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

基本信息

批准号：
10594460
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
项目类别：
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/10594460
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 Frequencies Future Gene Expression Gene Expression Profile Genetic Transcription HIV HIV Infections HIV-1 Human Immunologic Deficiency Syndromes Individual Infection Inflammation Inflammatory Inflammatory Response Interferons Laboratories Learning Macrophage 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 Persons 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 fentanyl use human tissue induced pluripotent stem cell interdisciplinary approach neuroAIDS neuron loss novel opioid exposure opioid use phenotypic biomarker single-cell RNA sequencing transcriptome sequencing

项目摘要

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 感染参与体内许多致病过程。虽然免疫缺陷和机会主义感染代表疾病过程的终点，中枢神经系统受累会出现显着的合并症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研究的难题感染 HIV-1 或处于模型系统中。然而，iPSC 系及其开发的进展分化为特定细胞类型甚至多细胞谱系类器官为研究提供了新的机会在细胞培养环境中大脑中发现的细胞类型受到损伤的影响。有持续的、并发的 HIV-1、阿片类药物和淀粉样原纤维疾病的流行都会对大脑造成损害。经常感染 HIV-1 包括使用抑制疗法来解决中枢神经系统渗透和病毒潜伏期的问题。此外，HIV-1 导致炎症加剧，这是对大脑的另一种有毒损伤。 HIV-1 感染和/或阿片类药物使用发生在自然衰老的背景下，通常包括淀粉样原纤维的亚临床沉积。在这个我们将研究这些现象的交叉点，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以研究它们在类器官中的相互作用。这个应用程序带来了汇集了一支在神经艾滋病毒、转录分析、阿片类药物和 HIV-1 相互作用、类器官和纤维疾病。这种跨学科方法将使我们能够利用中枢神经系统类器官模型来开发新的最终可以在未来的整个有机体研究中验证的信息。