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/文摘