Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction

HIV相关肠上皮屏障功能障碍的分子机制

• 批准号: 10630643
• 负责人: Kathleen L. Collins
• 金额: $ 10.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630643
• 关键词: Cells; Chronic; Data; Defect; Development; Epithelial; Epithelial Attachment; Exposure to; Functional disorder; HIV; HIV-1; Health; Immune; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intercellular Junctions; Intestinal permeability; Intestines; Link; Mediator of activation protein; Molecular; Morbidity - disease rate; Pathology; Permeability; Persons; Play; Proteins; Research; Role; Signal Transduction; T-Lymphocyte; Work; antiretroviral therapy; cytokine; improved; injury and repair; intestinal barrier; intestinal epithelium; migration; novel therapeutics; parent grant; repair function; repaired; wound healing

Abstract Compromised intestinal permeability leads to release of epithelial cytokines and antigenic exposure to underlying immune cells. Cytokine release by immune cells in turn perturbs intercellular junction proteins that are crucial for formation of an intact intestinal epithelial barrier. Our data suggest that co-incubation of IECs with HIV-1 infected T cells results in a Nef dependent loss of IEC barrier integrity due to increased epithelial expression of TNFa. Past studies, including work from our group, suggest that pro-inflammatory cytokines disrupt IEC function with preliminary data indicating that TNFa plays an important role HIV-associated intestinal pathology. Interestingly, our research has identified pro-repair functions of TNFa in wounded IEC. At initial glance, intestinal epithelial barrier disruption and enhanced wound repair seem disconnected and even contradictory, but these effects may be explained by signaling mechanisms that result in loosening of epithelial junctions to enhance migration to repair injuries resulting from the inflammatory response. Thus, a leaky barrier as well as increased migration of IEC are interconnected functions triggered by soluble mediators such as TNFa. As the parent grant focuses on barrier dysfunction, this supplemental proposal aims to look at the complementary effects of inflammatory mediators on IEC migration as it relates to repair. The overarching hypothesis is that cytokines such as TNFa impair barrier by altering expression of junctional proteins which in turn increases permeability while promoting IEC migration

抽象的 肠道渗透率受损会导致上皮细胞因子释放和抗原暴露于基础 免疫细胞。免疫细胞释放细胞因子，反过 完整的肠上皮屏障的形成。我们的数据表明，IEC与HIV-1感染的IEC结合 由于TNFA的上皮表达增加，T细胞导致IEC屏障完整性的NEF依赖性丧失。 过去的研究，包括我们小组的工作，表明促炎性细胞因子破坏IEC功能 初步数据表明TNFA起着与HIV相关的肠道病理的重要作用。有趣的是， 我们的研究已经确定了受伤的IEC中TNFA的促成功能。乍一看，肠上皮 障碍的破坏和增加的伤口修复似乎是断开连接甚至矛盾的，但是这些影响可能 可以通过信号传导机制来解释，这些机制导致上皮连接处松动以增强迁移到 炎症反应引起的修复伤害。因此，泄漏的障碍以及增加的迁移 IEC是由TNFA等可溶性介体触发的互连功能。作为父母的赠款专注于 障碍功能障碍，该补充建议旨在研究炎症的互补作用 IEC迁移的介体与维修有关。总体假设是诸如TNFA之类的细胞因子 通过改变连接蛋白的表达来损害障碍，从而促进渗透率 IEC迁移