Modeling HIV-1 Neuropathogenesis and neuronal dysregulation using 3D-organoids containing multiple CNS cell lineages

使用包含多个 CNS 细胞谱系的 3D 类器官模拟 HIV-1 神经发病机制和神经元失调

• 批准号: 10651458
• 负责人: VELPANDI AYYAVOO
• 金额: $ 68.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651458
• 关键词: 3-Dimensional; AIDS dementia; Address; Affect; Agonist; Astrocytes; Astrocytosis; Brain; Cell Lineage; Cells; Central Nervous System Diseases; Chronic; Clinical; Cognition; Dendrites; Development; Disease; Disease Management; Drug abuse; Electrophysiology (science); Environment; Equilibrium; Evaluation; Exhibits; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Immune; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Knock-out; Lead; Mediating; Microglia; Modeling; Molecular; Morphine; Morphology; Nerve Degeneration; Neuroglia; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropathogenesis; Opioid; Organoids; Pain management; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Physiological; Population; Process; RNA Interference; Research; Research Personnel; Role; Substance Use Disorder; Symptoms; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Viral; Viral Load result; Viral Proteins; Virus; Virus Replication; antiretroviral therapy; astrogliosis; brain dysfunction; cell type; comorbidity; drug of abuse; frontal lobe; illicit drug use; improved; in vitro Model; macrophage; mu receptors; mutant; neuroinflammation; neuron loss; neuronal survival; neurotoxic; novel; novel therapeutics; opioid epidemic; prevent; release factor; synaptic function; synaptic pruning; therapeutic development; three dimensional cell culture; virology

Project Summary HIV-associated neurocognitive disorder (HAND) range from mild to severe deficits in cognition and occurs in more than 60% of HIV-1 subjects receiving combined antiretroviral therapy (cART). Pathological evaluation of the frontal cortex of HIV-1 positive subjects revealed neuroinflammation with presence of HIV-1 infected microglia/macrophages, astrogliosis, dendrites loss and synaptic pruning in neurons. The degradation of dendrites that accompany these neuronal changes leads to synaptic loss, neuronal and cognitive decline, and this causes development of HAND in people living with HIV. Moreover, these effects may be exacerbated by illicit drug use abuse such as opioids, a drug commonly abused by this population, thus, there is a great and increasing need to study HAND and understand HIV-associated neuropathogenesis to develop better treatment options and improve disease management. However, these efforts are significantly hampered by the lack of a physiologically relevant brain/CNS model. To address this need, we developed a cutting-edge tri-culture human 3D-brain organoids (hBORGs) that contains primary neurons, astrocytes and microglia (HIV-1-infected and uninfected) to accurately model the brain environment, chronic virus replication, and neuroinflammatory milieu observed in HIV-1 infected individuals. Using this 3D-BORG model, we propose to test our hypothesis that neuroinflammation caused by HIV-1 infected microglia, induces degeneration of neurons, synaptic pruning and loss of dendrites, astrocytosis and these effects worsen by the addition of oipoid drug abuse. We propose the following aims to achieve the goals: Aim 1. Delineate how infected microglia contribute to pruning and scaling of synaptodendrites, loss of synaptic functions and neuronal loss; Aim 2. Determine how use of illicit drugs such as Morphine drives the development and/or worsening of the neuronal dysfunction and pathology; and Aim 3. Identify the how viral and cellular factors from HIV-1 infected microglia cause the HAND-associated pathological features. We have assembled a team of investigators who have expertise in HIV-1 Virology, 3D-Organoids and drug abuse and synaptic function, thus, are poised to define how infected microglia interact with neurons and astrocytes and further delineate the molecular mechanisms involved in dendritic damage, synaptic plasticity and neuronal survival in the presence and absence of drug abuse. This will help us develop novel therapeutics that can prevent neuronal damage and loss of synaptic function and cognitive impairment observed in PLWH.

项目摘要 艾滋病毒相关的神经认知障碍(手)范围从轻度到严重的认知障碍，并发生在 超过60%的HIV-1受试者接受联合抗逆转录病毒治疗(CART)。食管瘤的病理学评价 HIV-1阳性受试者的额叶皮质表现为神经炎症，并存在HIV-1感染 神经元中的小胶质细胞/巨噬细胞、星形胶质细胞增多症、树突丢失和突触修剪。生物多样性的退化 伴随这些神经元变化的树突会导致突触丧失，神经元和认知能力下降，以及 这会导致艾滋病毒携带者的手部发育。此外，这些影响可能会因以下原因而加剧 非法药物滥用，如阿片类药物，这是这一人群经常滥用的药物，因此，有很大的 越来越需要研究手部和了解艾滋病毒相关的神经发病机制，以开发更好的治疗方法 选择并改进疾病管理。然而，这些努力由于缺乏一个 生理相关脑/中枢神经系统模型。为了满足这种需求，我们开发了一种尖端的三种文化的人类 3D-脑器官(HBORGs)，包含初级神经元、星形胶质细胞和小胶质细胞(感染HIV-1和 未感染)以准确模拟脑环境、慢性病毒复制和神经炎性环境 在HIV-1感染者身上观察到。使用这个3D-Borg模型，我们建议测试我们的假设 由HIV-1感染的小胶质细胞引起的神经炎症，诱导神经元变性，突触修剪和 树突状细胞的丢失、星形胶质细胞增多和这些效应因类油类药物的滥用而恶化。我们建议 以下目标旨在实现目标：目标1.描述感染的小胶质细胞如何有助于修剪和鳞片 突触树突、突触功能丧失和神经元丧失；目标2.确定非法药物的使用情况 吗啡导致神经元功能障碍和病理的发展和/或恶化；和目标3。 确定HIV-1感染的小胶质细胞中的病毒和细胞因子如何导致手部相关的病理改变 功能。我们组建了一支研究团队，他们在HIV-1病毒学、3D-有机化合物和 因此，药物滥用和突触功能将决定受感染的小胶质细胞如何与神经元和 并进一步阐明了参与树突损伤、突触可塑性和 在有无药物滥用的情况下神经元存活。这将帮助我们开发新的疗法， 可预防PLWH中观察到的神经元损伤、突触功能丧失和认知功能障碍。