Integrative Modeling of HIV-Associated Neurocognitive Disorder in Human Brain Organoids

人脑类器官中 HIV 相关神经认知障碍的综合建模

• 批准号: 10055749
• 负责人: Oliver I Fregoso
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055749
• 关键词: 3-Dimensional; AIDS dementia; Acquired Immunodeficiency Syndrome; Acute; Affect; Astrocytes; Autopsy; Biological Assay; Biology; Brain; Cell Culture System; Cell Nucleus; Cells; Cessation of life; Chronic; Consequences of HIV; Development; Disease; Drug usage; Epidemic; Face; Foundations; Functional Imaging; Gene Expression; Genetic Transcription; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Heroin; Histopathology; Human; Immune; Immune response; Immune signaling; Individual; Infection; Inflammation; Innate Immune Response; Intravenous; Knowledge; Measures; Microglia; Modeling; Molecular; Monitor; Myeloid Cells; Nerve Degeneration; Neural Network Simulation; Neurocognitive; Neurocognitive Deficit; Neurons; Neurophysiology - biologic function; Neuroprotective Agents; Opioid; Organoids; Pathology; Patients; Pharmaceutical Preparations; Plant Roots; Play; Population; Preclinical Testing; Quality of life; Research; Role; Signal Transduction; Structure; Synapses; System; Systems Analysis; Testing; Therapeutic; Time; Tissues; Translating; Unmarried person; Viral Load result; acute infection; antiretroviral therapy; chronic infection; cytokine; experience; human pluripotent stem cell; human stem cells; human tissue; immune activation; in vitro Model; innovation; insight; method development; monocyte; nervous system disorder; neural network; neurocognitive disorder; neuroinflammation; neuropathology; new therapeutic target; prescription opioid abuse; relating to nervous system; response; stem cell technology; success

PROJECT SUMMARY Approximately 40 million people are currently infected by HIV, with an additional 1.7 million people newly infected each year. While only a single person has been functionally cured of HIV, advances in antiretroviral therapy (ART) have drastically decreased AIDS-related illnesses and deaths for individuals on ART. However, HIV+ patients on ART still face debilitating AIDS-independent diseases, including HIV-associated neurocognitive disorders (HAND). HAND refers to a spectrum of three neurocognitive disorders that influence survival, quality of life, and everyday function: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). While the number of patients with the more severe forms of HAND have declined since the introduction of ART, an estimated 15-55% of HIV+ patients taking ART still develop a neurocognitive disorder. Patients with ANI are two to six times more likely to progress to a more severe form of HAND when compared to HIV+ patients who are neurocognitively normal. Thus, HAND remains an important and prevalent HIV-associated disease to affect individuals in the ART era. It is now thought that HAND develops because of functional changes in neurons caused by chronic inflammation and HIV infection of an immune cell in the brain, microglia. Though they are not a neuronal cell, microglia do play an important role in the general health and function of neural tissue. The immune responses of microglia are thought to be tightly regulated and controlled as to not normally harm the surrounding neurons. We do know that HIV can infect microglia. However, little is known about the progression of acute and chronic HIV infection in microglia nor how and what impact these infected cells have on surrounding neuronal tissue. Moreover, HIV infection is frequently associated with intravenous drug us such as heroin along with the growing abuse of prescription opioids. It remains unclear how the use of these drugs alters both neuronal and innate immune signaling and further contributes to HAND. One major roadblock in understanding infection of microglia has been the lack of systems for analysis in culture, as well as means for studying their impact on human brain functions. Recent developments in human pluripotent stem cell (hPSC)-derived microglia and 3D-brain organoids have opened new doors to understand HIV infection in these otherwise intractable cells. We have begun to bridge this knowledge gap by leveraging our strengths in HIV and brain organoid biology to model HAND in culture, where we can finally begin to answer important questions in the roles of HIV, opioids, and microglia and other cells in this debilitating HIV- associated disease. Success of our proposed research will 1) define the response of microglia to HIV infection and opioid treatment, 2) characterize how dysregulated microglia affect brain organoid structure, neural network health, and signaling, and 3) establish a foundation for therapeutic discovery to reduce neuroinflammation and HAND.

项目总结 目前约有4000万人感染艾滋病毒，新增170万人 每年都会被感染。虽然只有一个人被功能性治愈了艾滋病毒，但抗逆转录病毒的进展 抗逆转录病毒治疗(ART)大大减少了接受抗逆转录病毒治疗的个人与艾滋病相关的疾病和死亡。然而， 接受抗逆转录病毒治疗的HIV+患者仍然面临着与艾滋病无关的衰弱疾病，包括与HIV相关的疾病 神经认知障碍(手)。手指的是三种神经认知障碍的频谱，这些障碍会影响 生存、生活质量和日常功能：无症状神经认知障碍(ANI)，轻度 神经认知障碍(MND)和艾滋病毒相关痴呆(HAD)。而患有这种疾病的患者数量 自抗逆转录病毒疗法引入以来，更严重的手部疾病有所下降，估计有15%-55%的艾滋病毒+ 服用抗逆转录病毒药物的患者仍然会出现神经认知障碍。ANI患者患ANI的可能性是普通人的两到六倍 与神经认知正常的HIV+患者相比，进展为更严重的手部形式。 因此，在ART时代，手部仍然是影响个人的一种重要和普遍的艾滋病毒相关疾病。 现在认为，手的发育是由于慢性精神分裂症引起的神经元功能变化 炎症和HIV感染大脑中的一种免疫细胞，即小胶质细胞。尽管它们不是神经细胞， 小胶质细胞确实在神经组织的总体健康和功能中发挥着重要作用。免疫反应 小胶质细胞的数量被认为受到严格的调控，通常不会对周围的神经元造成伤害。 我们确实知道艾滋病毒可以感染小胶质细胞。然而，人们对急性和慢性疾病的进展知之甚少。 HIV在小胶质细胞中的感染，也不知道这些感染细胞如何以及对周围神经元组织产生什么影响。 此外，艾滋病毒感染经常与静脉注射毒品有关，如海洛因以及 处方类阿片类药物的滥用日益严重。目前尚不清楚这些药物的使用如何改变神经元和 与生俱来的免疫信号，进而对手有贡献。 理解小胶质细胞感染的一个主要障碍是缺乏分析系统。 文化，以及研究它们对人脑功能的影响的手段。人类的最新发展 多能干细胞(HPSC)来源的小胶质细胞和3D脑有机体为理解 在这些原本难以治愈的细胞中感染艾滋病毒。我们已经开始通过利用 我们在艾滋病毒和脑有机生物学方面的优势，以模范手把手培养，在那里我们终于可以开始 回答艾滋病毒、阿片类药物、小胶质细胞和其他细胞在这种使人衰弱的艾滋病毒中所扮演的角色的重要问题- 相关疾病。我们提议的研究的成功将1)确定小胶质细胞对艾滋病毒感染的反应 和阿片类药物治疗，2)表征调节失调的小胶质细胞如何影响脑器官结构、神经 网络健康和信令，以及3)为治疗发现奠定基础，以减少 神经炎和手部。