The Synaptic Protein Economy in HIV/AID

HIV/AID 中的突触蛋白经济

• 批准号: 8699279
• 负责人: BENJAMIN B. GELMAN
• 金额: $ 38.57万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699279
• 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; 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.

描述（由申请人提供）：艾滋病毒/艾滋病患者幸存于年龄较大的年龄，但我们仍然不知道在衰老的大脑中是否会加剧与HIV相关的神经认知障碍（手）。我们将评估通过修饰泛素蛋白酶体系统（UPS），脑部炎症驱动手与大脑衰老之间相互作用的假设。 UPS是神经元蛋白更新的主要途径。突触增强，学习和记忆形成的正常生理变化是正常的分钟生理变化所必需的。 UPS在防止脑衰老期间病理神经退行性中错误折叠神经元蛋白的积累中起关键作用。我们确定，UPS在有手的人的脑皮层中是异常的：免疫蛋白酶体（IPS）是响应干扰素的诱导的。 IPS诱导与HIV相关的神经认知障碍（手）牢固地联系在一起。它在病理上是相关的，因为它在大脑中HIV脑炎（HIVE）和/或复制HIV浓度的受试者中很普遍。它在关键神经元区室中的解剖学普遍存在，包括突触，轴突和神经元核，周长和分离的突触体。该提案将检验以下假设，即IPS诱导通过在病理上转移UPS底物曲目，从而改变了底物曲目，突触蛋白更新和手动和脑衰变中的突触可塑性。第一个目标将使用人脑样本来确定IPS诱导如何影响UPS的大分子组装和酶促功能，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更新和全酶动力学，并确定抑制IPS的IPS是否会逆转突触蛋白经济中的这些变化。最终目标将使用尸检标本来确定在病理大脑衰老期间错误折叠蛋白的发作年龄或率是否与IPS诱导有关。该计划总体上解决了手头突触功能障碍的高度新颖机制，对病理脑衰老与艾滋病毒/艾滋病之间相互作用的机制具有重要意义。