ROLE OF HIF-1 GUT BARRIER DYSFUNCTION AND DISTANT ORGAN DAMAGE

HIF-1 肠道屏障功能障碍和远处器官损伤的作用

• 批准号: 7074172
• 负责人: RENA R FEINMAN
• 金额: $ 8.87万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074172
• 关键词: cell line; enteric bacteria; estrus; gene expression; hemorrhagic shock; hormone regulation /control mechanism; host organism interaction; hypoxia inducible factor 1; inflammation; injury; intestines; ischemia; laboratory mouse; laboratory rat; lipopolysaccharides; lung injury; lymph; mesentery; mitogen activated protein kinase; multiple organ failure; nitric oxide; pathologic process; protein structure function; reperfusion; serine threonine protein kinase; sex hormones; trauma; cell line; enteric bacteria; estrus; gene expression; hemorrhagic shock; hormone regulation /control mechanism; host organism interaction; hypoxia inducible factor 1; inflammation; injury; intestines; ischemia; laboratory mouse; laboratory rat; lipopolysaccharides; lung injury; lymph; mesentery; mitogen activated protein kinase; multiple organ failure; nitric oxide; pathologic process; protein structure function; reperfusion; serine threonine protein kinase; sex hormones; trauma

Elucidating the hypoxia-inducible factor (HIF-1) response in gut barrier dysfunction and distant organ damage is the overall objective of this proposal. The studies proposed in this grant will test the following global hypothesis that persistence of the ischemia-induced HIF-1alpha response by intestinal bacteria and their products shifts the HIF-1alpha response from an adaptive/protective response to a potentially maladaptive/injurious one. Consequently, in this proposal, we will test the concept that the sustained HIF- 1cc response in the gut acts as an effector in ischemia/reperfusion-mediated gut injury and the production of gut derived factors, thereby playing a role in gut-induced distant organ damage. By providing potentially important mechanistic information on the pathogenesis of T/HS-induced gut injury, the results obtained from our studies will help clarify key issues of the Center Grant's first global hypothesis, which is that gut-derived factors present in the mesenteric lymph of the ischemic gut contribute to distant organ injury. Additionally, the experiments proposed in our Specific Aims will contribute to the Center Grant's second major hypothesis by testing whether the resistance of proestrus female rats to T/HS-induced gut injury is associated with a differential HIF-1 intestinal response and that the intestinal HIF-1 response to T/HS is. at least in part. modulated by sex hormones. Aim 1 will elucidate the functional significance of l/R-mediated elevations of intestinal HIF-1 in vivo as well as the role of intestinal bacteria in prolonging the intestinal HIF-1 response. The effects of T/HS-induced gut injury, gut inflammation and acute lung injury will be examined in partially deficient HIF-1alpha+/- and HIF-1+/+ WT mice. To further evaluate the effect of intestinal bacteria on the HIF-1 response, intestinal antibiotic decontamination and bacterial overgrowth male rat T/HS models will be employed. The effects of partial HIF-1alpha deficiency on gut injury and inflammation will also be tested in the intestinal bacterial overgrowth and antibiotic decontaminated T/HS models. Aim 2 will test whether overexpression or inhibition of HIF-1 in enterocytic cell lines affects gut barrier function and gut inflammation utilizing enterocytic cell lines. Aim 3 will elucidate the mechanisms by which enteric bacteria or LPS regulate HIF-1 activation in enterocytes under normoxic conditions. Specifically, experiments will determine whether regulation of HIF-1 is via the activation of MARK, Akt or NO. Aim 4 will test the hypothesis that the resistance of proestrus female rats to T/HS-induced gut injury is associated with a blunted intestinal HIF-1 a response. A deeper insight of the intestinal HIF-1 response will identify potential targets for therapeutic intervention at the onset of intestinal ischemia.

阐明肠道功能障碍和远处器官中缺氧诱导因子（HIF-1）反应 损害是该提案的总体目标。该赠款中提出的研究将测试以下 全球假设是，肠道细菌和 他们的产品将HIF-1Alpha响应从自适应/保护性响应转移到了潜在的 适应不良/有害的人。因此，在此提案中，我们将检验以下概念，即持续的hif- 肠道中的1CC反应是缺血/再灌注介导的肠道损伤的效应器 肠道衍生的因素，从而在肠道引起的远处器官损伤中发挥作用。通过可能提供 关于T/HS诱导的肠道损伤的发病机理的重要机械信息，从 我们的研究将有助于阐明中心赠款的第一个全球假设的关键问题，即肠道衍生 缺血性肠道的肠系膜淋巴中存在的因素导致远处的器官损伤。此外， 我们具体目标中提出的实验将有助于中心赠款的第二个主要假设 通过测试雌性大鼠对T/HS诱导的肠道损伤的抗性是否与A有关 差异HIF-1肠反应以及肠道HIF-1对T/HS的反应是。至少部分。 由性激素调节。 AIM 1将阐明L/R介导的高程的功能意义 肠道HIF-1体内以及肠道细菌在延长肠道HIF-1反应中的作用。 T/HS诱导的肠道损伤，肠炎和急性肺损伤的影响将部分检查 缺陷HIF-1Alpha +/-和HIF-1+/+WT小鼠。进一步评估肠道对HIF-1的影响 反应，肠道抗生素去污和细菌过度生长的男性大鼠T/HS模型将是 雇用。部分HIF-1Alpha缺乏对肠道损伤和炎症的影响也将在 肠道细菌过度生长和抗生素去污染的T/HS模型。 AIM 2将测试是否 肠细胞系中HIF-1的过表达或抑制会影响肠道屏障功能和肠炎 利用肠细胞细胞系。 AIM 3将阐明肠细菌或LPS调节的机制 肠肠细胞中的HIF-1激活在常氧条件下。具体而言，实验将确定是否 HIF-1的调节是通过MARK，AKT或NO的激活。 AIM 4将检验以下假设 雌性大鼠对T/HS诱导的肠道损伤的抗性与钝性的肠道HIF-1 A有关 回复。对肠道HIF-1反应的更深入了解将确定治疗的潜在靶标 肠缺血发作时的干预。