Clearance Pathways in the CNS in Aging and HIV

描述（由申请人提供）：目前全球有超过3000万人感染艾滋病毒。在美国，老年人口是艾滋病毒感染者增长最快的群体之一。疾病控制中心估计，到2015年，一半感染艾滋病毒的美国人将超过50岁。老年人神经退行性变的机制尚不完全清楚，但HIV激活凋亡途径，失调钙稳态并促进氧化应激。此外，最近的研究表明，HIV蛋白可能干扰自噬等清除途径，自噬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。自噬缺陷已经在阿尔茨海默病（AD）、帕金森病（PD）和其他与衰老相关的疾病中被描述，同样，神经退行性疾病也与HIV患者的自噬缺陷有关。我们最近发现，自噬途径的异常功能与老年HIV患者和表达HIV-gp120蛋白（GFAP-gp120 tg）的转基因（tg）小鼠的中枢神经系统中淀粉样蛋白- β （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HIV蛋白（如Nef）可能通过与自噬细胞途径的组分（如Beclin1）相互作用来干扰自噬。在慢性HIV感染的老年患者中，这可能导致神经毒性蛋白清除率降低和神经变性。本研究的主要目的是：a)更好地理解HIV蛋白干扰自噬导致蛋白质积累和神经毒性的机制；b)确定自噬途径的激活是否对HIV神经毒性和衰老的临床前模型具有神经保护作用。为此，我们提出以下目标：目的1：分析老年慢性HIV感染患者大脑中HIV蛋白与自噬通路组分之间的相互作用。目的2：探讨HIV蛋白在细胞中的作用

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.