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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要这是指导研究科学家发展奖（K01）的重新提交申请斯蒂芬妮·马特（Stephanie Matt）博士的职业发展，以促进她向独立学术研究员的过渡艾滋病毒和神经免疫学研究领域。强烈而全面的心理和研究计划已有开发用于使用高通量技术来评估抗抑郁药介导的HIV病毒动力学和人髓样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机构对她的职业发展的承诺，以及艾滋病毒和 PsychOneuromummumumunology研究领域，每个研究领域都为此提供战略指导随着职业的进展，提案和指导。拟议的研究计划是自然的扩展最近的研究马特（Matt 检查临床队列中的HIV感染和感染，生物统计分析以及神经元分析。 HIV感染（NeuroHIV）的神经系统并发症即使接受抗逆转录病毒疗法也很普遍（艺术）。抑郁症是越来越常见的并发症之一，艾滋病毒越来越恶化疾病进展。巨噬细胞和小胶质细胞等髓样细胞是可以使用的主要HIV靶标作为病毒储存和驱动HIV神经病的发生，但它们的激活也介导了与抑郁相关的炎症。艾滋病毒，抑郁症和用于治疗它们的药物之间的炎症联系不好理解齿。但是，艾滋病毒，抑郁症和抗抑郁药作用于改变的受体和转运蛋白神经传递和神经递质接收器在免疫核管上的活性会影响炎症信号传导和HIV感染。这表明抗抑郁药的神经递质水平的变化可能会影响大小髓样HIV储层，加剧神经hiv并影响抑郁和治疗的进展反抗。这就是该提议的总体假设是特定的抗抑郁药可以激活CNS和周围髓样细胞，严重导致炎症和HIV 持久性。该提案将使用多方面的方法来评估IN的影响与认知相关的病毒动力学和炎症的体内抗抑郁药和艺术在患有艾滋病毒的抑郁症患者中起作用（AIM 1），抗抑郁药的影响，以减轻离散病毒动力学在受HIV感染的，ART治疗的IPSC CNS和外周髓样群体（AIM 2）以及抗抑郁药中影响病毒动力学和神经元功能在艾滋病毒感染的，艺术治疗的小胶质细胞和独特的共同培养中神经元亚型（AIM 3）。这些研究将大大提高我们对细胞的理解抗抑郁药在HIV神经病发生中作用的基础机制。这个机会将提供全面的培训和稳固的基础，以建立成功和独立的研究计划调查神经精神药物在HIV背景下驱动炎症的机制。