The Synaptic Protein Economy in HIV/AID

描述(申请人提供)：艾滋病毒/艾滋病患者可以活到较高的年龄，但我们仍然不知道艾滋病毒相关的神经认知障碍(手)在老化的大脑中是否或如何加剧。我们将通过修改泛素蛋白酶体系统(UPS)来评估脑部炎症导致手和脑老化之间相互作用的假说。UPS是神经元蛋白质周转的主要途径；它是突触增强、学习和记忆形成中正常的每分钟生理变化所必需的。UPS在防止错误折叠的神经元蛋白在脑老化过程中的病理性神经退变中积累方面发挥了关键作用。我们发现手部疾病患者大脑皮层中的UPS是异常的：干扰素诱导免疫蛋白酶体(IPS)。诱导iPS与HIV相关的神经认知障碍(HAND)密切相关。这在病理学上是相关的，因为它在患有艾滋病毒脑炎(蜂窝)和/或在大脑中复制艾滋病毒浓度的受试者中流行。在解剖学上，它广泛存在于包括突触、轴突和神经元核、核膜和孤立的突触小体在内的关键神经元室。该提案将检验这一假说，即IPS诱导通过从病理上改变UPS底物谱来扰乱突触蛋白质经济，从而改变底物谱、突触蛋白周转以及手和脑老化中的突触可塑性。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是否逆转突触蛋白经济中的这些变化。最终目标将使用尸检样本来确定在病理性脑老化过程中错误折叠蛋白的发病年龄或累积速度是否与IPS诱导有关。该计划总体上解决了一种非常新颖的突触功能障碍机制，并对病理性脑老化和艾滋病毒/艾滋病之间的相互作用机制具有重要意义。 与公共卫生相关：这个项目很重要，因为它将明确定义一种新的基本机制，即艾滋病毒感染大脑是如何扰乱学习和记忆的，以及艾滋病毒如何在衰老过程中加剧大脑退化。这些研究将确定是否可以阻止大脑蛋白质的变化，以阻止艾滋病毒感染者的痴呆症和脑老化。

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"