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: 10220929
• 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/10220929
• 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; Exposure to; 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.

项目摘要 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 为社会虽然有证据表明HIV-1和甲基苯丙胺都可以导致 行为，神经认知和组织病理学变化的大脑，并影响免疫 防御，病毒和药物的联合作用和潜在相互作用仍然存在 不完全理解。此外，关于艾滋病毒如何- 感染小胶质细胞以建立潜伏感染，并且感染的小胶质细胞改变神经组织结构， 生理学和脑功能仍有待解决。本提案的总体目标是 描述HIV感染改变细胞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CNS，导致神经元损伤， 手的发病机制。胚胎干细胞与诱导多能干细胞研究进展 多能干细胞（iPSC）技术开辟了体外疾病建模的新途径。我们把 提出了一个前所未有的概念和实验系统来模拟人类小胶质细胞脑 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感染如何改变HIV感染期间的小胶质细胞和CNS 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。我们的结果将与使用单核细胞的基因表达程序相证实。 从HAND患者的死后组织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风险变体活性。此外，我们将 通过国家神经艾滋病组织联盟验证我们在人脑组织中的发现， （NNTC）和SIV感染的恒河猴脑。这些研究的结果将提供 对HIV改变的分子机制的基本理解， 甲基苯丙胺的使用导致免疫和大脑功能障碍。