Role of Opioids and Complements in AIDS Pathogenesis

阿片类药物和补体在艾滋病发病机制中的作用

• 批准号: 7781399
• 负责人: Prasun K Datta
• 金额: $ 10.71万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781399
• 关键词: AIDS Dementia Complex; AIDS neuropathy; AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; Adult; African American; Anaphylatoxins; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Astrocytes; Astrocytosis; Attenuated; Award; B-Lymphocytes; Binding; Biology; Brain; C3 gene; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Cognitive; Complement; Complement 1q; Complement 3 Convertase; Complement 3a; Complement 3b; Complement Activation; Complement Receptor; Creatinine; Cytolysis; DNA Binding; Demyelinations; Deposition; Development; Dilatation - action; Doctor of Philosophy; Dominant-Negative Mutation; Drug abuse; End stage renal failure; Epidemiologic Studies; Epithelial Cells; Family; Focal Segmental Glomerulosclerosis; Gene Activation; Giant Cells; Goals; HIV; HIV encephalitis; HIV-1; Health; Homeostasis; Human; Immune system; In Vitro; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Injecting drug user; Injury; Kidney; MAP Kinase Gene; MAP2K6 gene; MAPK14 gene; Macaca; Macaca mulatta; Mediating; Mentors; Microglia; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphine; Neocortex; Neuropathogenesis; Neurovirology; Nodule; Opiates; Opioid; Opioid Receptor; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral Nervous System Diseases; Play; Principal Investigator; Production; Property; Proteins; Proteinuria; Regulation; Renal Tissue; Reporting; Research; Resistance; Risk; Risk Factors; Role; SIV; Serum; System; Therapeutic; Time; Training; Training Programs; Tubular formation; United States; Universities; Up-Regulation; Viral Proteins; Virion; Virus; Virus Diseases; autocrine; axonal degeneration; career; complement system; cytokine; drug abuser; drug of abuse; factor C; interstitial; macrophage; monocyte; motor disorder; mu opioid receptors; neuron loss; neutralizing antibody; opioid abuse; overexpression; prevent; programs; promoter; psychosocial; receptor; simian human immunodeficiency virus; skills; transcription factor; transmission process

DESCRIPTION (provided by applicant): This proposal is for a three year mentored research award at the Center for Neurovirology, Temple University for the development of a career in AIDS pathogenesis. The principal investigator will expand upon his skills and solicits further training in field of AIDS research and drug abuse prior to independent research in the field of AIDS. The long-term goal of this research is to define the mechanism(s) of regulation and role of the complement system in the pathogenesis of neuroAIDS and HIVAN and the potentiating role of drugs of abuse. HIV and HTLV are unique in their resistance to complement mediated virolysis. HIV-specific antibodies augment both activation and deposition of complement components as C3 and C5 on virions thus protecting them from neutralizing antibodies and the same time enhance infection of macrophages through complement receptors. In view of these properties, complement may facilitate virus transmission, dissemination within the host, and contribute to evasion of immune system. Furthermore, complement proteins activated by HIV have pro-inflammatory and chemotactic properties relevant to the pathogenesis of both NeuroAIDS and HIVAN. Inhibition of complement synthesis and activation may represent a putative therapeutic goal to prevent virus-induced damage. Our preliminary studies indicate that inflammatory cytokines, and C/EBP-beta and delta activate C3 promoter. Overexpression of dominant negative p38alpha or MKK6 attenuates C3 promoter activity, while morphine stimulates cytokine induced C3 expression. We hypothesize that opiates may play a detrimental role in the pathogenesis of NeuroAIDS and HIVAN by inducing C3 expression via upregulation of MKK6 and p38 MAPK activity which in turn modulates C/EBP's, the critical player in C3 promoter activation. The proposed studies will elucidate the molecular mechanism of complement activation by host proteins, and the effects of opioids on complement activation in in vitro ceil culture systems and in a rhesus macaque model of simian immunodeficiency virus (SIV) infection. Dr. Jay Rappaport, an expert in NeuroAIDS, will mentor the Pi's scientific development. To enhance the training, the program will include Dr. Thomas J. Rogers, expert in opioid receptor biology. The results of these studies will facilitate a better understanding of the mechanisms of complement-mediated injury in HIV infection and drug abuse, and serve as an effective training/mentoring mechanism for the PI.

描述（由申请人提供）：此提案为坦普尔大学神经病毒学中心的三年指导研究奖，用于发展艾滋病发病机制的职业生涯。首席研究员将扩展他的技能，并要求在艾滋病研究和药物滥用领域进行进一步的培训，然后在艾滋病领域进行独立研究。本研究的长期目标是明确补体系统在神经艾滋病和hiv发病机制中的调节机制和作用，以及滥用药物的增强作用。HIV和HTLV在抵抗补体介导的病毒溶解方面是独一无二的。hiv特异性抗体增强补体成分如C3和C5在病毒粒子上的激活和沉积，从而保护它们免受中和抗体的侵害，同时通过补体受体增强巨噬细胞的感染。鉴于这些特性，补体可能促进病毒在宿主内的传播和传播，并有助于逃避免疫系统。此外，被HIV激活的补体蛋白具有与神经艾滋病和HIV发病机制相关的促炎和趋化特性。抑制补体的合成和激活可能是预防病毒引起的损伤的一个假定的治疗目标。我们的初步研究表明，炎症细胞因子和C/ ebp - β和δ激活C3启动子。显性负p38alpha或MKK6的过表达会减弱C3启动子活性，而吗啡会刺激细胞因子诱导的C3表达。我们假设阿片类药物可能通过上调MKK6和p38 MAPK活性来诱导C3表达，从而调节C3启动子激活的关键参与者C/EBP，从而在神经aids和HIVAN的发病机制中发挥有害作用。本研究旨在阐明宿主蛋白激活补体的分子机制，以及阿片类药物在体外培养系统和猴免疫缺陷病毒（SIV）感染恒河猴模型中对补体激活的影响。神经艾滋病专家Jay Rappaport博士将指导Pi的科学发展。为了加强培训，该计划将包括阿片受体生物学专家托马斯·j·罗杰斯博士。这些研究结果将有助于更好地理解补体介导的损伤在HIV感染和药物滥用中的机制，并为PI提供有效的培训/指导机制。