Intranasal Tat: A Mouse Model for NeuroAIDS and Aging

鼻内 Tat：神经艾滋病和衰老的小鼠模型

• 批准号: 6842916
• 负责人: WILLIAM H FREY
• 金额: $ 20.9万
• 依托单位: HEALTHPARTNERS INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842916
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; HIV infections; age difference; aging; amyloid proteins; autoradiography; brain metabolism; disease /disorder model; drug delivery systems; enzyme linked immunosorbent assay; genetically modified animals; human immunodeficiency virus 1; immunocytochemistry; inflammation; inhalation drug administration; laboratory mouse; model design /development; neprilysin; pharmacokinetics; protein localization; protein metabolism; virus protein

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.

描述（由申请人提供）：即使在高效抗逆转录病毒疗法（HAART）时代，HIV-1感染个体仍有发生HIV-1相关痴呆（HAD）的风险。在HAART治疗中，外周单核细胞继续感染HIV-1，大脑继续成为储存库。我们的实验室利用小鼠鼻内（IN）递送系统将肽和生长因子直接递送至大脑。IN递送系统提供了对中枢神经系统的非侵入性、快速递送，消除了对全身递送的需要，从而减少了不希望的全身副作用。我的合作研究者有新的数据表明，在体外，HIV-1达特抑制一种主要的分解酶，脑啡肽酶，并增加淀粉样蛋白β（Abeta）。我们的总体假设是，大脑持续暴露于HIV-1感染及其蛋白质达特将导致Abeta加速积累，为了证明这一点，我们将利用IN递送达特至小鼠。我们的具体目标是：1）将1251-达特递送至正常小鼠并建立其分布，2）将达特IN递送至正常小鼠并通过免疫组织化学评估神经炎症的水平和A β的患病率，以及3）将达特IN递送至APPSW小鼠并评估神经炎症和A β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，以减少脑病毒载量和Abeta积累。

项目成果

Intranasal tat alters gene expression in the mouse brain.

鼻内tat改变小鼠大脑中的基因表达。

• DOI: 10.1007/s11481-006-9053-z
• 发表时间: 2007
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Pulliam,Lynn;Sun,Bing;Rempel,Hans;Martinez,PaulaM;Hoekman,JohnD;Rao,ReshmaJ;Frey2nd,WilliamH;Hanson,LeahR
• 通讯作者: Hanson,LeahR