Mechanism underlying Morphine modulation of gut barrier function in the Context o

吗啡调节肠道屏障功能的机制

• 批准号: 9189597
• 负责人: Sabita Roy
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189597
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Acute; Animals; Apical; Attenuated; Bacterial Translocation; CD4 Positive T Lymphocytes; Chloroquine; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Disease Progression; Drug abuse; Drug usage; Drug user; Epidemic; Epithelial Cells; Functional disorder; HIV; HIV Infections; HIV tat Protein; HIV-1; HIV-associated neurocognitive disorder; Health; Heroin; Homeostasis; Immune System Diseases; Infection; Inflammatory Bowel Diseases; Intestines; Intravenous; Knockout Mice; Knowledge; MAP Kinase Gene; MYLK gene; Messenger RNA; Microbe; Morphine; Naltrexone; Opiates; Opioid; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phosphotransferases; Placebos; Play; Population; Predisposition; Proteins; Publishing; Receptor Activation; Receptor Signaling; Reporting; Role; Serum; Symbiosis; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tight Junctions; Toll-like receptors; Transgenic Organisms; antimicrobial peptide; attenuation; base; cytokine; drug abuser; gastrointestinal epithelium; immune activation; mRNA Expression; microbial; mouse model; non-drug; novel; novel therapeutic intervention; occludin; pathogen; prevent; promoter; protein distribution; protein expression; public health relevance; receptor; receptor expression; rho; statistics

DESCRIPTION (provided by applicant): Translocation of gut microbes following CD4+ T cell depletion in acute HIV infection has been implicated as a potential mechanism for immune activation in chronic HIV-1 infection and a hallmark for HIV disease progression. Interestingly, HIV patients that use intravenous heroin have higher bacterial loads when compared to non-drug using HIV infected patients. However, the mechanism underlying this defect has not been well studied. We show in preliminary data, in a murine model of drug abuse, significant increase in gut bacterial translocation in morphine treated animals when compared to placebo treated animals, which is further exacerbated in the TATtg mice treated with morphine. Strategic localization and expression of Toll-like- receptors (TLRs), on intestinal epithelial cells prevents excessive activation by gut commensal bacterial and promotes secretion of antimicrobial peptides into the gut lumen. However, dysregulated TLR activation results in barrier dysfunction, sustained bacterial translocation and chronic systemic immune activation. We show in preliminary data that morphine treatment results in a significant increase in both TLR2 and TLR4 mRNA and protein levels in gut epithelial cells and morphine induced increase in bacterial translocation is significantly attenuated in TLR2KO and TLR2/4 double knockout mice. Based on our preliminary results we hypothesize that morphine modulation of TLR expression and distribution on intestinal epithelial cells (IEL) results in tight junction proteins disruption leaing to increased bacterial translocation. Based on our preliminary data, we hypothesize, that morphine induced activation of TLRs on IEC contributes to gut barrier disruption leading to increased bacterial translocation. We further hypothesize that HIV-protein TAT will further exacerbate the pathological state. In Aim 1: We will determine that morphine treatment and morphine treatment in the context of HIV-1 TAT results in dysregulated TLR2 and 4 expression, aberrant TLR2 and 4 localization and persistent activation contributing to barrier disruption and gut bacterial translocation. Aim 2: We will determine the mechanisms how TLR expression and activation by morphine and morphine in the context of HIV 1 TAT disrupts tight junction protein organization and function. In Aim 3: we will determine the therapeutic potential of methylnaltrexone in the presence of Chloroquine in mitigating morphine and HIV-1 TAT modulation of gut barrier function. The results from these studies will allow for the development of new therapeutic strategies to attenuate immune activation and reverse HIV disease progression both in HIV infected patients and in HIV infected drug abusing population.

描述（由申请方提供）：急性HIV感染中CD 4 + T细胞耗竭后肠道微生物易位被认为是慢性HIV-1感染中免疫激活的潜在机制和HIV疾病进展的标志。有趣的是，使用静脉注射海洛因的艾滋病毒患者与非药物使用的艾滋病毒感染患者相比具有更高的细菌载量。然而，这种缺陷的机制尚未得到很好的研究。我们在初步数据中显示，在药物滥用的鼠模型中，与安慰剂治疗的动物相比，吗啡治疗的动物中肠道细菌易位显著增加，这在用吗啡治疗的TATtg小鼠中进一步加剧。Toll样受体（TLR）在肠上皮细胞上的策略性定位和表达可防止 肠道细菌的过度激活，并促进抗菌肽分泌到肠腔中。然而，TLR激活失调导致屏障功能障碍、持续的细菌移位和慢性全身免疫激活。我们在初步数据中显示，吗啡治疗导致肠上皮细胞中TLR 2和TLR 4 mRNA和蛋白水平的显著增加，并且在TLR 2KO和TLR 2/4双敲除小鼠中吗啡诱导的细菌易位增加显著减弱。基于我们的初步结果，我们假设吗啡调节TLR在肠上皮细胞（IEL）上的表达和分布导致紧密连接蛋白的破坏，导致细菌移位增加。基于我们的初步数据，我们假设，吗啡诱导的IEC上TLR的激活有助于肠道屏障破坏，导致细菌移位增加。我们进一步假设HIV蛋白达特会进一步加重病理状态。目标1：我们将确定，吗啡治疗和吗啡治疗的背景下，HIV-1达特的TLR 2和4的表达失调，异常TLR 2和4的本地化和持续激活，促进屏障破坏和肠道细菌易位。目标二：我们将确定TLR的表达和激活的机制，吗啡和吗啡的背景下，HIV 1达特破坏紧密连接蛋白的组织和功能。目标3：我们将确定甲基纳洛酮在氯喹存在下减轻吗啡和HIV-1达特对肠道屏障功能的调节的治疗潜力。这些研究的结果将有助于开发新的治疗策略，以减弱HIV感染患者和HIV感染药物滥用人群的免疫激活并逆转HIV疾病进展。