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

项目摘要 HIV-1感染涉及体内的许多致病过程。虽然免疫缺陷和机会主义 感染代表疾病过程的终点，显著的共病发生与CNS受累 导致神经认知能力下降和生活质量下降。这些都是很难研究的问题， HIV-1感染者或在模型系统中。然而，iPSC细胞系的发展及其在人类基因组中的应用进展并不乐观。 分化成特定的细胞类型，甚至多细胞谱系类器官提供了新的研究机会。 在细胞培养环境中对脑中发现的细胞类型的损伤的影响。有正在进行的，并发的 HIV-1、阿片样物质和淀粉样纤维疾病的流行，这些疾病都对大脑造成了损害。HIV-1感染通常 包括使用抑制性治疗，并存在CNS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伤害。HIV-1感染和/或阿片类药物使用 在自然老化的背景下发生，其通常包括淀粉样纤维的亚临床沉积。在这 应用程序，我们将看看这些现象的交叉点，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。该应用程序带来了 一个在神经HIV，转录分析，阿片类药物和HIV-1相互作用，类器官和 纤维病这种跨学科的方法将使我们能够利用CNS类器官模型来开发新的 这些信息最终可以在未来的整个生物体研究中得到验证。

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.