Role of Myeloid Cells in Human Parkinson Disease

项目摘要：项目3 最近的研究已经开始阐明大脑和身体之间复杂的相互作用。 帕金森氏症患者。遗传学、病理学研究和模型系统都强调了 髓系细胞，特别是巨噬细胞和其他单核细胞，在这种脑/体相互作用中。在……里面 大脑中常驻的髓细胞是小胶质细胞。然而，重要的是，在几个疾病状态中， 已证明循环中的髓系细胞可以渗透到血脑屏障，以应对 神经炎性刺激并分化为巨噬细胞和树突状细胞。虽然它的形态结构 这些入侵者可能与常驻的小胶质细胞相似，他们的行为可能截然不同，也可能是 要么是促炎，引发神经元损伤或死亡，要么是抗炎，有助于解决 局部发炎。 而髓系细胞通常分为M1促炎和M2抗炎 表型，最近的工作强调，这些是光谱的极端，而不是离散的状态。 这些激活状态是差异基因程序的产物，因此，编码和非编码 RNA签名是检查髓系细胞功能状态的强大工具。一个关键的监管者 外周血单核细胞的活化及其向促炎巨噬细胞和树突状细胞的分化 细胞是microRNA 155(miR-155)。 该项目将利用高通量基因组技术的最新进展来了解 帕金森病患者外周血髓系细胞功能正常。基于我们之前对小鼠的研究，我们将确定是否存在 MiR-155在人类疾病早期升高。此外，我们还将对mRNAs和 外周髓系细胞中的miRNAs用于识别调节髓系的基因程序中的重要变化 细胞分化和激活，并评估M1极化的程度。所有受试者 这项研究招募的患者将患有早期、未经治疗的无慢性帕金森氏症 多巴胺能或抗炎治疗。这是一个至关重要的患者群体，因为它避免了问题 产生于抗帕金森症治疗的效果。这些目标加在一起，将是对 假设外周髓系细胞的促炎激活发生在早期帕金森病中，并且这一假设 激活是神经退化过程中的关键部分。它还将协助我们建立这一进程。 以及未来开发Udall临床核心所需的路径。

Project Summary: Project 3 Recent studies have begun to shed light on the complex interactions between the brain and body involved in Parkinson disease. Genetics, pathological studies, and model systems have highlighted the importance of cells of the myeloid lineage, particularly macrophages and other monocytes, in this brain/body interaction. In the brain, the resident myeloid cells are the microglia. Importantly, however, in several disease states it has been shown that circulating myeloid cells can infiltrate across the blood brain barrier in response to neuroinflammatory triggers and differentiate into macrophages and dendritic cells. Although the morphology of these “invaders” may be similar to the resident microglia, their actions may be quite different, and they may be either pro-inflammatory, triggering neuron injury or death, or anti-inflammatory, contributing to resolution of local inflammation. While myeloid cells are conventionally dichotomized into M1 pro-inflammatory and M2 anti-inflammatory phenotypes, recent work has emphasized that these are extremes of a spectrum rather than discrete states. These activation states are the product of differential gene programs, and therefore, coding and non-coding RNA signatures are powerful tools for examining the functional states of myeloid cells. A key regulator of the activation of peripheral monocytes and their differentiation into pro-inflammatory macrophages and dendritic cells is microRNA 155 (miR-155). This project will employ recent advances in high-throughput genomic techniques to understand how peripheral myeloid cells function in PD. Based on our previous studies in mice, we will determine whether there is elevated miR-155 early in human disease. In addition, we will conduct transcriptional profiling of mRNAs and miRNAs in peripheral myeloid cells to identify important alterations in the gene programs regulating myeloid cell differentiation and activation, and assess the extent to which there is M1 polarization. All of the subjects recruited for this study will have early stage, untreated (“de novo”) Parkinson disease without chronic dopaminergic or anti-inflammatory treatment. This is a critically important patient population as it avoids issues arising from the effects of antiparkinsonian treatment. Together, these aims will provide an important test of the hypothesis that pro-inflammatory activation of peripheral myeloid cells occurs in early PD and that this activation is a critical part of the neurodegenerative process. It will also assist us in establishing the process and pathways needed for the future development of a Udall clinical core.