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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：急性HIV感染中CD4+ T细胞耗竭后肠道微生物的易位已被视为慢性HIV-1感染中免疫激活的潜在机制，也是HIV疾病进展的标志。有趣的是，与使用HIV感染患者相比，使用静脉注射海洛因的HIV患者具有较高的细菌负荷。但是，该缺陷的基础机制尚未得到很好的研究。我们在初步数据中显示了药物滥用的鼠模型，与安慰剂治疗的动物相比，吗啡治疗的动物的肠道细菌易位显着增加，这在用吗啡治疗的纹身小鼠中进一步加剧了。在肠上皮细胞上的策略性定位和表达类似受体（TLR）的表达可防止肠道共生细菌过度激活并促进抗菌肽向肠道内腔的分泌。然而，失调的TLR激活导致屏障功能障碍，持续的细菌易位和慢性全身免疫激活。我们在初步数据中表明，吗啡治疗导致肠道上皮细胞中TLR2和TLR4 mRNA和蛋白质水平的显着增加，并且吗啡诱导的细菌易位升高在TLR2KO和TLR2/4双双敲门小鼠中显着减弱。基于我们的初步结果，我们假设肠上皮细胞（IEL）对TLR表达和分布的吗啡调节导致紧密的连接蛋白破坏跃升至细菌易位的增加。根据我们的初步数据，我们假设吗啡诱导的TLR在IEC上的激活有助于肠道屏障破坏，从而导致细菌易位增加。我们进一步假设HIV蛋白TAT将进一步加剧病理状态。在AIM 1中：我们将在HIV-1 TAT的背景下确定吗啡治疗和吗啡处理导致TLR2和4表达失调，异常TLR2和4定位以及持续激活导致屏障破坏和肠道细菌易位。 AIM 2：我们将确定在HIV 1中吗啡和吗啡的TLR表达和激活如何破坏紧密连接蛋白的组织和功能。在AIM 3中：我们将在氯喹存在缓解肠道屏障功能的吗啡和HIV-1 TAT调节中的存在下确定甲基甲曲霉的治疗潜力。这些研究的结果将允许开发新的治疗策略，以减轻HIV感染患者和HIV感染的滥用药物滥用人群的免疫激活和反向HIV疾病进展。