17α-estradiol and sex-differences in HAND with methamphetamine

项目摘要 ART时代HIV相关神经认知障碍（HAND）的发病机制复杂， HIV-1复制/HIV-1蛋白水平低、抗逆转录病毒药物、滥用药物和滥用兴奋剂 例如甲基苯丙胺。据设想，这些艾滋病毒相关因素的综合暴露导致 可逆性突触树突损伤，有助于HAND的发展。越来越多的证据 表明在HAND和甲基苯丙胺滥用方面存在性别差异; 艾滋病毒有更大的神经认知障碍，甲基苯丙胺滥用导致更严重的灰色 物质损害和认知缺陷。这些性别差异的一个因素是雌二醇（E2），一个主要的 雌激素的一种形式，有两种亚型（17β-E2和17α-E2）。虽然这两种亚型都具有神经保护作用，但17α-E2， 大脑中占主导地位的雌激素可能在HAND中起重要作用。值得注意的是，我们的发现表明 内溶酶体是17α-E2、HIV蛋白（gp 120和达特）、ART药物和 甲基苯丙胺可以交叉影响突触树突损伤和性别差异的手。 内溶酶体在调节神经元可塑性中是重要的，因为它们广泛的 这些过程需要持续的囊泡膜运输来维持轴突和体树突 膜。HIV相关因素的联合暴露导致的内溶酶体功能障碍可能导致 突触树突损伤相反，17α-E2的内溶酶体增强作用可逆转 突触-树突损伤，并导致HAND的性别差异。这里的目标是调查 内溶酶体在HAND中突触树突损伤和性别差异中的作用。我们将测试 雌激素受体-α（ERα）内溶酶体定位是雌激素受体保护作用的关键假设 17α-E2对联合用药引起的内溶酶体功能障碍和突触树突损伤的作用 暴露于HIV相关因素（gp 120、达特、ART药物和甲基苯丙胺）。根据我们初步的 研究结果，我们的新假设将通过追求两个具体目标进行测试。(1)确定ERα在 17α-E2对内溶酶体功能障碍和突触树突损伤的保护作用， HIV-1蛋白（gp 120和达特）、抗逆转录病毒药物和甲基苯丙胺的联合暴露。(2)确定 17α-E2影响认知障碍和内溶酶体功能障碍的程度 和突触树突损伤的HIV-1转基因大鼠暴露与ART药物和/或甲基苯丙胺。的 这项工作的重点是确定17α-E2和内溶酶体在性别差异中的新作用， 滥用甲基苯丙胺。从机制上讲，内溶酶体是关键部位，17α-E2，HIV 蛋白质、抗逆转录病毒药物和甲基苯丙胺交叉影响突触树突损伤和性别- 手的差异。将使用体外和体内模型确定17α-E2的治疗潜力。 这些研究的结果将有助于更好地理解在滥用 甲基苯丙胺，并可能为开发基于17α-E2的疗法提供坚实的机制基础 反对手。因此，我们拟定的研究响应了NOT-DA-21-020（性别差异评价 在兴奋剂使用的情况下，艾滋病毒相关的合并症）。

Project Abstract The pathogenesis of HIV-associated neurocognitive disorders (HAND) in ART era is complex and may result from low levels of HIV-1 replication/HIV-1 proteins, ART drugs, drug of abuse, and the misuse of stimulants such as methamphetamine. It is envisioned that combined exposure of these HIV-related factors leads to reversible synaptodendritic impairment that contribute to the development of HAND. Growing evidence indicates the existence of sex differences in both HAND and in methamphetamine misuse; Women living with HIV have greater neurocognitive impairments, and methamphetamine misuse leads to more severe gray matter damage and cognitive deficits in female. One factor for these sex-differences is estradiol (E2), a major form of estrogen with two isoforms (17β-E2 and 17α-E2). Although both isoforms are neuroprotective,17α-E2, the predominant estrogen in the brain, may play an important role in HAND. Significantly, our findings indicate that endolysosomes represent as critical sites, where 17α-E2, HIV proteins (gp120 and Tat), ART drugs, and methamphetamine could intersect to affect synaptodendritic impairment and sex-differences in HAND. Endolysosomes are important for important in modulating neuronal plasticity because their extensive processes require constant vesicular membrane trafficking to maintain axonal and somatodendritic membranes. Endolysosome dysfunction resulting from combined exposure of HIV-related factors could lead to synaptodendritic impairment. Conversely, the endolysosome enhancing effect of 17α-E2 could reverse synaptodendritic impairment and contribute to sex-differences in HAND. The objective here is to investigate the role of endolysosomes in synaptodendritic impairment and sex-differences in HAND. We will test the hypothesis that endolysosome localization of estrogen receptor-α (ERα) is critical for the protective effects of 17α-E2 against endolysosome dysfunction and synaptodendritic impairments resulting from combined exposure of HIV-related factors (gp120, Tat, ART drugs, and methamphetamine). Guided by our preliminary findings, our novel hypothesis will be tested by pursuing two specific aims. (1) Determine the role of ERα in the protective effects of 17α-E2 against endolysosome dysfunction and synaptodendritic impairments, resulting from combined exposure of HIV-1 proteins (gp120 and Tat), ART drugs, and methamphetamine. (2) Determine the extent to which 17α-E2 affects cognitive impairment and the development of endolysosome dysfunction and synaptodendritic impairments in HIV-1 Tg rats exposed with ART drugs and/or methamphetamine. The proposed work is focused to determine the novel role of 17α-E2 and endolysosomes in sex-differences in HAND with misuse of methamphetamine. Mechanistically, endolysosomes are critical sites, where 17α-E2, HIV proteins, ART drugs, and methamphetamine intersect to affect synaptodendritic impairment and sex- differences in HAND. The therapeutic potential of 17α-E2 will be determined using in vitro and in vivo models. Results of these studies will help in understanding better sex-differences in HAND in the context of misuse of methamphetamine and may provide a solid mechanistic basis for the development of 17α-E2-based therapies against HAND. Thus, our proposed studies are responsive to NOT-DA-21-020 (Evaluation of sex differences on HIV-associated comorbidities in the context of stimulant use).