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

描述（由申请人提供）：本修订后的研究提案的目标是确定尼古丁对由HIV-1病毒蛋白存在引起的学习和记忆缺陷的药理学作用，并通过新创建的非传染性HIV-1转基因（HIV-1Tg）大鼠模型确定与这些作用相关的基因和生物学途径。虽然HIV-1基因gag和pol被删除，但包括LTRs在内的其他病毒基因仍保持完整，并在HIV-1Tg大鼠的大多数组织（包括脑和血液）中表达。随着年龄的增长，这只HIV- 1tg大鼠出现了人类HIV疾病的临床表现，因此，模仿了宿主体内HIV蛋白持续存在所导致的感染。当我们检查HIV-1Tg大鼠在改良Morris水迷宫中的表现时，它们表现出与HIV-1感染患者相似的空间学习缺陷。在人类和啮齿动物模型中进行的大量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。基于这些发现，我们假设HIV-1Tg大鼠暴露于尼古丁可以改变由于HIV-1病毒蛋白在大鼠体内持续存在而导致的观察到的学习和认知缺陷。为了验证这一假设，我们建议首先在行为水平上确定尼古丁对HIV-1Tg大鼠的影响，然后确定尼古丁在HIV-1Tg大鼠中受影响的基因和生物学途径。最后，我们将描述介导尼古丁对hiv -1诱导的学习和记忆缺陷的影响的特定基因和途径。具体而言，我们的目标是：1)利用改进的Morris水迷宫测试和非视觉提示导航来确定尼古丁对HIV-1Tg大鼠学习和记忆的影响；2)利用高密度寡核苷酸芯片鉴定尼古丁显著影响HIV-1Tg大鼠的生物学通路；3)利用各种传统的生物化学和分子生物学技术，在RNA和蛋白质水平上表征尼古丁对HIV- 1Tg大鼠学习和记忆的影响，包括那些负责神经保护和神经炎症的生物通路相关的特定基因。据我们所知，这是首次在啮齿动物模型中研究尼古丁如何影响由HIV-1病毒蛋白引起的学习和认知缺陷。这些研究的数据将揭示在HIV-1病毒蛋白存在的情况下，尼古丁对学习行为影响的分子机制，并在理解和治疗与HIV感染和艾滋病相关的神经功能障碍方面具有重要的临床意义。公共卫生相关性：本研究的主要目标是确定尼古丁对HIV-1病毒蛋白导致的学习和记忆缺陷的药理学作用，并通过使用新创建的非传染性HIV-1转基因大鼠模型确定与这些作用相关的基因和生物学途径。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The primary goal of this proposed research is to determine the pharmacological 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 rat model.