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：
10379970
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/10379970
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 Gene Expression Profile 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 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 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

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感染与体内许多致病过程有关。而免疫缺陷和机会主义感染代表疾病过程的终点，CNS参与发生了明显的合并症导致神经认知能力下降和生活质量丧失。这些是很难在人中学习的问题使用HIV-1或模型系统生活。但是，如果IPSC线和他们的发展区分特定的细胞类型，甚至多细胞谱系类器官都提供了新的研究机会侮辱对细胞培养环境中大脑中细胞类型的影响。有持续的，并发 HIV-1，阿片类药物和淀粉样纤维疾病的流行病，这些疾病都提供了侮辱大脑。 HIV-1经常感染包括使用抑制疗法以及中枢神经系统渗透和病毒潜伏期的问题。另外，HIV-1 导致炎症状态增强，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衰老的背景下，通常包括淀粉样蛋白纤维的亚临床沉积。在这个应用我们将考虑这些现象的交集，因为它们会影响HIV-1感染和潜伏期以及还影响正常的细胞功能。我们将分别专注于小胶质细胞，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其在器官中的相互作用。此应用程序带来一支具有神经hiv专业知识，转录分析，阿片类药物和HIV-1相互作用的团队原纤维疾病。这种跨学科的方法将使我们能够利用CNS器官模型开发新的未来整个生物研究中最终可以验证的信息。