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

HIV 感染期间巨噬细胞诱导的神经炎症中雌激素对年龄和 PTSD 相关变化的调节。

• 批准号: 10707319
• 负责人: Kimberly S. Williams
• 金额: $ 21.1万
• 依托单位: SPELMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707319
• 关键词: Acceleration; Address; Affect; Age; Aging; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antibodies; Antioxidants; Astrocytes; Automobile Driving; Autopsy; Award; Binding; Biological; Biometry; Biotechnology; Calcium; Clinical Trials; Coculture Techniques; Collecting Cell; Computer software; Conditioned Culture Media; Coupled; Cytometry; Data; Development; Diagnosis; Disease; Disease Progression; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Exposure to; Female; Flow Cytometry; Future; GTP-Binding Proteins; Gender; Generations; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Historically Black Colleges and Universities; Human; In Vitro; Inflammation; Inflammatory; Institution; Knowledge; Lead; Learning; Life; Life Expectancy; Macrophage; Macrophage Activation; Mass Spectrum Analysis; Measures; Mediating; Membrane; Menopause; Mentors; Microglia; Modeling; Morphology; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurons; Neuropathogenesis; Neurotoxins; Nuclear Receptors; Pathogenesis; Patients; Persons; Phenotype; Post-Traumatic Stress Disorders; Postmenopause; Premenopause; Principal Investigator; Process; Production; Property; Proteins; Quantitative Reverse Transcriptase PCR; RBM5 gene; Rattus; Receptor Activation; Recording of previous events; Regulation; Reporting; Research; Research Personnel; Role; Science; Signal Pathway; Signal Transduction; System; TNF gene; Techniques; Testing; Training; Viral; Western Blotting; Woman; aged; aging population; antagonist; antiretroviral therapy; brain tissue; career; career development; clinical diagnosis; college; comorbidity; data submission; experience; human pluripotent stem cell; imaging software; induced pluripotent stem cell; male; men; monocyte; nervous system disorder; neuroAIDS; neuroinflammation; neuroprotection; neurotoxicity; novel; novel therapeutic intervention; psychiatric comorbidity; receptor; receptor expression; skill acquisition; skills; success; synergism; targeted treatment; therapeutic target; training opportunity; translational research program

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.

项目概要/摘要 30-50% 的艾滋病毒感染者仍然患有神经系统并发症，包括与艾滋病毒相关的疾病 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 抗逆转录病毒疗法（cART）被视为持续性巨噬细胞和小胶质细胞驱动的神经炎症。 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的神经炎症过程的基本机制 针对更具体的内源性信号传导机制来开发新的治疗方法。 在这项研究中，我们将探索巨噬细胞和小胶质细胞中的雌激素信号传导作为可能的治疗靶点。 雌二醇是雌激素最活跃的形式，在绝经后女性中，17β- 会减少。 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 然而，雌激素进展浓度及其受体的变化如何调节 HIV 诱导的 患有 PTSD 的绝经后妇女的神经认知障碍尚不清楚。 雌激素会迅速抑制巨噬细胞和小胶质细胞诱导的神经炎症， 与男性和绝经前女性相比，老年女性以 GPER 依赖性方式 患有创伤后应激障碍和艾滋病毒的人为了解决这一假设，我们将利用 2 种体外艾滋病毒。 神经炎症模型：1.大鼠皮质神经元和人单核细胞组成的共培养系统 2. 衍生自 PTSD 供体的巨噬细胞和 iMicroglia 和 iNeurons 的共培养系统 来自健康捐赠者的人类多能干细胞和来自前和后的巨噬细胞。 绝经后妇女和年龄匹配的男性将在术前接受不同浓度的雌激素预处理 HIVADA 暴露探索以下具体目标： 1) 评估雌激素抑制 HIV 的能力 PTSD-hMDM 和小胶质细胞中诱导的神经炎症 2) 评估雌激素受体在 PTSD-hMDM 和小胶质细胞中的作用。 在这个拟议的奖项中，我们预计绝经后会出现 HIV 和 PTSD 诱发的神经炎症。 女性 PTSD 捐献者和 iMicroglia 会增加 HIV 诱发的神经炎症，这可能是 首席研究员的职业目标是领导独立翻译。 在历史悠久的黑人学院和大学开展研究计划，同时增加科学的多样性 为了实现这一目标，PI 制定了一项强有力的培训计划，以扩展她在该领域的专业知识。 NeuroAIDS 和 PTSD 领域，提高她在 iPSC 生成、流式细胞术、质谱流式细胞术、 生物统计分析并为未来的 R 奖项生成数据，该培训将得到强有力的指导。 斯佩尔曼学院和邻近的研究机构 1 的研究人员委员会取得了成功。 项目中，我们将阐明雌激素信号传导作为潜在内源性靶向治疗途径的作用 适用于患有手部疾病、创伤后应激障碍和其他神经炎症性疾病的人。