The Synaptic Protein Economy in HIV/AID

HIV/AID 中的突触蛋白经济

• 批准号: 8113302
• 负责人: BENJAMIN B. GELMAN
• 金额: $ 38.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113302
• 关键词: AIDS neuropathy; AIDS/HIV problem; Address; Affect; Age; Age of Onset; Aging; Amyloid; Autopsy; Axon; Brain; Brain Diseases; Catalytic Domain; Cell Culture Techniques; Cell Nucleus; Cells; Chemistry; Chemosensitization; Dementia; Deposition; Diffuse; Disease; Encephalitis; Functional disorder; HIV; HIV Infections; HIV encephalitis; HIV-1; Holoenzymes; Human; Infection; Inflammatory; Interferons; Kinetics; Learning; Lewy Bodies; Link; Memory; Messenger RNA; Nerve Degeneration; Neurocognitive; Neurons; Organ; Perikaryon; Physiological; Play; Process; Proteins; Regulation; Role; Route; Specimen; Synapses; Synaptic plasticity; Synaptosomes; System; Testing; Therapeutic; Ubiquitin; Work; aging brain; base; brain cell; clinically relevant; innovation; knock-down; link protein; macromolecular assembly; multicatalytic endopeptidase complex; neurophysiology; novel; novel strategies; prevent; programs; protein degradation; protein misfolding; public health relevance; response; synaptic function; synuclein; tau Proteins

DESCRIPTION (provided by applicant): People with HIV/AIDS survive to older ages, but we still do not know if or how HIV-associated neurocognitive disorders (HAND) is exacerbated in the aging brain. We will evaluate the hypotheses that brain inflammation drives an interaction between HAND and brain aging by modifying the ubiquitin proteasome system (UPS). The UPS is the main route of neuronal protein turnover; it is required for normal minute-to-minute physiological changes in synaptic potentiation, learning and memory formation. The UPS plays a key role in preventing the accumulation of misfolded neuronal proteins in pathological neurodegeneration during brain aging. We established that the UPS is abnormal in brain cortex of people with HAND: Immunoproteasomes (IPS) are induced in response to interferons. IPS induction was linked solidly with HIV-associated neurocognitive disorders (HAND). It was relevant pathologically because it was prevalent in subjects with HIV encephalitis (HIVE) and/or replicating HIV concentration in the brain. It was anatomically pervasive in critical neuronal compartments including synapses, axons and neuronal nuclei, perikarya, and isolated synaptosomes. The proposal will test the hypothesis that IPS induction perturbs the synaptic protein economy by diverting the UPS substrate repertoire pathologically, which alters the substrate repertoire, synaptic protein turnover, and synaptic plasticity in HAND and brain aging. The first aim will use human brain specimens to determine how IPS induction affects macromolecular assembly and enzymatic functions of the UPS, including the dynamic interaction with synaptic proteins. The second aim will use interferon-stimulated mixed brain cell cultures to determine how IPS induction influences synaptic protein turnover and holoenzyme kinetics, and will determine whether inhibiting the IPS reverses these changes in the synaptic protein economy. A final aim will use autopsy specimens to determine if the age-of-onset or rate-of-accumulation of misfolded proteins during pathological brain aging is perturbed in association with IPS induction. The program overall addresses a highly novel mechanism for synaptic dysfunction in HAND and has important implications for the mechanism of interaction between pathological brain aging and HIV/AIDS. PUBLIC HEALTH RELEVANCE: "The project is important because it will clearly define a novel basic mechanism regarding how HIV infection in the brain disturbs learning and memory, and how HIV worsens brain degeneration during aging. The studies will determine if changes in brain proteins that occur can be blocked, in order to stop dementia and brain aging in HIV infected people"

描述（由申请人提供）：艾滋病毒/艾滋病患者可以活到老年，但我们仍然不知道艾滋病毒相关的神经认知障碍（HAND）是否或如何在衰老的大脑中加剧。我们将通过修改泛素蛋白酶体系统 (UPS) 来评估大脑炎症驱动 HAND 与大脑衰老之间相互作用的假设。 UPS是神经元蛋白质周转的主要途径；它是突触增强、学习和记忆形成中每分钟正常生理变化所必需的。 UPS 在防止大脑衰老过程中病理性神经退行性变中错误折叠的神经元蛋白积累方面发挥着关键作用。我们确定 HAND 患者大脑皮层的 UPS 异常：免疫蛋白酶体 (IPS) 是响应干扰素而诱导的。 IPS 诱导与 HIV 相关神经认知障碍 (HAND) 密切相关。它在病理学上是相关的，因为它在患有艾滋病毒脑炎（HIVE）和/或在大脑中复制艾滋病毒浓度的受试者中普遍存在。它在解剖学上普遍存在于关键神经元区室中，包括突触、轴突和神经元核、核周和孤立的突触体。该提案将测试这样的假设：IPS 诱导通过病理性地转移 UPS 底物库来扰乱突触蛋白经济，从而改变手和大脑衰老中的底物库、突触蛋白周转以及突触可塑性。第一个目标将使用人脑标本来确定 IPS 诱导如何影响 UPS 的大分子组装和酶功能，包括与突触蛋白的动态相互作用。第二个目标将使用干扰素刺激的混合脑细胞培养物来确定 IPS 诱导如何影响突触蛋白周转和全酶动力学，并将确定抑制 IPS 是否会逆转突触蛋白经济的这些变化。最终目标将使用尸检标本来确定病理性大脑衰老过程中错误折叠蛋白的发病年龄或积累率是否与 IPS 诱导相关。该项目总体上解决了 HAND 突触功能障碍的一种高度新颖的机制，并对病理性脑衰老和艾滋病毒/艾滋病之间的相互作用机制具有重要意义。 公共健康相关性：“该项目很重要，因为它将明确定义一种新的基本机制，涉及大脑中的艾滋病毒感染如何扰乱学习和记忆，以及艾滋病毒如何恶化衰老过程中的大脑退化。这些研究将确定大脑蛋白质的变化是否会发生可以被阻断，以阻止艾滋病毒感染者的痴呆和大脑老化”