PERK Dependent Mechanisms of Neuroinflammation

神经炎症的 PERK 依赖性机制

• 批准号: 9383118
• 负责人: Gordon P. Meares
• 金额: $ 32.81万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383118
• 关键词: Affect; Alzheimer' s Disease; Astrocytes; Attenuated; Automobile Driving; Biochemistry; Brain; Cell Communication; Cell Survival; Cells; Chronic; Coculture Techniques; Complex; Cytokine Signaling; Data; Disease; Endoplasmic Reticulum; Experimental Autoimmune Encephalomyelitis; Gene Expression; Genes; Goals; Homeostasis; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; JAK1 gene; Janus kinase 1; Knock-out; Knockout Mice; Knowledge; Label; Lymphoid Cell; Membrane; Modeling; Molecular; Molecular Biology; Molecular and Cellular Biology; Multiple Sclerosis; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Phosphotransferases; Protein Tyrosine Kinase; Public Health; RNA; Reaction; Regulation; Research; Role; Signal Pathway; Signal Transduction; Specificity; Testing; Transactivation; base; cytokine; effective therapy; endoplasmic reticulum stress; immune activation; immune function; immunoreaction; immunoregulation; in vivo; insight; knock-down; mouse model; nervous system disorder; neuroinflammation; neuropathology; new therapeutic target; next generation; novel therapeutics; repaired; restoration; therapeutic target; transcription factor; transcriptomics

Neurological diseases are a growing public health concern with no cures and few treatments. Inflammation in the central nervous system (neuroinflammation) is observed in most neurological diseases and is thought to contribute to neuropathology. Our long-term goal is to identify targets for selective regulation of pathological inflammation in the CNS. Endoplasmic reticulum (ER) stress in neuronal and glial cells is associated with most neurodegenerative diseases. ER stress also drives inflammation, however the underlying mechanisms and impact on disease are unknown. Our central hypothesis is that PERK signaling in astrocytes contributes to neuroinflammation. This will be tested in three specific aims. 1) Determine the molecular mechanisms of PERK-dependent signaling leading to neuroinflammatory gene expression. Using traditional cellular and molecular biology and hypothesis-driven transcriptomics, the mechanisms of PERK-dependent neuroinflammation will be elucidated. 2) Determine the mechanisms by which PERK deletion affects neuroinflammation in vivo. Using in vivo cell-specific RNA labeling and conditional knockout mice we will define the spatial and temporal occurrence of ER stress and inflammatory gene expression in astrocytes, and how astrocyte-specific knockout of PERK affects the neuroinflammatory disease of experimental autoimmune encephalomyelitis. 3) Determine the non-cell autonomous mechanisms of ER stress signaling in astrocytes. Using in vitro primary cell co-cultures and in vivo conditional knockout mice, the PERK-dependent effects of astrocytes on the function and viability of resident and infiltrating cells of the CNS will be established. This project is significant because it will define basic mechanisms driving neuroinflammation and establish a potential therapeutic target for immune modulation in the CNS.

神经疾病是日益增长的公共卫生问题，没有治疗方法和疗法很少。 在大多数神经系统疾病中观察到中枢神经系统中的炎症（神经炎症）， 被认为有助于神经病理学。我们的长期目标是确定选择性调节的目标 中枢神经系统中的病理炎症。神经元和神经胶质细胞中的内质网（ER）应激为 与大多数神经退行性疾病有关。 ER应力也会引起炎症，但是基础 机制和对疾病的影响尚不清楚。我们的中心假设是星形胶质细胞中的PERK信号传导 有助于神经炎症。这将以三个具体目标进行测试。 1）确定分子 PERK依赖性信号传导的机制导致神经炎症基因表达。使用传统 细胞和分子生物学以及假设驱动的转录组学，依赖PERK的机制 神经炎症将被阐明。 2）确定Perk缺失影响的机制 体内神经炎症。使用体内细胞特异性RNA标记和条件敲除小鼠，我们将定义 ER应力和星形胶质细胞中炎症基因表达的空间和时间出现，以及如何 PERK的星形胶质细胞特异性敲除影响实验自身免疫性的神经炎症疾病 脑脊髓炎。 3）确定星形胶质细胞中ER应力信号传导的非电池自主机制。 使用体外原代细胞共培养和体内条件基因敲除小鼠 将建立有关中枢神经系统的居民和浸润细胞功能和生存能力的星形胶质细胞。这 项目很重要，因为它将定义驱动神经炎症的基本机制并建立一个 中枢神经系统中免疫调节的潜在治疗靶标。