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％的艾滋病毒患者仍患有神经系统合并症，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），dospite联合的成功 抗逆转录病毒疗法（CART）。持续的巨噬细胞和小胶质细胞驱动神经炎症被视为 手工和PTSD疾病进展中的常见潜在因素。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底下机制 靶向更具体的内源信号传导机制，用于开发新型治疗方法。在 这项研究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。 17β- 雌二醇是雌激素最活跃的形式，在绝经后妇女中降低了。研究表明17β- 雌二醇是神经保护性的，其降低的表达可能与较差的HIV和PTSD疾病相关 进展。但是，雌激素浓度及其接收器的变化如何调节HIV诱导 尚不清楚患有PTSD的绝经后妇女的神经认知障碍。因此，我们 假设巨噬细胞和小胶质细胞诱导的神经炎症将被雌激素抑制， 与男性和绝经前女性相比，以GPER依赖的方式，在衰老的女性中 患有创伤后应激障碍和艾滋病毒。为了解决这一假设，我们将利用2种体外HIV 神经炎症模型：1。由大鼠皮质神经元和人单核细胞组成的共培养系统 从PTSD供体分离的衍生巨噬细胞和2个。 来自健康供体的人类多能干细胞。来自前后 绝经后妇女和老年匹配的男性将通过各种浓度的雌激素预处理 海瓦达暴露于探索以下特定目的：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 HIV和PTSD诱导的神经炎症。在这个拟议的奖项中，我们预计Meropausal的HMDMS 雌性PTSD供体和imicroglia将增加HIV诱导的神经炎症，这可以是 被GPER激活抑制。主要研究者的职业目标是领导独立翻译 研究计划的同时，在历史悠久的黑人学院和大学中增加了科学的多样性 （HBCU）。为此，PI制定了一个强大的培训计划，该计划将扩大她的专业知识 神经辅助和PTSD领域，提高了她在IPSC的产生，流式细胞仪，质量细胞仪的产生方面的技能 生物统计分析并生成未来R奖项的数据。这项培训将由强烈的心理指导 Spelman College和邻近研究1机构的调查人员委员会。成功 项目，我们将阐明雌激素信号传导作为潜在的内源性靶向治疗大道的作用 适用于手工，PTSD和其他神经炎症性疾病的人。