The role of antidepressants in central and peripheral myeloid HIV persistence and inflammation

抗抑郁药在中枢和外周髓系 HIV 持续存在和炎症中的作用

• 批准号: 10762810
• 负责人: Stephanie Marie Matt
• 金额: $ 18.52万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762810
• 关键词: Acceleration; Affect; Agonist; Antidepressive Agents; Behavioral; Biometry; Bupropion; Cells; Chronic; Clinical; Coculture Techniques; Collection; Complex; Data; Depressed mood; Development; Diagnosis; Disease Progression; Drug usage; Environment; Experimental Designs; Foundations; Genetic Transcription; Glutamates; Goals; HIV; HIV Infections; Health; Human; Image; Immune; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Institution; Investigation; Knowledge; Laboratories; Link; Macrophage; Mediating; Mental Depression; Mentored Research Scientist Development Award; Mentors; Messenger RNA; Microglia; Modeling; Myelogenous; Myeloid Cells; NF-kappa B; Neurobehavioral Manifestations; Neurologic; Neurons; Neuropathogenesis; Neuropsychological Tests; Neurotransmitter Receptor; Neurotransmitters; Nuclear Translocation; Pathogenesis; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Population; Psychoneuroimmunology; Public Health; Quality of life; Receptor Activation; Regimen; Research; Research Personnel; Residual state; Resistance; Role; Sampling; Series; Signal Transduction; Solid; Techniques; Testing; Time; Training; Treatment Efficacy; Viral; Viral reservoir; antidepressant effect; antiretroviral therapy; biotypes; career; career development; chronic infection; cognitive function; cohort; combinatorial; comorbidity; cytokine; depressive symptoms; design; efficacious treatment; immunoregulation; improved; in vivo; induced pluripotent stem cell; monocyte; neuroimmunology; neuropsychiatry; neurotransmission; novel; programs; receptor; skills; therapy adherence; therapy resistant; treatment-resistant depression

Project Summary/Abstract This is a resubmission application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Stephanie Matt to facilitate her transition to an independent academic investigator in the HIV and neuroimmunology research fields. An intense and comprehensive mentoring and research plan has been developed to use high-throughput techniques to assess antidepressant-mediated HIV viral dynamics and inflammatory signaling in human myeloid and co-culture models. Dr. Matt’s training will be supported by a firm institutional commitment to her career development and a strong mentoring team of leaders in the HIV and psychoneuroimmunology research fields, each providing strategic guidance in both the development of this proposal and mentoring as her career progresses. The proposed research plan is a natural extension of the recent studies Dr. Matt has been conducting in her mentor Dr. Peter Gaskill’s laboratory but is distinguished by examination of HIV infection and inflammation in clinical cohorts, biostatistical analyses, as well as neuronal profiling. Neurological complications of HIV infection (neuroHIV) remain prevalent even with antiretroviral therapy (ART). Depression is one of these increasingly common complications that can substantively worsen HIV disease progression. Myeloid cells such as macrophages and microglia are primary HIV targets that can serve as viral reservoirs and drive HIV neuropathogenesis, but their activation also mediates depression-associated inflammation. Inflammatory links between HIV, depression, and the drugs used to treat them are not well understood. However, HIV, depression, and antidepressants act on receptors and transporters that alter neurotransmission, and neurotransmitter receptor activity on immune cells can influence inflammatory signaling and HIV infection. This suggests that changes in neurotransmitter levels by antidepressants could affect the size of myeloid HIV reservoirs, exacerbating neuroHIV and influencing the progression of depression and treatment resistance. Thus, the overarching hypothesis of this proposal is that specific antidepressants can activate both CNS and peripheral myeloid cells that critically contribute to inflammation and HIV persistence. This proposal will test this hypothesis using a multifaceted approach to evaluate the effects of in vivo antidepressants and ART on viral dynamics and inflammation in myeloid cells in association with cognitive function in depressed people living with HIV (Aim 1), effects of antidepressants regulating discrete viral dynamics in HIV-infected, ART-treated iPSC CNS and peripheral myeloid populations (Aim 2), and how antidepressants influence viral dynamics and neuronal function in co-cultures of HIV-infected, ART-treated microglia and distinct neuronal subtypes (Aim 3). These studies will significantly advance our understanding of the cellular mechanisms underlying the role of antidepressants in HIV neuropathogenesis. This opportunity will provide comprehensive training and a solid foundation on which to build a successful and independent research program to investigate mechanisms by which neuropsychiatric drugs could drive inflammation in the context of HIV.

项目总结/摘要 这是一个重新提交的申请辅导研究科学家发展奖（K 01），以支持 斯蒂芬妮·马特博士的职业发展，以促进她过渡到一个独立的学术研究者， HIV和神经免疫学研究领域。一个密集和全面的指导和研究计划， 已开发使用高通量技术来评估抗抑郁药介导的HIV病毒动力学， 在人骨髓和共培养模型中的炎症信号传导。马特博士的培训将由一家公司提供支持 机构对她的职业发展的承诺和一个强大的指导团队的领导人在艾滋病毒和 心理神经免疫学研究领域，每个提供战略指导，在这两个发展， 在她的职业发展过程中提供建议和指导。拟议中的研究计划是 马特博士最近的研究一直在她的导师彼得Gaskill博士的实验室进行，但突出的是 检查临床队列中的HIV感染和炎症，生物统计学分析，以及神经元 侧写HIV感染的神经系统并发症（neuroHIV）即使在抗逆转录病毒治疗的情况下仍然普遍存在 （ART）。抑郁症是这些越来越常见的并发症之一，可以大大恶化艾滋病毒 疾病进展。骨髓细胞如巨噬细胞和小胶质细胞是HIV的主要靶点， 作为病毒储存库并驱动HIV神经发病机制，但它们的激活也介导抑郁相关的 炎症艾滋病毒、抑郁症和治疗药物之间的炎症联系并不清楚 明白然而，艾滋病毒、抑郁症和抗抑郁药作用于受体和转运蛋白， 免疫细胞上的神经递质受体活性可以影响炎症信号传导 和艾滋病毒感染。这表明抗抑郁药引起的神经递质水平的变化可能会影响 骨髓HIV储库，加重神经HIV，影响抑郁症和治疗的进展 阻力因此，这一建议的首要假设是，特定的抗抑郁药可以 激活中枢神经系统和外周骨髓细胞，这些细胞对炎症和HIV有重要作用 坚持不懈本提案将使用多方面的方法来测试这一假设， 体内抗抑郁药和ART对与认知障碍相关的骨髓细胞中病毒动力学和炎症的影响 HIV感染者抑郁症的功能（目的1），抗抑郁药调节离散病毒动力学的作用 在HIV感染、ART治疗的iPSC CNS和外周髓系人群中（目标2），以及抗抑郁药如何 在HIV感染、ART处理小胶质细胞和不同的神经细胞的共培养物中影响病毒动力学和神经元功能 神经元亚型（Aim 3）。这些研究将大大推进我们对细胞的理解。 抗抑郁药在HIV神经发病机制中的作用机制。这个机会将提供 全面的培训和坚实的基础上，建立一个成功的和独立的研究计划 研究神经精神药物在HIV感染情况下驱动炎症的机制。