Role of Epithelia In Ischemia Reperfusion Injury

上皮细胞在缺血再灌注损伤中的作用

• 批准号: 7386650
• 负责人: Sean P Colgan
• 金额: $ 29.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-25 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386650
• 关键词: 5' -Nucleotidase; ABCB1 gene; Adenine Nucleotides; Adenosine; Anatomy; Apical; Binding Sites; Blood Vessels; Blood flow; CD55 Antigens; Colitis; Colon; Disease; Disruption; Elements; Enzymes; Epithelial; Epithelial Cells; Epithelium; Event; Generations; Genes; Genus Cola; Health; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Leukocyte Trafficking; Leukocytes; Ligands; Localized; Location; Lung; Measures; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolic acidosis; Metabolism; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Myeloid Cells; Numbers; Organ; Oxygen; P-Glycoprotein; P-Glycoproteins; Pathway interactions; Phenotype; Positioning Attribute; Principal Investigator; Proteins; Purinergic P1 Receptors; Regulation; Reperfusion Injury; Role; Signal Pathway; Signal Transduction; Staging; Surface; Testing; Tissues; Transgenic Mice; Ursidae Family; Work; apical membrane; base; cell type; extracellular; gain of function; in vitro Model; in vivo; insight; intestinal epithelium; monocyte; neutrophil; nucleotide metabolism; programs; promoter; response; trafficking; transcription factor; trefoil factor

DESCRIPTION (provided by applicant): Mucosal organs such as the intestine and lung are highly vascular organs with extensive metabolic demands. Epithelial cells which line the intestine function to orchestrate a multitude of mucosal responses, and given their anatomic location, are primary targets for diminished blood flow and resultant hypoxia-mediated damage. Our previous studies have explored the response of intestinal epithelial cells to hypoxia and these studies defined a transcriptional signaling pathway mediated by hypoxia-inducible factor (HIF). Activation of HIF results in the coordinated induction of a cluster of apically-localized, barrier protective gene products. In this proposal, we will test the hypothesis that HIF coordinates protective epithelial responses to hypoxia. 3 specific aims are proposed to test this hypothesis. First, we will utilize newly developed murine models which express intestinal specific loss and gain of HIF function to answer basic questions regarding HIF activation in health and during intestinal disease in vivo. Second, we will build on recent findings to explore the influence of adenine nucleotide metabolism and signaling in vitro and in vivo. In particular, we will study how apically-localized membrane adenine nucleotide ecto-enzymes and adenosine receptors contribute to the regulation of leukocyte-mediated barrier disruption during hypoxia. Third, we will define molecular events of leukocyte trafficking across intestinal epithelial cells as they relate to hypoxia. In particular, we will elucidate the molecular details of hypoxia-regulated surface molecules which orchestrate leukocyte transit across the apical membrane surface. The overall aim of this proposal is to elucidate the transcriptional signaling events mediating mucosal epithelial responses to hypoxia and inflammation.

描述（由申请人提供）：肠和肺等粘膜器官是血管丰富的器官，具有广泛的代谢需求。肠道内的上皮细胞具有协调多种粘膜反应的功能，并且考虑到它们的解剖位置，是血流减少和由此产生的缺氧介导的损伤的主要目标。我们之前的研究探索了肠上皮细胞对缺氧的反应，这些研究定义了缺氧诱导因子（HIF）介导的转录信号通路。 HIF 的激活导致一系列顶部定位的屏障保护基因产物的协调诱导。在本提案中，我们将检验 HIF 协调上皮细胞对缺氧的保护性反应的假设。提出了 3 个具体目标来检验这一假设。首先，我们将利用新开发的表达肠道特异性 HIF 功能丧失和增强的小鼠模型来回答有关健康和肠道疾病期间 HIF 激活的基本问题。其次，我们将在最近的研究结果的基础上探索腺嘌呤核苷酸代谢和信号传导在体外和体内的影响。特别是，我们将研究顶端定位的膜腺嘌呤核苷酸胞外酶和腺苷受体如何在缺氧期间调节白细胞介导的屏障破坏。第三，我们将定义白细胞跨肠上皮细胞运输的分子事件，因为它们与缺氧有关。特别是，我们将阐明缺氧调节表面分子的分子细节，这些分子协调白细胞穿过顶膜表面。该提案的总体目的是阐明介导粘膜上皮对缺氧和炎症反应的转录信号事件。