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）从认知的轻度到严重缺陷，发生在 超过60％的HIV-1受试者接受抗逆转录病毒疗法（CART）。病理评估 HIV-1阳性受试者的额叶皮层揭示了神经炎症，存在HIV-1感染的神经炎症 神经元中的小胶质细胞/巨噬细胞，星形胶质病，树突损失和突触修剪。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，并且 这导致艾滋病毒感染者的手发展。此外，这些影响可能会因 非法滥用滥用药物，例如阿片类药物，这是该人群通常滥用的药物，因此，有一个伟大的和 越来越需要研究手并理解与HIV相关的神经病发生以发展更好的治疗 选择并改善疾病管理。但是，由于缺乏 生理上相关的大脑/CNS模型。为了满足这一需求，我们开发了一个尖端的三个文化人 3D-脑类器官（Hborgs），其中包含原发性神经元，星形胶质细胞和小胶质细胞（HIV-1感染和 未感染）准确地对大脑环境，慢性病毒复制和神经炎性环境建模 在HIV-1感染的个体中观察到。使用这种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，诱导神经元的变性，突触修剪和 树突丧失，星形细胞增多症和这些作用因添加欧打药而恶化。我们建议 以下目的是实现目标：目标1。描述感染的小胶质细胞如何有助于修剪和缩放 突触行为，突触功能的丧失和神经元丧失；目标2。确定如何使用非法药物（例如 吗啡驱动神经元功能障碍和病理的发育和/或恶化；和目标3。 确定来自HIV-1感染的小胶质细胞的病毒和细胞因子如何引起与手动相关的病理学 特征。我们已经组建了一个在HIV-1病毒学，3D-甲型机构和的调查员团队 因此，药物滥用和突触功能有望定义感染的小胶质细胞与神经元相互作用和 星形胶质细胞并进一步描述了与树突状损伤，突触可塑性和 在存在和缺乏药物滥用的情况下，神经元生存。这将有助于我们开发新颖的治疗剂 可以防止在PLWH中观察到的神经元损伤和突触功能的丧失和认知障碍。