Clearance Pathways in the CNS in Aging and HIV

衰老和艾滋病毒中枢神经系统的清除途径

基本信息

批准号：
8662672
负责人：
ELIEZER MASLIAH
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662672
关键词：
3-methyladenine Age Aging Aging-Related Process Alzheimer&apos s Disease American Anti-Retroviral Agents Apoptotic Autophagocytosis Behavioral Binding Sites Biochemical Biological Assay Brain Calcium Cell Culture Techniques Cells Centers for Disease Control and Prevention (U.S.)Cerebrum Chronic Co-Immunoprecipitations Conditioned Culture Media Confocal Microscopy Defect Development Disease Electron Microscopy Functional disorder Glial Fibrillary Acidic Protein HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Highly Active Antiretroviral Therapy Homeostasis Human Immunosuppression Individual Infection Inflammation Injection of therapeutic agent Lead Lentivirus Vector Life Link Mediating Mediator of activation protein Methods Microglia Modeling Mus Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neurons Organelles Oxidative Stress Parkinson Disease Pathway interactions Patients Performance Population Pre-Clinical Model Prevalence Proteins Quality Control Recovery Regimen Rodent Model Role Sirolimus Subfamily lentivirinae Therapeutic Transgenic Mice Transgenic Model Transgenic Organisms abeta accumulation age related aged aging brain aging population bafilomycin A1 gene therapy in vivo inflammatory marker inhibitor/antagonist macrophage mutant nef Protein neuroprotection neurotoxic neurotoxicity research study response small hairpin RNA synuclein tau Proteins

项目摘要

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.

描述（由申请人提供）：目前全世界有超过 3000 万人感染艾滋病毒，美国疾病控制中心估计，到 2015 年，老龄化人口将成为艾滋病毒感染者增长最快的群体之一。感染艾滋病毒的人年龄将超过 50 岁。老年人神经退行性变的机制尚不完全清楚，但艾滋病毒会激活细胞凋亡途径，失调钙稳态并促进氧化应激。此外，最近的研究表明，HIV 蛋白可能会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。自噬缺陷已在阿尔茨海默病 (AD) 和帕金森病 (PD) 中得到描述。）和其他与衰老相关的疾病，类似地，神经退行性变与艾滋病毒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β淀粉样蛋白的逐渐积累有关。（一个), ¿老年 HIV 人类病例和表达 HIV-gp120 蛋白 (GFAP-gp120 tg) 的转基因 (tg) 小鼠的中枢神经系统中的突触核蛋白 (¿-syn) 和 Tau 蛋白在这种情况下，我们的假设是，Nef 等 HIV 蛋白可能会干扰。在慢性 HIV 感染的老年患者中，这可能会导致神经毒性蛋白清除率降低和神经变性。该提案的主要目标是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，b)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为此，我们提出以下目标：目标 1：分析 HIV 蛋白与老年慢性 HIV 感染患者大脑中自噬途径成分之间的相互作用。目标 2：研究 HIV 蛋白在慢性 HIV 感染中的作用。细胞的目标 3. 确定体内自噬激活是否可以改善 HIV 神经毒性的老年转基因啮齿动物模型的神经退行性和行为缺陷。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，可能会导致 HIV 相关神经退行性变和神经保护的新疗法和模型的开发，因为自噬的改变也存在于 AD 和 PD 中，因此该项目可能会促进 HIV 相关神经变性和神经保护的新疗法和模型的开发。在其他与年龄相关的神经退行性疾病的治疗进展中具有更广泛的应用。