Clearance Pathways in the CNS in Aging and HIV

描述(申请人提供)：目前全球有3000多万艾滋病毒携带者。在美国，老龄化人口是感染艾滋病毒增长最快的群体之一。疾病控制中心估计，到2015年，一半的美国艾滋病毒携带者将超过50岁。老年人神经退行性变的机制尚不完全清楚，但HIV激活了凋亡途径，调节了钙稳态，并促进了氧化应激。此外，最近的研究表明，HIV蛋白可能会干扰清除途径，如自噬，这是蛋白质质量控制和消除有缺陷的旧细胞内细胞器所必需的途径。阿尔茨海默病(AD)、帕金森病(PD)和其他与衰老相关的疾病都有自噬缺陷，类似地，HIV患者的神经退化与自噬缺陷有关。我们最近发现，自噬途径的异常功能与老年HIV病例和表达HIV-gp120蛋白的转基因(TG)小鼠(GFAP-gp120 Tg)中枢神经系统中淀粉样β蛋白(A？)、突触核蛋白(？-syn)和Tau的进行性积累有关。在这种情况下，我们的假设是，像Nef这样的HIV蛋白可能通过与自噬途径的组件相互作用来干扰自噬，比如Beclin1。在患有慢性HIV感染的老年患者中，这可能会导致神经毒性蛋白清除减少和神经变性。这项建议的主要目的将是a)更好地了解HIV蛋白干扰自噬导致蛋白质积累和神经毒性的机制，以及b)在HIV神经毒性和衰老的临床前模型中确定自噬途径的激活是否具有神经保护作用。为此，我们提出了以下目标：目的1：分析老年慢性HIV感染患者脑组织中HIV蛋白与自噬途径组分之间的相互作用。目的2：研究HIV蛋白在细胞中的作用 自噬功能障碍和神经毒性的机制。目的3.确定体内自噬激活是否能改善HIV神经毒性的老年转基因啮齿动物的神经退行性变和行为缺陷。这个项目有可能进一步阐明 自噬作为HIV蛋白神经毒性的关键下游介质在衰老过程中的作用，这可能导致HIV相关神经退化和神经保护的新疗法和模型的发展。由于自噬的改变也出现在AD和PD中，该项目可能会在其他年龄相关的神经退行性疾病的治疗进展中有更广泛的应用。 与公共卫生相关：在美国，人口老龄化是艾滋病毒携带者增长最快的群体之一，但老年艾滋病毒感染者神经变性的机制仍不清楚。最近的研究表明，HIV蛋白可能会干扰自噬，这是蛋白质质量控制所必需的一条途径。在这个项目中，我们建议更好地了解HIV蛋白干扰自噬导致蛋白质积累和神经毒性的机制，并确定自噬途径的激活在HIV神经毒性和衰老的临床前模型中是否具有神经保护作用。

DESCRIPTION (provided by applicant): Currently over 30 million people live with HIV worldwide. In the US, the aging population represents one of the fastest growing groups with HIV. The Center for Disease Control estimates that by the year 2015, half of all Americans living with HIV will be over the age of 50. The mechanisms of neurodegeneration in aged individuals are not completely understood, however HIV activates apoptotic pathways, dysregulates calcium homeostasis and promotes oxidative stress. Moreover, recent studies have shown that HIV proteins might interfere with clearance pathways such as autophagy, a pathway necessary for protein quality control and elimination of defective older intracellular organelles. Deficits i autophagy have been described in Alzheimer's Disease (AD), Parkinson's Disease (PD) and other aging-related disorders, similarly, neurodegeneration has been linked to defects in autophagy in patients with HIV. We have recently shown that abnormal functioning of the autophagy pathway is associated with progressive accumulation of Amyloid-beta (A¿), ¿-synuclein (¿-syn) and Tau in the CNS of aged HIV human cases and in transgenic (tg) mice expressing HIV-gp120 protein (GFAP-gp120 tg). In this context our hypothesis is that HIV proteins such as Nef might interfere with autophagy by interacting with components of the autophagocytic pathway such as Beclin1. In aged patients with chronic HIV infection, this might result in reduced clearance of neurotoxic proteins and neurodegeneration. The main objectives of this proposal will be to a) better understand the mechanisms through which HIV proteins interfere with autophagy leading to protein accumulation and neurotoxicity, and b) to determine whether activation of the autophagy pathway is neuroprotective in preclinical models of HIV neurotoxicity and aging. For this purpose we propose the following Aims: Aim 1: To analyze interactions between HIV proteins and components of the autophagy pathway in brains of aged patients with chronic HIV infection. Aim 2: To investigate the role of HIV proteins in the cellular mechanisms of autophagy dysfunction and neurotoxicity. Aim 3. To determine whether autophagy activation in vivo ameliorates neurodegenerative and behavioral deficits in aged transgenic rodent models of HIV neurotoxicity. This project has the potential to further elucidate the role of autophagy as key downstream mediator of HIV-protein neurotoxicity during aging, which could lead to the development of new therapies and models of HIV-associated neurodegeneration and neuroprotection. Since alterations in autophagy are also present in AD and PD, this project may have broader applications for therapeutic advancements in other age-related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: In the US, the aging population represents one of the fastest growing groups with HIV however the mechanisms underlying neurodegeneration in aged HIV individuals remain unclear. Recent studies have shown that HIV proteins might interfere with autophagy, a pathway necessary for protein quality control. For this project we propose to better understand the mechanisms through which HIV proteins interfere with autophagy leading to protein accumulation and neurotoxicity, and to determine whether activation of the autophagy pathway is neuroprotective in preclinical models of HIV neurotoxicity and aging.