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

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.

阐明肠道屏障功能障碍和远端器官中缺氧诱导因子 (HIF-1) 的反应 损害是该提案的总体目标。这笔赠款中提出的研究将测试以下内容 全球假设认为，肠道细菌持续存在缺血诱导的 HIF-1α 反应， 他们的产品将 HIF-1alpha 反应从适应性/保护性反应转变为潜在的 适应不良/有害的。因此，在本提案中，我们将测试持续的 HIF- 肠道中的 1cc 反应在缺血/再灌注介导的肠道损伤和产生 肠道衍生因素，从而在肠道引起的远端器官损伤中发挥作用。通过提供潜在的 关于 T/HS 诱导的肠道损伤发病机制的重要机制信息，结果来自 我们的研究将有助于澄清格兰特中心第一个全球假说的关键问题，即肠道来源的假说 缺血性肠道肠系膜淋巴中存在的因素会导致远处器官损伤。此外， 我们的具体目标中提出的实验将有助于格兰特中心的第二个主要假设 通过测试发情前期雌性大鼠对 T/HS 诱导的肠道损伤的抵抗力是否与 差异 HIF-1 肠道反应和肠道 HIF-1 对 T/HS 的反应是。至少部分如此。 受性激素调节。目标 1 将阐明 l/R 介导的升高的功能意义 肠道HIF-1在体内以及肠道细菌的作用下延长肠道HIF-1反应。 T/HS 诱导的肠道损伤、肠道炎症和急性肺损伤的影响将得到部分研究 缺陷型 HIF-1alpha+/- 和 HIF-1+/+ WT 小鼠。进一步评估肠道细菌对HIF-1的影响 反应、肠道抗生素净化和细菌过度生长雄性大鼠 T/HS 模型将 受雇。部分 HIF-1α 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净化 T/HS 模型。目标 2 将测试是否 肠细胞系中 HIF-1 的过度表达或抑制会影响肠道屏障功能和肠道炎症 利用肠细胞系。目标 3 将阐明肠道细菌或 LPS 调节的机制 常氧条件下肠细胞中 HIF-1 的激活。具体来说，实验将确定是否 HIF-1 的调节是通过 MARK、Akt 或 NO 的激活来实现的。目标 4 将检验以下假设： 发情前期雌性大鼠对 T/HS 诱导的肠道损伤的抵抗力与肠道 HIF-1 a 钝化有关 回复。更深入地了解肠道 HIF-1 反应将确定潜在的治疗靶点 肠道缺血发生时进行干预。