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Regulation of the Microglial Neuroimmune Response by Long Non-Coding RNAs

长非编码 RNA 对小胶质细胞神经免疫反应的调节

基本信息

批准号：
10514892
负责人：
Annemarie Shibata
金额：
$ 43.65万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514892
关键词：
Acute Address Anti-Inflammatory Agents Antigen Presentation Area Astrocytes B-Lymphocytes Bacterial Infections Behavioral Biological Biological Assay Biological Models Biological Process Brain CCL2 gene Cells Chronic Coculture Techniques Complex Data Demyelinating Diseases Demyelinations Development Disease Disease model Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Etiology Exposure to FDA approved Gene Expression Genes Genetic Transcription Host Defense Human Immune Immune response In Vitro Inflammatory Injury Interleukin-4 Investigation Link Luciferases Lymphocyte Mediating Methodology Microglia Molecular Mouse Strains Multiple Sclerosis Mus Myelin Names Nerve Degeneration Neurodegenerative Disorders Neuroimmune Neurons Nitric Oxide Nitrogen Oxygen Pathogenesis Pathology Phagocytosis Pharmaceutical Preparations Phenotype Prevention Primary Cell Cultures Process Production Publishing Quantitative Reverse Transcriptase PCR RNA Interference Regulation Regulator Genes Reporter Research Training Resistance Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Spinal Cord Students Synapses T-Lymphocyte TLR4 gene TMEV Tissues Untranslated RNA Viral Virus Diseases Western Blotting Work base cell injury chromatin remodeling cytokine differential expression effective therapy experimental study functional plasticity genetic risk factor genome-wide gliogenesis immune function in vitro Model innovation interest knock-down mRNA Expression macrophage mouse model neurogenesis neuroimmunology neuroinflammation neuropathology neurotoxic neurotoxicity neurotrophic factor novel novel therapeutic intervention overexpression pathogen pathogenic bacteria pathogenic virus prevent protein expression response systemic inflammatory response therapeutic target transcriptome

项目摘要

PROJECT SUMMARY/ABSTRACT Systemic inflammation due to viral or bacterial infection is a direct cause of dysregulated neuroimmune responses and is linked to several neurodegenerative pathologies such as multiple sclerosis (MS). Microglia participate in innate immune processes of pathogen clearance contributing to both neurorecovery and neurotoxicity. Proper microglial immune function supports neurogenesis and synapse development, regulates homeostatic neuronal and glial activity, and provides host defense against pathogens and injury. Dysregulation microglial immune function is likely to contribute to neuroinflammatory processes that cause neurotoxicity. The mechanisms governing microglial functional plasticity and whether microglial immune responses are neuroprotective or neurotoxic are not well understood. Long intergenic non-coding RNAs (lincRNAs) are prime candidates for regulating microglial plasticity because many lincRNAs are early-primary response genes whose expression is stimulated by environmental signals. LincRNAs are associated with human inflammatory disease and neuropathologies such as MS. Our collaborative work has identified lincRNAs that regulate pro-inflammatory gene expression in TLR4-stimulated macrophages and microglia through modulation of chromatin remodeling. Based on these studies, we hypothesize that differential expression of lincRNAs act as regulators of gene transcription to control microglial expression of neuroprotective or neurotoxic phenotypes. Further, we propose that differential expression of lincRNAs will contribute to whether microglial responses are effective in clearing pathogens and promoting normal function or causing neurotoxicity and promoting neurodegeneration. To address this hypothesis, we mined whole-transcriptome data and used an in vitro model system to identify lincRNAs that are inversely expressed in microglial pro- inflammatory neurotoxic (TLR4-stimulated) and anti-inflammatory neurotrophic (IL-4-stimulated) functional states. Our recently published work shows that lincRNAs are differentially expressed in microglial neuroinflammatory and neurotrophic states and that silencing neuroinflammatory lincRNAs can reduce neurotoxicity. Preliminary evidence shows that specific lincRNAs are overexpressed in degenerating cortical tissue of a mouse model for progressive, chronic MS. The objectives of this proposal are to investigate the mechanisms by which lincRNAs mediate a proinflammatory state in microglia (Aim 1) and to determine whether differential lincRNA expression underlies viral-induced acute and chronic mouse models of MS (Aim 2). This proposal is conceptually innovative as it will provide information about lincRNA-regulated mechanisms of neuroimmunity and neurotoxicity. These studies are directly applicable to the development of new therapeutic strategies for limiting the neurodegeneration associated with inflammatory neuropathologies.

项目总结/文摘