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.

项目摘要/摘要 30%-50%的艾滋病毒携带者仍然患有神经系统共病，包括与艾滋病毒相关的 神经认知障碍(手)和创伤后应激障碍(PTSD)，尽管联合治疗取得成功 抗逆转录病毒疗法(CART)持续性巨噬细胞和小胶质细胞引起的神经炎被视为 手部和创伤后应激障碍疾病进展的共同潜在因素。这项研究的长期目标是 了解影响神经性疾病中神经炎性过程的潜在机制 针对更具体的内源性信号机制，开发新的治疗方法。在……里面 在本研究中，我们将探索巨噬细胞和小胶质细胞中的雌激素信号，作为可能的治疗靶点。17β- 雌激素是雌激素中最活跃的形式，在绝经后的女性中会减少。研究表明，17β- 雌二醇具有神经保护作用，其表达减少可能与更严重的艾滋病毒和创伤后应激障碍相关 进步。然而，雌激素浓度及其受体的变化可能如何调节艾滋病毒诱导的 患有创伤后应激障碍的绝经后妇女的神经认知损害尚不清楚。因此，我们 假设巨噬细胞和小胶质细胞引起的神经炎症将被雌激素抑制， 在GPER依赖的方式下，在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毒。为了解决这一假设，我们将使用2个体外艾滋病毒 神经炎性模型：1.大鼠皮层神经元与人单核细胞共培养体系 创伤后应激障碍供者来源的巨噬细胞及2.小胶质细胞与神经细胞来源的共培养体系 来自健康捐赠者的人类多能干细胞。前和后的小胶质细胞和巨噬细胞 绝经后妇女和匹配的老年男子将在治疗前接受不同浓度的雌激素。 以探索以下具体目标：1)评估雌激素抑制艾滋病毒的能力- 诱导PTSD-HMDM和小胶质细胞的神经炎症。2)评估雌激素受体在 艾滋病毒和创伤后应激障碍引起的神经炎症。在这个提议的奖项中，我们期望来自绝经后的hmdm。 女性创伤后应激障碍捐赠者和小胶质细胞将增加艾滋病毒诱导的神经炎症，这可能是 被GPER激活抑制。首席调查员的职业目标是领导独立翻译 在一所历史悠久的黑人学院和大学增加科学多样性的同时进行研究计划 (HBCU)。为了实现这一目标，私家侦探制定了一项强有力的培训计划，以扩大她在 神经艾滋病和创伤后应激障碍领域，提高了她在IPSC、流式细胞术、质量细胞术、 生物统计分析，并为未来的R奖生成数据。本次培训将在强有力的指导下进行 来自斯佩尔曼学院和邻近研究机构的调查委员会。随着这件事的成功 项目中，我们将阐明雌激素信号作为潜在的内源性靶向治疗途径的作用。 适用于手部、创伤后应激障碍和其他神经炎症性疾病患者。