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

基本信息

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
项目类别：
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

项目摘要

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）：该提案是在坦普尔大学神经病毒学中心的三年指导研究奖，以开发艾滋病发病机理的职业。首席研究者将在艾滋病领域进行独立研究之前，扩大他在艾滋病研究和药物滥用领域进行进一步培训的技能和寻求。这项研究的长期目标是确定补体系统在神经辅助和Hivan的发病机理中的调节和作用机制，以及滥用药物的增强作用。艾滋病毒和HTLV在抵抗介导的毒化方面是独一无二的。 HIV特异性抗体增强了补体成分的激活和沉积为C3和C5在病毒体上，从而保护它们免受中和抗体的影响，同时通过补体受体增强了巨噬细胞的感染。鉴于这些特性，补体可以促进病毒传播，宿主内部传播，并有助于逃避免疫系统。此外，由HIV激活的补体蛋白具有与神经辅助和Hivan的发病机理有关的促炎和趋化特性。抑制补体合成和激活可能代表了预防病毒诱导损伤的假定治疗目标。我们的初步研究表明，炎性细胞因子，C/EBP-beta和Delta激活C3启动子。显性负P38Alpha或MKK6的过表达减弱了C3启动子活性，而吗啡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表达在神经辅助和Hivan的发病机理中发挥有害作用，从而调整C3启动子激活中的关键参与者C/EBP。拟议的研究将阐明宿主蛋白补体激活的分子机制，以及阿片类药物对体外CEIL培养系统中补体激活的影响以及邻肌免疫缺陷病毒（SIV）感染的恒河猴猕猴模型。神经辅助专家Jay Rappaport博士将指导PI的科学发展。为了增强培训，该计划将包括阿片受体生物学专家Thomas J. Rogers博士。这些研究的结果将有助于更好地理解艾滋病毒感染和药物滥用中补体介导的损伤的机制，并作为PI的有效培训/指导机制。