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: 10224904
• 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/10224904
• 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.

项目摘要 目前约有4000万人感染了艾滋病毒，新又有170万人 每年被感染。虽然只有一个人在功能上治愈了HIV，但抗逆转录病毒的进展 治疗（ART）大大减少了与ART的人相关的疾病和死亡。然而， ART的HIV+患者仍面临与艾滋病无关的疾病，包括与HIV相关的疾病 神经认知障碍（手）。手是指影响的三种神经认知障碍 生存，生活质量和日常功能：无症状的神经认知障碍（ANI），轻度 神经认知障碍（MND）和与HIV相关的痴呆症（HAT）。而患者人数 自从引入艺术以来，更严重的手已经下降了，估计艾滋病毒+的15-55％ 服用艺术的患者仍会患有神经认知障碍。 ANI患者的可能性是 与神经认知正常的HIV+患者相比，进展到更严重的手。 因此，手仍然是一种重要且普遍的HIV相关疾病，以影响艺术时代的个体。 现在认为，由于由慢性引起的神经元的功能变化，手的发展 小胶质细胞中免疫细胞的炎症和HIV感染。尽管它们不是神经元细胞，但 小胶质细胞确实在神经组织的一般健康和功能中起重要作用。免疫反应 小胶质细胞被认为受到严格调节和控制，以免损害周围的神经元。 我们确实知道艾滋病毒会感染小胶质细胞。但是，关于急性和慢性的进展知之甚少 小胶质细胞中的HIV感染或这些感染细胞对周围神经元组织的影响以及如何影响。 此外，艾滋病毒感染经常与静脉药物有关，例如海洛因，例如 处方阿片类药物的滥用日益严重。尚不清楚这些药物的使用如何改变神经元和 先天免疫信号传导并进一步有助于手。 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脑功能的影响的手段。人类的最新发展 多能干细胞（HPSC）衍生的小胶质细胞和3D-脑类器官已经打开了新的门以了解 这些原本棘手的细胞中的HIV感染。我们已经开始利用这一知识差距 我们在艾滋病毒和脑器官生物学方面的优势在文化中建模，我们最终可以开始 回答艾滋病毒，阿片类药物，小胶质细胞和其他细胞的重要问题 相关疾病。我们提出的研究的成功将为1）定义小胶质细胞对HIV感染的反应 和阿片类药物治疗，2）表征了小胶质细胞如何影响脑器官结构，神经 网络健康和信号传导，以及3）为减少治疗发现的基础建立基础 神经炎症和手。