Investigating the molecular mechanisms of HIV/AIDS associated neurological disorders using microglia and cerebral organoids derived from induced pluripotent stem cells

利用诱导多能干细胞衍生的小胶质细胞和脑类器官研究 HIV/AIDS 相关神经系统疾病的分子机制

• 批准号: 10450873
• 负责人: TARIQ M RANA
• 金额: $ 78.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450873
• 关键词: AIDS/HIV problem; ATAC-seq; Address; Affect; Autopsy; Behavioral; Brain; Cell Nucleus; Cell physiology; Cells; Cerebrum; Code; Development; Disease; Disease model; Environment; Epigenetic Process; Gene Expression; Gene Targeting; Generations; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype; Glass; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; High Prevalence; Human; Immune; Immune System Diseases; Immunity; Immunologic Receptors; In Vitro; Individual; Infection; Macaca mulatta; Mental disorders; Methamphetamine; Microglia; Molecular; National NeuroAids Tissue Consortium; Nerve Degeneration; Nervous System Physiology; Nervous System Trauma; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuronal Injury; Neurons; Neuropathogenesis; Organoids; Pathogenesis; Patients; Pharmaceutical Preparations; Physiology; Play; Proteins; Publishing; Rana; Regulator Genes; Reporting; Role; SIV; Schizophrenia; Societies; Specific qualifier value; Structure; System; TLR3 gene; Tissues; Trauma recovery; United States; Untranslated RNA; Virus; Virus Diseases; Virus Replication; Zika Virus; autism spectrum disorder; brain cell; brain dysfunction; brain tissue; cell type; cofactor; embryonic stem cell; functional genomics; human model; immune function; in vitro Model; induced pluripotent stem cell; induced pluripotent stem cell technology; insight; latent infection; methamphetamine exposure; methamphetamine use; nerve stem cell; nervous system disorder; pathogen; programs; relating to nervous system; risk variant; single cell analysis; single-cell RNA sequencing; stem cells; success

PROJECT SUMMARY High prevalence of HIV-associated neurocognitive disorders (HAND) poses a major challenge for the society. While there is evidence that both HIV-1 and methamphetamine can cause behavioral, neurocognitive and histopathological changes in the brain, and affect immune defense, the combined effect and potential interaction of both the virus and the drug remains incompletely understood. In addition, fundamental and critical questions regarding how HIV- infects microglia to establish latent infection and infected microglia alter neural tissue structure, physiology, and function in brain remain to be addressed. The overall objective of this proposal is to delineate the molecular and cellular mechanisms by which HIV infection alters the function of microglia, resident immune cells of the brain, and CNS that leads to neuronal injury and pathogenesis of HAND. Recent advances in embryonic stem cell and induced pluripotent stem cells (iPSCs) technologies have opened up new avenues of disease modeling in vitro. We put forward an unprecedented concept and experimental system to model human microglia-brain interactions as well as opportunities to illuminate how genetic variation affects gene expression. Our project has three specific aims: Specific Aim 1: Establish iPSC-derived cerebral organoids and define the cellular diversity, neural tissue structure, physiology, and gene expression programs. Specific Aim 2: Determine how HIV infection alters microglia and CNS during HIV neuropathogenesis. Specific Aim 3: Determine the molecular mechanisms of neuronal injury by HIV. Our results will be corroborated with gene expression programs using single nuclei of microglia and neurons obtained from postmortem tissues of HAND patients. Gene targets of HAND risk variants activity in disease-relevant cell types will be determined. Further, we will validate our findings in human brain tissues through the National NeuroAIDS Tissue Consortium (NNTC) and SIV infected brains of rhesus monkeys. Results of these studies will provide fundamental understanding of the molecular mechanisms that are altered by HIV and methamphetamine use leading to immune and brain dysfunctions.

项目总结 艾滋病毒相关神经认知障碍(HAND)的高患病率构成了一个重大挑战 为社会服务。虽然有证据表明HIV-1和甲基苯丙胺都会导致 大脑中的行为、神经认知和组织病理学变化，并影响免疫 防御，病毒和药物残留物的综合作用和潜在的相互作用 不完全理解。此外，关于艾滋病毒如何-- 感染小胶质细胞建立潜伏感染，感染的小胶质细胞改变神经组织结构， 大脑的生理和功能仍有待解决。这项提案的总体目标是 是描绘HIV感染改变功能的分子和细胞机制 小胶质细胞，大脑的常驻免疫细胞，和中枢神经系统，导致神经元损伤和 手的发病机制。胚胎干细胞及诱导多能干细胞研究进展 细胞(IPSCs)技术开辟了体外疾病建模的新途径。我们把 提出一种前所未有的概念和实验系统来模拟人的小胶质细胞脑 相互作用以及阐明遗传变异如何影响基因表达的机会。 我们的项目有三个具体目标：具体目标1：建立IPSC衍生的脑器官 并定义了细胞多样性、神经组织结构、生理和基因表达 程序。具体目标2：确定艾滋病毒感染如何改变艾滋病毒期间的小胶质细胞和中枢神经系统 神经发病机制。具体目标3：确定神经元损伤的分子机制 爱滋病毒。我们的结果将通过使用单核的基因表达程序得到证实 从手部患者死后组织中获得小胶质细胞和神经元。基因靶点的研究 将确定与疾病相关的细胞类型中的手部风险变异活性。此外，我们还将 通过国家神经艾滋病组织联盟在人脑组织中验证我们的发现 (NNTC)和SIV感染恒河猴的大脑。这些研究的结果将提供 对艾滋病毒和艾滋病改变的分子机制有基本的了解 使用甲基苯丙胺会导致免疫和大脑功能障碍。