Intranasal Tat: A Mouse Model for NeuroAIDS and Aging

描述(申请人提供)：即使在高效抗逆转录病毒治疗(HAART)的时代，感染艾滋病毒-1的个人仍有患上艾滋病毒-L相关性痴呆(HAD)的风险。在HAART上，外周血单核细胞继续感染HIV-1，大脑仍然是一个储备者。我们的实验室利用小鼠的鼻腔(IN)递送系统将多肽和生长因子直接递送到大脑。IN给药系统向中枢神经系统提供非侵入性、快速的给药，消除了全身给药的需要，从而减少了不必要的全身副作用。我的合作调查员有新的数据表明，在体外，HIV-1Tat抑制主要的分解酶neprilysin，并增加淀粉样β蛋白(Abeta)。我们的总体假设是，大脑持续暴露于HIV-1感染及其蛋白质TAT将导致Abeta加速积累，为了证明这一点，我们将利用IN向小鼠传递TAT。我们的具体目标是：1)向正常小鼠传递1251-TAT并建立其分布；2)将TAT IN传递给正常小鼠并通过免疫组织化学方法评价神经炎症水平和Abeta的患病率；3)将TAT IN传递给APPSW小鼠并评价神经炎症和Abeta的患病率。这些研究的结果可能会导致一种新的神经艾滋病和衰老模型，以及一种潜在的治疗方法，既可以减少脑病毒载量，又可以减少Abeta的积累。

DESCRIPTION (provided by applicant): Even in the era of highly active antiretroviral therapy (HAART), individuals with HIV-1 infection continue to be at risk for developing HIV-l-associated dementia (HAD). Peripheral monocytes continue to be infected with HIV-1 on HAART and the brain continues to be a reservoir. Our laboratory utilizes an intranasal (IN) delivery system in the mouse to deliver peptides and growth factors directly to the brain. The IN delivery system provides noninvasive, rapid delivery to the central nervous system, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. My Co-Investigator has new data to show that in vitro, HIV-1 Tat inhibits a major catabolizing enzyme, neprilysin, and increases amyloid beta (Abeta). It is our overall hypothesis that continued exposure of the brain to HIV-1 infection and its' protein Tat will cause an accelerated Abeta accumulation and to prove this, we will utilize the IN delivery of Tat to mice. Our specific aims are: 1) To deliver 1251-Tat to normal mice and establish its distribution, 2) To deliver Tat IN to normal mice and evaluate by immunohistochemistry the level of neuroinflammation and prevalence of Abeta and 3) To deliver Tat IN to APPSW mice and evaluate neuroinflammation and the prevalence of Abeta. Results from these studies could lead to a new model of NeuroAIDS and aging as well as a potential method of delivery of therapeutics to both decrease brain viral load and Abeta accumulation.