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

基本信息

批准号：
10454418
负责人：
Kathleen L. Collins
金额：
$ 74.83万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454418
关键词：
AIDS/HIV problem Address Area Biology CD4 Positive T Lymphocytes Cardiovascular Diseases Cell physiology Cells Chronic Collaborations Data Defect Development Epithelial Epithelial Cells Exposure to Functional disorder Funding Gastrointestinal tract structure Goals HIV HIV Infections HIV-1 Health Homeostasis Human Immune Impairment Individual Infection Inflammation Inflammatory Interleukin-1 beta Interleukin-6 Intestines Lamina Propria Lead Link Metabolic syndrome Methodology Molecular Morbidity - disease rate Pathway interactions Permeability Persons Prevention Process Production Research Research Personnel Signal Transduction Source T-Lymphocyte TNF gene Testing antiretroviral therapy bone comorbidity cytokine experimental study gut inflammation immune activation improved insight intestinal barrier intestinal epithelium microbial mortality nef Protein neurocognitive disorder novel therapeutics premature response therapeutic target trafficking

项目摘要

Abstract The goal of proposed experiments in this application is to determine how HIV infection disrupts intestinal barrier function. It is now appreciated that microbial translocation across an impaired epithelial barrier leads to circulating LPS, persistent immune activation and chronic inflammation in people living with HIV (PLWH). These HIV associated effects are important contributors to premature development of neurocognitive disorders, cardiovascular disease, metabolic syndrome and bone abnormalities even in PLWH on optimal combination antiretroviral therapy (cART). Untreated infection is characterized by the production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNFα). Following therapy, cytokine levels decline but chronic inflammation continues. Prevention of inflammation-induced comorbidities requires the development of more specific therapeutics targeting the underlying cause. However, a gap exists in our understanding of the underlying molecular pathways involved. This proposal will capitalize on an established collaboration between investigators with expertise in HIV biology and intestinal barrier function/pathobiology. We have generated strong preliminary data that provides a framework for understanding the underlying link between disrupted intestinal epithelial barrier function and HIV infection. While the overall chronic inflammatory manifestations of HIV infection are likely to be multi-factorial, our exciting results support an overarching hypothesis that lamina propria HIV-1 infected primary human CD4+T lymphocytes that closely interact with intestinal epithelial initiate a process leading to enhanced production of pro-inflammatory cytokines that negatively impact epithelial homeostasis resulting in a leaky intestinal barrier. Given these important new insights, funding is requested to support a major collaborative effort between established investigators in the areas of HIV biology and intestinal inflammation/barrier disruption to determine the mechanism(s) through which primary human intestinal epithelial cells (IECs) and HIV-infected primary T cells synergize to cause intestinal pathobiology. Specifically, we will determine the HIV-dependent mechanisms that alter T-cell function and disrupt the intestinal barrier. In addition, we will identify the pathways altered in IECs exposed to HIV infected T-cells that lead to barrier dysfunction. Findings generated from these studies will allow a better understanding of the mechanisms underlying HIV related enteropathy that is known to be a major source of morbidity and mortality in HIV-infected individuals and will lead to development of new strategies to improve the health of HIV infected people. 1

抽象的本应用程序中提出的实验的目的是确定艾滋病毒感染如何破坏肠道屏障功能。现在，人们认为，微生物跨越受损的上皮屏障会导致艾滋病毒（PLWH）患者的循环lps，持续的免疫激活和慢性感染。这些相关的HIV相关影响是神经认知过早发展的重要促进者疾病，心血管疾病，代谢综合征和骨异常，即使在最佳状态下组合抗逆转录病毒疗法（CART）。未经处理的感染的特征是产生促炎细胞因子，例如白介素（IL）-1β，IL-6和肿瘤坏死因子（TNFα）。下列的治疗，细胞因子水平下降，但慢性感染仍在继续。预防感染引起的合并症需要开发针对根本原因的更具体的治疗。然而，我们对所涉及的潜在分子途径的理解存在差距。该提议将大写关于具有HIV生物学专业知识和肠道障碍专业知识的调查人员的既定合作功能/病理学。我们已经生成了强大的初步数据，该数据提供了理解的框架肠上皮屏障功能与HIV感染中断的基本联系。而整体艾滋病毒感染的慢性炎症表现可能是多因素的，我们令人兴奋的结果支持一个总体假设，即固有椎板HIV-1感染了原发性人CD4+T淋巴细胞，该淋巴细胞紧密与肠上皮相互作用启动一个过程，导致增强促炎的产生对上皮稳态产生负面影响的细胞因子导致肠道泄漏。鉴于这些重要的新见解，要求资金支持既定的艾滋病毒生物学和肠道注射/屏障破坏领域的研究人员确定原代人肠上皮细胞（IEC）和HIV感染的原代T细胞的机制协同作用引起肠道病理学。具体而言，我们将确定HIV依赖性机制改变T细胞功能并破坏肠壁。此外，我们将确定IEC中发生的途径暴露于受HIV感染的T细胞，导致屏障功能障碍。这些研究产生的发现将可以更好地了解与HIV相关的肠病的机制，该机制已知是一种艾滋病毒感染者的发病率和死亡率的主要来源，将导致新的发展改善艾滋病毒感染者健康的策略。 1