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

这项修订后的研究方案的目标是确定尼古丁对心脏的药理作用。 由于HIV-1病毒蛋白的存在而导致的学习和记忆障碍，并定义了基因 以及通过使用新创建的非传染性HIV-1与这些影响相关的生物途径 转基因(HIV-1TG)大鼠模型。虽然HIV-1基因Gag和pol1已经被删除，但其他病毒 包括ltrs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-1TG大鼠。随着年龄的增长，这只HIV-1TG大鼠出现了人类HIV的临床表现 疾病，因此，模拟了由于HIV蛋白在体内持续存在而引起的感染 主持人。当我们在改进的Morris水迷宫中测试HIV-1TG大鼠的表现时，他们 表现出与HIV-1感染患者类似的空间学习障碍。数不胜数 对人类和啮齿动物模型的流行病学和基础研究表明，尼古丁可以 增强认知能力，说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观察到的学习和 认知缺陷是由于HIV-1病毒蛋白在大鼠体内持续存在造成的。至 为了验证这一假设，我们建议首先确定尼古丁对HIV-1TG大鼠的影响 行为水平，然后确定受尼古丁影响的基因和生物途径 HIV-1TG大鼠。最后，我们将描述调节尼古丁的特定基因和途径。 对HIV-1诱导的学习和记忆障碍的影响。具体来说，我们的目标是：1)确定 尼古丁对HIV-1TG大鼠学习记忆影响的改良Morris水迷宫实验 用于导航的非视觉提示；2)识别受 用高密度寡核苷酸芯片研究HIV-1TG大鼠体内的尼古丁；3)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学习和记忆的影响- 1TG大鼠在RNA和蛋白质水平上使用各种常规生物化学和分子生物学 技巧。据我们所知，这是第一次研究尼古丁对人体健康的影响。 在啮齿动物模型中，学习和认知缺陷是由HIV-1病毒蛋白造成的。数据 从拟议的研究中产生的数据将有助于阐明(S) 在HIV-1病毒蛋白存在的情况下，尼古丁对学习行为的影响，并可能 神经功能障碍的认识和治疗具有重要的临床意义 与艾滋病毒感染和艾滋病有关。

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.