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: 10619582
• 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/10619582
• 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; Dimensions; 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; Persons; Pharmaceutical Preparations; Play; Population; Preclinical Testing; Productivity; Quality of life; Research; Role; Signal Transduction; Structure; Synapses; System; Systems Analysis; Testing; Therapeutic; 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; neural network; neurocognitive disorder; neuroinflammation; neuropathology; new therapeutic target; prescription opioid abuse; 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.

项目概要 目前约有 4000 万人感染艾滋病毒，另有 170 万人感染艾滋病毒 每年都会被感染。虽然只有一个人的艾滋病毒得到功能性治愈，但抗逆转录病毒药物的进展 抗逆转录病毒治疗（ART）已大大减少接受 ART 治疗的个体与艾滋病相关的疾病和死亡。然而， 接受抗逆转录病毒疗法的艾滋病毒+患者仍然面临与艾滋病无关的疾病，包括与艾滋病毒相关的疾病 神经认知障碍（HAND）。 HAND 是指影响三种神经认知障碍的范围 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 HIV 相关痴呆 (HAD)。虽然患者数量 自引入 ART 以来，更严重的 HAND 形式已有所减少，估计 HIV + 患者的 15-55% 接受 ART 的患者仍会出现神经认知障碍。患有 ANI 的患者发生这种情况的可能性是其他人的两到六倍 与神经认知正常的 HIV+ 患者相比，进展为更严重的 HAND 形式。 因此，HAND 仍然是影响 ART 时代个体的一种重要且普遍的 HIV 相关疾病。 现在认为，手部疾病的发生是由于慢性疾病引起的神经元功能变化所致。 大脑中的免疫细胞小胶质细胞发生炎症和艾滋病毒感染。虽然它们不是神经细胞， 小胶质细胞确实在神经组织的整体健康和功能中发挥着重要作用。免疫反应 小胶质细胞被认为受到严格调节和控制，通常不会伤害周围的神经元。 我们确实知道艾滋病毒可以感染小胶质细胞。然而，对于急性和慢性的进展知之甚少。 小胶质细胞中的 HIV 感染以及这些受感染细胞对周围神经组织的影响如何以及有何影响。 此外，艾滋病毒感染通常与静脉注射毒品有关，例如海洛因以及毒品 处方阿片类药物的滥用日益增多。目前尚不清楚这些药物的使用如何改变神经元和 先天免疫信号传导进一步促进 HAND。 了解小胶质细胞感染的一个主要障碍是缺乏分析系统 文化，以及研究其对人类大脑功能影响的方法。人类的最新发展 多能干细胞 (hPSC) 衍生的小胶质细胞和 3D 脑类器官为理解打开了新的大门 HIV感染在这些原本棘手的细胞中。我们已经开始通过利用 我们在 HIV 和脑类器官生物学方面的优势，可以在文化中模拟 HAND，我们终于可以开始 回答有关艾滋病毒、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的作用的重要问题 相关疾病。我们提出的研究的成功将 1) 定义小胶质细胞对 HIV 感染的反应 和阿片类药物治疗，2) 描述失调的小胶质细胞如何影响大脑类器官结构、神经 网络健康和信号传导，以及 3) 为治疗发现奠定基础，以减少 神经炎症和手。

项目成果

Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy.

• DOI: 10.1016/j.isci.2021.103140
• 发表时间: 2021-10-22
• 期刊: iScience
• 影响因子: 5.8
• 作者: Taniguchi-Ikeda M;Koyanagi-Aoi M;Maruyama T;Takaori T;Hosoya A;Tezuka H;Nagase S;Ishihara T;Kadoshima T;Muguruma K;Ishigaki K;Sakurai H;Mizoguchi A;Novitch BG;Toda T;Watanabe M;Aoi T
• 通讯作者: Aoi T