Estrogen regulation of age and PTSD-associated changes in macrophage-induced neuroinflammation during HIV infection.

项目总结/摘要 30-50%的艾滋病毒感染者仍然患有神经系统并发症，包括艾滋病毒相关的神经系统并发症。 神经认知障碍（HAND）和创伤后应激障碍（PTSD），尽管联合治疗取得了成功， 抗逆转录病毒治疗（cART）。持续性巨噬细胞和小胶质细胞驱动的神经炎症被视为一种 HAND和PTSD疾病进展的共同潜在因素。这项研究的长期目标是 了解影响神经系统疾病中神经炎症过程的潜在机制 靶向更特异的内源性信号传导机制，用于开发新的治疗方法。在 本研究将探讨雌激素在巨噬细胞和小胶质细胞中的信号传导作为可能的治疗靶点。17β- 雌二醇是雌激素最活跃的形式，在绝经后妇女中减少。研究表明，17β- 雌二醇具有神经保护作用，其表达减少可能与HIV和PTSD疾病恶化相关 进展然而，雌激素浓度及其受体的变化如何调节艾滋病毒诱导的 患有PTSD的绝经后妇女的神经认知障碍尚不清楚。所以我们 假设巨噬细胞和小胶质细胞诱导神经炎症将被雌激素抑制， 以GPER依赖性方式，老年女性与男性和绝经前女性相比 患有创伤后应激障碍和艾滋病为了解决这一假设，我们将利用2个体外HIV 神经炎症模型：1.大鼠皮层神经元与人单核细胞共培养体系的建立 从PTSD供体分离的衍生巨噬细胞和2. iMicroglia和iNeurons的共培养系统 从健康捐赠者身上提取的人类多能干细胞来自前和后的iMicroglia和巨噬细胞 绝经后女性和年龄匹配的男性将在绝经前用各种浓度的雌激素预处理， 探讨以下具体目的：1）评价雌激素抑制HIV的能力- 在PTSD-hMDM和小胶质细胞中诱导神经炎症。2)评价雌激素受体在 HIV和PTSD诱导的神经炎症在这个提议的奖项中，我们希望绝经后的hMDM 女性PTSD捐赠者和iMicroglia将增加HIV诱导的神经炎症，这可能是 被GPER激活抑制。首席研究员的职业目标是领导一个独立的翻译 研究计划，同时增加科学的多样性在历史上黑人学院和大学 （HBCU）。为了实现这一目标，PI制定了一个强有力的培训计划，将扩大她在 神经艾滋病和创伤后应激障碍领域，增加她的技能，在一代iPSC，流式细胞术，质谱仪， 生物统计分析和生成数据为未来的R奖。本次培训将以强导强训为指导 来自斯佩尔曼学院和邻近研究机构的调查委员会。随着这一成功 项目，我们将阐明雌激素信号作为一个潜在的内源性靶向治疗途径的作用 对于患有HAND、PTSD和其他神经炎性疾病的人。

Project Summary/Abstract 30-50% of persons living with HIV still suffer from neurological co-morbidities, including HIV-associated Neurocognitive Disorders (HAND) and Post-traumatic stress disorder (PTSD), despite the success of combined Antiretroviral Therapy (cART). Persistent macrophage and microglia driven neuroinflammation is seen as a common underlying factor in HAND and PTSD disease progression. The long-term objective of this research is to understand the underling mechanisms that influence neuroinflammatory processes in neurological disorders to target more specific endogenous signaling mechanisms for development of novel therapeutic approaches. In this study we will explore estrogen signaling in macrophages and microglia as a possible therapeutic target. 17β- estradiol, the most active form of estrogen, is reduced in postmenopausal women. Studies have shown that 17β- estradiol is neuroprotective and its reduced expression may correlate with worse HIV and PTSD disease progression. However, how changes in estrogen concentrations and its receptors may modulate HIV-induced neurocognitive impairment in the post-menopausal women living with PTSD is unknown. Therefore, we hypothesize that macrophage and microglia induced neuroinflammation will be suppressed by estrogen, in an GPER dependent manner, in the aging female compared to males and pre-menopausal females living with Post-traumatic stress disorder and HIV. To address this hypothesis, we will utilize 2 in vitro HIV neuroinflammatory models: 1. A co-culture system composed of rat cortical neurons and human monocytes derived macrophages isolated from PTSD donors and 2. A co-culture system of iMicroglia and iNeurons derived from human pluripotent stem cells from healthy donors. iMicroglia and macrophages from pre and postmenopausal women and aged matched men will be pretreated with various concentrations of estrogen prior to HIVADA exposure to explore the following Specific Aims: 1) Evaluate estrogen’s ability to suppress HIV- induced neuroinflammation in PTSD-hMDM and Microglia. 2) Evaluate the role of estrogen receptors in HIV and PTSD-induced neuroinflammation. In this proposed award, we expect hMDMs from post-menopausal female PTSD donors and iMicroglia will have increased HIV-induced neuroinflammation, which can be suppressed by GPER activation. The principal investigator’s career goals are to lead an independent translation research program while increasing diversity in the sciences at a Historically Black College and University (HBCU). To accomplish this, the PI has developed a strong training plan that will expand her expertise in the NeuroAIDS and PTSD field, increase her skillset in the generation of iPSC, flow cytometry, mass cytometry, biostatistical analysis and generate data for future R awards. This training will be guided by the strong mentoring committee of investigators from Spelman College and neighboring Research 1 institutions. With success of this project, we will elucidate the role of estrogen signaling as a potential endogenous targeted therapeutic avenue for persons living with HAND, PTSD and other neuroinflammatory disorders.