Intersection of HIV, Opiods, and Amyloid Fibrils in a CNS Organoid Model

CNS 类器官模型中 HIV、阿片类药物和淀粉样原纤维的交集

• 批准号: 10055342
• 负责人: SARAH BETH JOSEPH
• 金额: $ 32.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055342
• 关键词: Affect; Aging; Amyloid Fibrils; Amyloid deposition; Astrocytes; Autopsy; Biological Assay; Biological Models; Blood; Brain; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Line; Cell Lineage; Cell physiology; Cells; Central Nervous System Infections; Collaborations; Development; Disease; Environment; Epidemic; Evolution; Exposure to; Fentanyl; Frequencies; Future; Gene Expression; Genetic Transcription; HIV; HIV Infections; HIV-1; Human; Immunologic Deficiency Syndromes; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Laboratories; Learning; Methadone; Microglia; Microscopy; Modeling; Morphology; National Institute of Allergy and Infectious Disease; Neurocognitive Deficit; Neurons; Normal Cell; Opioid; Opportunistic Infections; Organoids; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Penetration; Predisposition; Process; Quality of life; Sampling; Science; Technology; Testing; Therapeutic; Virus; Virus Latency; Whole Organism; Work; aging population; brain cell; brain tissue; cell type; comorbidity; density; human tissue; induced pluripotent stem cell; interdisciplinary approach; macrophage; neuroAIDS; neuron loss; novel; opioid exposure; opioid use; phenotypic biomarker; single-cell RNA sequencing; transcriptome sequencing

PROJECT ABSTRACT HIV-1 infection is involved in many pathogenic processes in the body. While immunodeficiency and opportunistic infections represent the end-point of the disease process, significant co-morbidity occurs with CNS involvement resulting in neurocognitive decline and loss of quality of life. These are difficult problems to study either in people living with HIV-1 or in model systems. However, advances in the development if iPSC lines and in their differentiation into specific cell types and even multi-cell lineage organoids provide new opportunities to study the effects of insults to the cell types found in the brain in the cell culture setting. There are ongoing, concurrent epidemics of HIV-1, opioids, and amyloid fibril disease that all provide insults to the brain. HIV-1 infection often includes the use of suppressive therapy with questions of CNS penetration and viral latency. In addition, HIV-1 leads to a heightened state of inflammation, another toxic insult to the brain. HIV-1 infection and/or opioid use occur in a background of natural aging which often includes the subclinical deposition of amyloid fibrils. In this application we will look at the intersection of these phenomena as they affect HIV-1 infection and latency and also impact normal cell function. We will focus individually on microglia, astrocytes, and neurons then use the information obtained from the individual cells to study their interactions in organoids. This application brings together a team with expertise in neuroHIV, transcription analysis, opioid and HIV-1 interactions, organoids, and fibril disease. This interdisciplinary approach will allow us to exploit the CNS organoid model to develop new information that can ultimately be validated in whole organism studies in the future.

项目摘要 HIV-1感染参与了体内许多致病过程。虽然免疫缺陷和机会主义 感染是疾病过程的终点，与中枢神经系统的累及发生显著的共病 导致神经认知能力下降和生活质量下降。这些都是在人类身上很难研究的问题 携带HIV-1病毒或在模型系统中生活。然而，如果IPSC线的发展和他们的进展 分化为特定细胞类型甚至多细胞谱系的有机体为研究提供了新的机会 在细胞培养环境中，侮辱对大脑中发现的细胞类型的影响。有持续的、并发的 HIV-1、阿片类药物和淀粉样纤维病的流行，所有这些都对大脑造成了侮辱。HIV-1感染经常 包括使用抑制疗法，解决中枢神经系统渗透和病毒潜伏的问题。此外，艾滋病毒-1 导致炎症状态加剧，这是对大脑的另一种有毒侮辱。HIV-1感染和/或阿片类药物使用 发生在自然老化的背景下，通常包括亚临床淀粉样纤维沉积。在这 应用程序我们将查看这些现象的交集，因为它们影响HIV-1感染和潜伏期 也会影响正常的细胞功能。我们将分别关注小胶质细胞、星形胶质细胞和神经元，然后使用 从单个细胞获得的信息，用于研究它们在有机体中的相互作用。这个应用程序带来了 拥有神经艾滋病毒、转录分析、阿片类药物和艾滋病毒-1相互作用、有机化合物和 纤维性疾病。这种跨学科的方法将使我们能够利用CNS有机模型来开发新的 这些信息最终可以在未来的整个生物体研究中得到验证。