Nicotine in HIV-1 and Mycobacterium tuberculosis Neuropathogenesis

描述（由申请人提供）： 由HIV-1和结核分枝杆菌引起的感染都被视为全球公共卫生危机。在中枢神经系统中，这些物质导致两种最具破坏性的传染病。小胶质细胞在HIV-1和M.结核病和滥用药物不仅有助于这些因子的传播，而且可能促进它们在小胶质细胞中的表达。尽管对可卡因和阿片类药物等精神活性药物对小胶质细胞的影响进行了大量研究，但对药物依赖个体广泛使用的尼古丁对这些感染因子的神经发病机制的影响知之甚少或一无所知。本研究项目的目的是提高对尼古丁（已知具有免疫调节活性）可能影响HIV-1和M的神经致病机制的方式的理解。结核本研究项目中要检验的主要假设是尼古丁增强了HIV-1和M的神经致病机制。结核病通过其对小胶质细胞的影响。我们关注HIV-1和M的两个关键方面。结核病神经发病机制：在小胶质细胞内复制以及响应HIV-1蛋白gp 41和达特和M.结核为了验证这一假设，我们将使用培养的原代人类小胶质细胞和各种方法（包括微阵列技术）进行实验，以评估尼古丁对这些感染因子与小胶质细胞相互作用的影响。主要重点将放在定义尼古丁增强这些病原体的神经致病过程的机制。沿着开展尼古丁对小胶质细胞靶向功能和基因组反应影响的拟议研究，主要研究者将在本研究项目期间接受分子遗传学和分子流行病学领域的强化培训。该培训将使主要研究者成为一名医生科学家，致力于研究精神活性物质对分子/细胞、个体和群体水平上宿主-微生物相互作用的潜在影响。

DESCRIPTION (provided by applicant): Infections caused by HIV-1 and Mycobacterium tuberculosis are each regarded as global public health crises. In the central nervous system, these agents cause two of the most devastating infectious diseases. It is also well recognized that microglial cells play a pivotal role in the neuropathogenesis of HIV-1 and M. tuberculosis and that drugs of abuse not only contribute to the spread of these agents but may facilitate their expression in microglial cells. Despite considerable research on the effects of psychoactive drugs such as cocaine and opiates on microglial cells, little or nothing is known about the effect of nicotine, which is extensively used by drug-dependent individuals, on the neuropathogenesis of either of these infectious agents. The intent of this research project is to improve understanding of the manner by which nicotine, which is known to have immunomodulatory activities, may affect neuropathogenic mechanisms of HIV-1 and M. tuberculosis. The principal hypothesis to be tested in this research project is that nicotine enhances neuropathogenic mechanisms of HIV-1 and M. tuberculosis through its effects on microglial cells. We have focused on two critical aspects of HIV-1 and M. tuberculosis neuropathogenesis: replication within microglia and induction of cytokines and chemokines in response to HIV-1 proteins gp41 and Tat and M. tuberculosis. To test this hypothesis, we will conduct experiments using primary human microglial cells in culture and various methodologies, including microarray techniques, to assess nicotine's effect on the interactions of these infectious agents with microglia. Major emphasis will be placed on defining the mechanisms whereby nicotine enhances the neuropathogenic processes of each of these pathogens. Along with carrying out the proposed studies of the effects of nicotine on targeted functional and genomic responses of microglia, intensive training will be undertaken by the principal investigator during the course of this research project both in the fields of molecular genetics and molecular epidemiology. This training will prepare the principal investigator as a physician scientist for a career devoted to investigation of the potential impact of psychoactive substances on host-microbe interactions at the molecular/cellular, individual and population levels.