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，老龄化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，一半的美国艾滋病毒感染者将超过50岁。老年人神经退行性变的机制尚不完全清楚，但HIV激活凋亡途径，钙稳态失调并促进氧化应激。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。自噬缺陷已在阿尔茨海默病（AD）、帕金森病（PD）和其他衰老相关疾病中描述，类似地，神经变性已与HIV患者中的自噬缺陷相关联。 我们最近发现，自噬途径的功能异常与老年HIV患者和表达HIV-gp 120蛋白（GFAP-gp 120 tg）的转基因（tg）小鼠CNS中β淀粉样蛋白（A <$）、<$-突触核蛋白（<$-syn）和Tau蛋白的进行性积累有关。在这种情况下，我们的假设是，HIV蛋白，如Nef可能会干扰自噬与自噬途径的组件，如Beclin 1相互作用。在慢性HIV感染的老年患者中，这可能导致神经毒性蛋白的清除减少和神经变性。本提案的主要目的是a）更好地了解HIV蛋白干扰自噬导致蛋白积累和神经毒性的机制，以及B）确定自噬途径的激活是否在HIV神经毒性和衰老的临床前模型中具有神经保护作用。为此，我们提出了以下目的：目的1：分析慢性HIV感染的老年患者脑中HIV蛋白和自噬通路组分之间的相互作用。目的2：研究HIV蛋白在细胞内的作用， 自噬功能障碍和神经毒性的机制。目标3。确定体内自噬激活是否能改善老年转基因啮齿动物HIV神经毒性模型的神经退行性和行为缺陷。 这个项目有可能进一步阐明 自噬作为衰老过程中HIV蛋白神经毒性的关键下游介质的作用，这可能导致开发新的HIV相关神经变性和神经保护的治疗方法和模型。由于自噬的改变也存在于AD和PD中，因此该项目可能在其他年龄相关神经退行性疾病的治疗进展中具有更广泛的应用。 公共卫生相关性：在美国，老龄化人口是艾滋病毒感染者增长最快的群体之一，但老年艾滋病毒患者神经退行性变的机制仍不清楚。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途径。对于这个项目，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，并确定自噬通路的激活是否在HIV神经毒性和衰老的临床前模型中具有神经保护作用。

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.