子治疗奠定基础。