Tat endolysosome escape and HAND

Tat 内溶酶体逃逸和 HAND

• 批准号: 10094719
• 负责人: Xuesong Chen
• 金额: $ 35.25万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-24 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094719
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Administrative Supplement; Aging; Alzheimer like pathology; Alzheimer' s Disease; Amyloid beta-Protein; Anti-Retroviral Agents; Arginine; Attenuated; Award; Cells; Clinical; Dementia; Development; Functional disorder; Generations; HIV-1; HIV-associated neurocognitive disorder; High Prevalence; Hydrolase; Impaired cognition; Individual; Lead; Longevity; Lysosomes; Membrane; Mitotic; Molecular; Neurons; Outcome; Pathogenesis; Pathologic; Pharmaceutical Preparations; Prevalence; Preventive Intervention; Process; Proteins; Proton Pump; Public Health; Research; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; antiretroviral therapy; base; experience; insight; knock-down; large-conductance calcium-activated potassium channels; mutant; novel; novel therapeutics; polarized cell; protein aggregation; sensor; social; tat Protein; tau Proteins; tau-1; trafficking; vacuolar H+-ATPase

Project Abstract Antiretroviral therapeutic (ART) drugs have greatly increased the lifespan of people living with HIV-1/AIDS. However, these same people experience ~50% prevalence rates of HIV-1 associated neurocognitive disorders (HAND). Increasingly noted in HIV-1 infected individuals are clinical manifestations and pathological features of Alzheimer’s disease (AD) including cognitive impairment, increased levels of amyloid beta protein (Aβ), increased levels of phosphorylated tau protein (p-tau), and synaptic dysfunction. Not only is the pathogenesis of HAND unclear, but relatively little is known about the extent to which HIV-1, HIV-1 proteins, and/or ART drugs act as “aging and AD accelerators”. The objective for this Alzheimer’s-focused Administrative Supplement (NOT-AG-20-008) is to determine the extent to which and mechanisms by which HIV-1 Tat protein contributes to the development of AD-like pathology. Our central hypothesis is that HIV-1 Tat interacts with the SLC38A9 arginine sensor in endolysosomes, promotes the disassembly of the v-ATPase proton pump in endolysosomes, and causes AD-like pathology. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing two specific aims. (1) Determine the extent to which and mechanisms by which Tat causes v-ATPase disassembly. (2) Determine the extent to which and mechanisms by which Tat induced v- ATPase disassembly causes AD-like pathology in primary cultured neurons. The proposed studies here will explore novel mechanisms whereby Tat induces disassembly of v-ATPase via a lysosome arginine sensor, and we will focus on how Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. Further, we expect that promoting the assembly of v-ATPase will attenuate Tat-induced AD-like pathology. The proposed studies are within the scope of the awarded R01 (MH119000-01) that is focused not on AD or its related dementias, but rather an involvement of v-ATPase in Tat endolysosome escape and HAND. Results of the proposed studies will not only lead to novel mechanistic insights into the co-pathogenesis of HAND and AD, but also provide rationale for developing endolysosome-acidifying agents as novel therapeutic strategies.

项目摘要 抗逆转录病毒治疗（ART）药物大大延长了HIV-1/AIDS患者的寿命。 然而，这些人经历了约50%的HIV-1相关神经认知障碍患病率 （手）。在HIV-1感染者中越来越多地注意到， 阿尔茨海默病（AD），包括认知障碍、淀粉样β蛋白（A β）水平升高， 增加的磷酸化tau蛋白（p-tau）水平和突触功能障碍。不仅是发病机制 目前尚不清楚，但对HIV-1、HIV-1蛋白和/或ART在多大程度上 药物充当"衰老和AD加速剂"。这一以老年痴呆症为重点的行政管理的目标 补充（NOT-AG-20 - 008）是为了确定HIV-1达特蛋白 有助于AD样病理学的发展。我们的中心假设是HIV-1达特与 SLC38A9精氨酸传感器，促进v-ATP酶质子泵的分解， 内溶酶体，并导致AD样病理。根据我们的初步发现，这一新的假设将 通过追求两个具体目标进行测试。(1)确定达特 导致v-ATP酶分解。(2)确定达特诱导v- ATP酶分解导致原代培养神经元AD样病变。这里的研究建议将 探索达特通过溶酶体精氨酸传感器诱导v-ATP酶分解的新机制， 我们将重点关注Tat诱导的v-ATP酶分解如何参与AD样发病机制。此外，本发明还 我们预期促进v-ATP酶的组装将减弱Tat诱导的AD样病理。的 拟议的研究在授予的R01（MH119000 - 01）的范围内，该研究的重点不是AD或其 相关的痴呆，而是v-ATP酶参与达特内溶酶体逃逸和HAND。结果 所提出的研究不仅将导致对HAND的共同发病机制的新的机制见解， AD，而且还为开发内溶酶体酸化剂作为新的治疗策略提供了理论基础。