Mechanisms of Nicotine's Behavioral Effects on the HIV-1 Transgenic Rat

这项修订后的研究计划的目标是确定尼古丁对人体的药理作用， HIV-1病毒蛋白的存在导致的学习和记忆缺陷，并确定基因 以及与这些效应相关的生物学途径， 转基因（HIV-1 Tg）大鼠模型。虽然HIV-1基因gag和pol已经被删除，但其他病毒 包括LTR在内的基因仍然保持完整，并在包括脑和血液在内的大多数组织中表达。 HIV-1 Tg大鼠。随着年龄的增长，这只HIV-1 Tg大鼠出现了人类HIV的临床表现 疾病，因此，模仿感染，导致持续存在的艾滋病毒蛋白质在 主持人当我们在改良的Morris水迷宫中检查HIV-1 Tg大鼠的表现时， 在空间学习能力方面表现出与HIV-1感染患者相似的缺陷。许多 在人类和啮齿动物模型中进行的流行病学和基础研究表明，尼古丁可以 增强认知能力，表明尼古丁具有神经保护作用。根据这些发现， 我们假设HIV-1 Tg大鼠暴露于尼古丁可以改变观察到的学习， 认知缺陷是由大鼠体内HIV-1病毒蛋白的持续存在引起的。到 为了验证这一假设，我们建议首先确定尼古丁在HIV-1 Tg大鼠中的作用， 行为水平，然后确定基因和生物途径，受尼古丁的影响， HIV-1 Tg大鼠。最后，我们将描述特定的基因和途径，介导尼古丁的 对HIV-1诱导的学习和记忆缺陷的影响。具体而言，我们的目标是：1）确定 尼古丁对HIV-1 Tg大鼠学习和记忆的影响，使用改良的Morris水迷宫试验， 导航的非视觉线索; 2）识别受以下因素显著影响的生物学途径 尼古丁在HIV-1 Tg大鼠中使用高密度寡核苷酸微阵列;和3）为了表征 与这些生物途径相关的特定基因，包括那些负责 神经保护和神经炎症，介导尼古丁对艾滋病毒感染者学习和记忆的影响， 使用各种常规生物化学和分子生物学方法，在RNA和蛋白质水平上对1 Tg大鼠进行研究 技术.据我们所知，这是第一次研究尼古丁如何影响 在啮齿动物模型中，HIV-1病毒蛋白导致的学习和认知缺陷。数据 从拟议的研究中产生的结果将揭示潜在的分子机制， 尼古丁在HIV-1病毒蛋白存在的情况下对学习行为的影响， 在理解和治疗神经功能障碍方面具有重要的临床意义 与HIV感染和艾滋病有关。

The goal of this revised research proposal is to determine the pharmacologic effects of nicotine on the learning and memory deficits resulted from the presence of HIV-1 viral proteins and to define the genes and biological pathways associated with those effects by using a newly created non-infectious HIV-1 transgenic (HIV-1Tg) rat model. Although the HIV-1 genes gag and pol had been deleted, other viral genes including LTRs still kept intact and are expressed in most tissues including brain and blood of the HIV-1Tg rats. With advancing age, this HIV-1Tg rat develops clinical manifestations of human HIV disease, and, thus, mimics the infection that results from the persistent presence of HIV proteins in the host. When we examined the performance of HIV-1Tg rats in a modified Morris water maze, they showed deficits in spatial learning similar to those in patients with HIV-1 infection. Numerous epidemiological and basic research studies in both humans and rodent models reveal that nicotine can enhance cognitive abilities, indicating nicotine has neuroprotective effects. Based on these findings, we hypothesize that exposure of HIV-1Tg rats to nicotine can alter the observed learning and cognitive deficits resulted from the continuous presence of HIV-1 viral proteins in the rats. To test this hypothesis, we propose to first determine nicotine's effects in the HIV-1Tg rats at the behavioral level and then identify the genes and biological pathways that are affected by nicotine in the HIV-1Tg rats. Finally, we will characterize the specific genes and pathways that mediate nicotine's effects on HIV-1-induced learning and memory deficits. Specifically, our aims are: 1) To determine nicotine's effects on learning and memory in HIV-1Tg rats using a modified Morris water maze test with non-visual cues for navigation; 2) To identify the biological pathways that are significantly affected by nicotine in HIV-1Tg rats using high-density oligonucleotide microarray; and 3) To characterize the specific genes associated those biological pathways, including those are responsible for neuroprotection and neuroinflammation, that mediate nicotine's effects on learning and memory in HIV- 1Tg rats at both RNA and protein levels using various conventional biochemistry and molecular biology techniques. To our knowledge, this represents the first study of investigating how nicotine affects on learning and cognitive deficits resulted from the HIV-1 viral proteins in a rodent model. The data generated from the proposed studies will shed light on the molecular mechanism(s) underlying nicotine's effects on learning behaviors in the presence of HIV-1 viral proteins, and can have substantial clinical significance in the understanding and treatment of neurological dysfunctions associated with HIV infection and AIDS.