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.

项目概要 HIV 相关神经认知障碍 (HAND) 的高患病率构成了重大挑战 为社会。虽然有证据表明 HIV-1 和甲基苯丙胺均可导致 大脑的行为、神经认知和组织病理学变化，并影响免疫 防御，病毒和药物的综合作用和潜在相互作用仍然存在 不完全理解。此外，有关艾滋病毒如何传播的基本和关键问题 感染小胶质细胞以建立潜伏感染，受感染的小胶质细胞改变神经组织结构， 生理学和大脑功能仍有待解决。本提案的总体目标 旨在描述 HIV 感染改变功能的分子和细胞机制 小胶质细胞、大脑和中枢神经系统的常驻免疫细胞会导致神经元损伤和 手的发病机制。胚胎干细胞和诱导多能干细胞的最新进展 细胞（iPSC）技术开辟了体外疾病建模的新途径。我们把 提出了前所未有的概念和实验系统来模拟人类小胶质细胞大脑 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 衍生的大脑类器官 并定义细胞多样性、神经组织结构、生理学和基因表达 程序。具体目标 2：确定 HIV 感染在 HIV 期间如何改变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 艾滋病病毒。我们的结果将通过使用单核的基因表达程序得到证实 从 HAND 患者死后组织中获得的小胶质细胞和神经元。基因靶点 将确定疾病相关细胞类型中的 HAND 风险变异活性。此外，我们将 通过国家神经艾滋病组织联盟验证我们在人类脑组织中的发现 (NNTC) 和 SIV 感染恒河猴的大脑。这些研究的结果将提供 对 HIV 改变的分子机制的基本了解 使用甲基苯丙胺会导致免疫和大脑功能障碍。