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.

项目概要/摘要 这是重新提交指导研究科学家发展奖（K01）的申请，以支持 斯蒂芬妮·马特博士的职业发展，以促进她过渡为独立学术研究员 HIV和神经免疫学研究领域。密集而全面的指导和研究计划 被开发用于使用高通量技术来评估抗抑郁药介导的 HIV 病毒动力学 人类骨髓和共培养模型中的炎症信号传导。马特博士的培训将得到一家公司的支持 对她职业发展的机构承诺以及艾滋病毒和艾滋病领域领导者的强大指导团队 心理神经免疫学研究领域，每个领域都为该领域的发展提供战略指导 随着她职业生涯的发展，提出建议和指导。拟议的研究计划是该研究计划的自然延伸 马特博士最近在她的导师彼得·加斯基尔博士的实验室中进行了研究，但其特点是 检查临床队列中的 HIV 感染和炎症、生物统计分析以及神经元 分析。即使采用抗逆转录病毒治疗，HIV 感染 (neuroHIV) 的神经系统并发症仍然普遍存在 （艺术）。抑郁症是日益常见的并发症之一，可导致艾滋病毒严重恶化 疾病进展。巨噬细胞和小胶质细胞等骨髓细胞是 HIV 的主要靶标 作为病毒储存库并驱动 HIV 神经发病机制，但它们的激活也会介导抑郁相关的 炎。艾滋病毒、抑郁症和用于治疗这些疾病的药物之间的炎症联系尚不明确 明白了。然而，艾滋病毒、抑郁症和抗抑郁药作用于受体和转运蛋白，从而改变 神经传递和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。这表明抗抑郁药改变神经递质水平可能会影响尺寸 髓样 HIV 储存库，加剧神经 HIV 并影响抑郁症和治疗的进展 反抗。因此，该提案的总体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，这些细胞对炎症和艾滋病毒至关重要 坚持。该提案将使用多方面的方法来测试这一假设，以评估in的影响 体内抗抑郁药和 ART 对与认知相关的骨髓细胞病毒动力学和炎症的影响 艾滋病毒感染者抑郁症患者的功能（目标 1），抗抑郁药调节离散病毒动力学的作用 在 HIV 感染者、接受 ART 治疗的 iPSC CNS 和外周髓细胞群体中的影响（目标 2），以及抗抑郁药如何 影响 HIV 感染、ART 处理的小胶质细胞和不同神经元共培养物中的病毒动力学和神经元功能 神经元亚型（目标 3）。这些研究将极大地增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 全面的培训和建立成功的独立研究项目的坚实基础 研究神经精神药物在艾滋病毒背景下驱动炎症的机制。