Nicotine in HIV-1 and M 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，这些病原体会导致两种最具破坏性的传染病。人们还认识到，小胶质细胞在HIV-1和结核分枝杆菌的神经发病机制中发挥着关键作用，滥用药物不仅有助于这些药物的传播，而且可能促进它们在小胶质细胞中的表达。尽管对可卡因和鸦片等精神活性药物对小胶质细胞的影响进行了大量研究，但对尼古丁对这两种感染性物质的神经发病机制的影响知之甚少，甚至一无所知。尼古丁被药物依赖者广泛使用。这项研究项目的目的是提高对尼古丁可能影响HIV-1和结核分枝杆菌神经致病机制的理解，尼古丁已知具有免疫调节活性。在这项研究项目中要检验的主要假设是尼古丁通过对小胶质细胞的影响而增强了HIV-1和结核分枝杆菌的神经致病机制。我们集中在HIV-1和结核分枝杆菌神经发病机制的两个关键方面：小胶质细胞内的复制和对HIV-1蛋白gp41和Tat以及结核分枝杆菌的细胞因子和趋化因子的诱导。为了验证这一假设，我们将使用原代培养的人类小胶质细胞和包括微阵列技术在内的各种方法进行实验，以评估尼古丁对这些感染性病原体与小胶质细胞相互作用的影响。主要的重点将放在确定尼古丁增强这些病原体的神经致病过程的机制上。除了开展尼古丁对小胶质细胞靶向功能和基因组反应的拟议研究外，首席研究人员还将在分子遗传学和分子流行病学领域进行强化培训。这项培训将使首席研究员成为一名内科科学家，为今后致力于研究精神活性物质在分子/细胞、个人和群体层面上对宿主-微生物相互作用的潜在影响做好准备。

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.