Project 3: LRRK2 mediated macrophage responses in PD

项目 3：LRRK2 介导的 PD 巨噬细胞反应

• 批准号: 9976625
• 负责人: Andrew B West
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976625
• 关键词: Alabama; Animal Model; Antisense Oligonucleotides; Attenuated; Automobile Driving; Autopsy; Basic Science; Biochemical Pathway; Bioinformatics; Blood; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Diseases; Brain region; Cell membrane; Cell physiology; Cells; Clinical; Cytokine Receptors; Derivation procedure; Disease model; Disease susceptibility; GTP Binding; Genes; Genetic; Genetic Variation; HLA-DR Antigens; Heritability; Immune; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Interferons; Knock-out; Knockout Mice; LRRK2 gene; Laboratories; Leukocytes; Link; Measures; Mediating; Mediation; Microglia; Midbrain structure; Modeling; Mosaicism; Mutation; Natural Immunity; Nerve Degeneration; Neurons; Ontology; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Pharmacology; Phosphotransferases; Production; Proteins; RNA Interference; Rattus; Rodent; Serum; Substantia nigra structure; Surface; System; Techniques; Therapeutic; Transgenic Mice; Transgenic Organisms; Transplantation; Up-Regulation; Vesicle; Work; adaptive immunity; alpha synuclein; bone cell; chemokine receptor; cohort; cytokine; disorder control; genetic variant; immune activation; immune function; induced pluripotent stem cell; kinase inhibitor; macrophage; molecular sequence database; monocyte; mutation carrier; neuroinflammation; neuroprotection; novel; pars compacta; predictive modeling; receptor; recruit; response; small molecule; synuclein; tool; trafficking; transcriptomics

Project 3- Summary “LRRK2 mediated macrophage responses in PD” Post-mortem studies show that brains susceptible to Parkinson disease (PD) develop α- synuclein inclusions in vulnerable neurons together with immune cell activation. Peripheral immune cells are recruited to the most vulnerable brain regions such as the substantia nigra pars compacta. Historically the interpretation of immune cell activation in the PD brain and pathogenesis has been difficult to understand. However, recent genetic and transcriptomic profiling studies using new sequence databases and gene ontology compendia show that immune cell function may underlie much of the heritable aspects of PD susceptibility. These recent studies highlight a gene known as leucine-rich repeat kinase 2 in driving some of the connection between immune function and PD susceptibility. Rare genetic variants in LRRK2 are among the most common known genetic causes of PD. In the P20 Exploratory center, we found that LRRK2 protein is highly expressed in peripheral macrophages that are recruited nearby neurons in the brain that harbor α-synuclein inclusions. Studies with global LRRK2-transgenic and knockout mice and rats suggest that LRRK2 may control damaging pro-inflammatory responses in the brain through function in these macrophages. As part of the proposed Alabama Udall Center to study “Innate and Adaptive Immunity in Parkinson Disease,” we will define peripheral macrophage responses driven by LRRK2 in α-synuclein induced neurodegeneration. Using genetic, pharmacological, and transplantation approaches, we will restrict LRRK2 activation and inhibition to the periphery and in bone-marrow derived immune cells in rat models of α-synuclein induced neurodegeneration. In parallel, we will study LRRK2 function in macrophages isolated from patient blood to determine whether LRRK2 mutations exacerbate pro- inflammatory responses in PD susceptibility. Further, we will examine whether macrophage responses from de novo PD patients with elevated LRRK2 expression show elevated pro- inflammatory responses and whether these can be rescued with LRRK2 kinase inhibitors and RNAi approaches. With this work, we hope to gain a better understanding of LRRK2 function in macrophages in neurodegeneration and proof-of-principle therapeutic approaches that might be explored for neuroprotection in LRRK2-linked PD.

项目3-总结“LRRK 2介导的PD巨噬细胞反应” 尸检研究表明，易患帕金森病（PD）的大脑会产生α- 突触核蛋白包涵体在脆弱的神经元与免疫细胞激活。外周免疫 细胞被募集到最脆弱的大脑区域，如黑质的背侧部。 从历史上看，PD脑中免疫细胞活化和发病机制的解释一直是 很难理解然而，最近的遗传和转录组学分析研究使用新的 序列数据库和基因本体纲要表明，免疫细胞功能可能是 帕金森病易感性的许多遗传方面。这些最近的研究强调了一种基因， 富含亮氨酸的重复序列激酶2在驱动免疫功能和PD之间的某些联系中的作用 易感性LRRK 2的罕见遗传变异是最常见的已知遗传原因之一， 警局在P20探索中心，我们发现LRRK 2蛋白在外周血中高表达， 巨噬细胞在大脑中含有α-突触核蛋白内含物的神经元附近被招募。 对LRRK 2转基因和基因敲除小鼠和大鼠的研究表明，LRRK 2可以控制 通过这些巨噬细胞的功能破坏大脑中的促炎反应。 作为拟议中的亚拉巴马尤德尔中心的一部分，该中心研究“先天和适应性免疫， 帕金森病，”我们将定义由α-突触核蛋白中的LRRK 2驱动的外周巨噬细胞反应， 诱发神经变性利用遗传学、药理学和移植方法，我们将 将LRRK 2激活和抑制限制在外周和骨髓来源的免疫细胞中， α-synuclein诱导的大鼠神经退行性变模型。同时，我们将研究LRRK 2在 从患者血液中分离的巨噬细胞，以确定LRRK 2突变是否加剧了前 炎症反应在PD易感性中的作用此外，我们将检查巨噬细胞是否 LRRK 2表达升高的原发性PD患者的反应显示， 炎症反应以及这些是否可以用LRRK 2激酶抑制剂和RNAi来挽救 接近。通过这项工作，我们希望能够更好地了解LRRK 2在 巨噬细胞在神经退行性疾病和原则性治疗方法的证明， 探索LRRK 2相关PD的神经保护作用。