TNF-alpha Modulation of Intestinal Epith. Permeability

肠上皮的 TNF-α 调节。

• 批准号: 6897793
• 负责人: THOMAS Y MA
• 金额: $ 29.54万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897793
• 关键词: actins; antisense nucleic acid; cell line; gastrointestinal epithelium; gel electrophoresis; gel mobility shift assay; immunocytochemistry; immunofluorescence technique; immunoprecipitation; inhibitor /antagonist; intracellular membranes; intracellular transport; membrane permeability; myosin light chain kinase; myosins; nuclear factor kappa beta; nucleic acid probes; oligonucleotides; posttranslational modifications; protein kinase A; tight junctions; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): Patients with Crohn's disease (CD) have a defective intestinal epithelial tight junction (TJ) barrier manifested by an increase in intestinal permeability. The defective intestinal epithelial TJ barrier appears to be an important pathogenic factor of CD, which allows intestinal penetration of toxic luminal antigens and substances leading to the intestinal inflammation. Tumor necrosis factor-alpha (TNF-alpha) plays a central causative role in intestinal inflammation of CD. Several recent studies including our preliminary studies demonstrated that TNF-alpha produces a persistent increase in intestinal epithelial TJ permeability. The TNF-alpha induced increase in intestinal epithelial TJ permeability could be an important pro-inflammatory mechanism, which allows increased intestinal permeation of toxic luminal antigens. Since TNF-alpha plays a central role in the intestinal inflammation of CD, understanding the intracellular mechanisms involved in TNF-( induced increase in intestinal TJ permeability will be crucial in developing potential therapeutic strategies to prevent the abnormal increase in intestinal TJ permeability. In this grant application, we propose to delineate the cellular and molecular mechanisms, which mediate the TNF-alpha induced increase in intestinal TJ permeability, using the Caco-2 Intestinal epithelial cells. Based on our preliminary data, we hypothesize that TNF-alpha induced NF-kappaB activation is a key intracellular process, which regulates the TNF-alpha modulation of the intestinal epithelial TJ barrier. The proposed specific aims of this grant application will test the hypothesis that NF-(B activation is a key intracellular process regulating the TNF-alpha induced increase in intestinal epithelial TJ (or paracellular) permeability. The proposed specific aims will also 1) delineate the intracellular mechanisms which regulate the TNF-alpha induced NF-kappaB activation and increase in intestinal epithelial TJ permeability, 2) determine the molecular and cellular mechanisms by which TNF-alpha regulates the TJ proteins, and 3) determine the possible intracellular targets for therapeutic intervention to prevent the TNF-alpha induced increase in intestinal TJ permeability.

描述（由申请人提供）：克罗恩病（CD）患者的肠上皮紧密连接（TJ）屏障有缺陷，表现为肠道通透性增加。 肠上皮TJ屏障缺陷似乎是CD的重要致病因素，它允许有毒的管腔抗原和物质渗透肠道，导致肠道炎症。 肿瘤坏死因子-α (TNF-α) 在 CD 肠道炎症中起重要作用。 最近的几项研究（包括我们的初步研究）表明，TNF-α 会持续增加肠上皮 TJ 通透性。 TNF-α 诱导的肠上皮 TJ 通透性增加可能是一种重要的促炎机制，它可以增加有毒管腔抗原的肠道渗透。 由于 TNF-α 在 CD 的肠道炎症中起着核心作用，因此了解 TNF-α 诱导的肠道 TJ 通透性增加所涉及的细胞内机制对于制定防止肠道 TJ 通透性异常增加的潜在治疗策略至关重要。在拨款申请中，我们建议使用 Caco-2 肠上皮细胞来描述介导 TNF-α 诱导肠道 TJ 通透性增加的细胞和分子机制。根据我们的初步数据，我们假设 TNF-α 诱导。 NF-κB 激活是一个关键的细胞内过程，调节肠上皮 TJ 屏障的 TNF-α 调节。本次拨款申请提出的具体目标将检验 NF-(B 激活是调节 TNF 的关键细胞内过程)这一假设。 -α 诱导肠上皮 TJ（或细胞旁）通透性增加。所提出的具体目标还将 1）描述调节 TNF-α 诱导 NF-κB 激活和增加的细胞内机制。肠上皮 TJ 通透性；2) 确定 TNF-α 调节 TJ 蛋白的分子和细胞机制；3) 确定治疗干预的可能细胞内靶标，以防止 TNF-α 诱导的肠 TJ 通透性增加。