Role of Microglial Hur in promoting neuroinflammation and ALS disease progression

小胶质细胞 Hur 在促进神经炎症和 ALS 疾病进展中的作用

• 批准号: 10046279
• 负责人: PETER H KING
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046279
• 关键词: Address; Adopted; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Area; Astrocytes; Attenuated; Cells; Central Nervous System Diseases; Cessation of life; Chemicals; Chemotaxis; Clinical; Data; Degenerative Disorder; Disease; Disease Progression; Elements; Emotional; Exhibits; Extracellular Matrix; Frustration; Genes; Genetic; Genetic Transcription; Goals; Hand; HuR protein; Immune; Immune response; In Vitro; Incidence; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Investigation; Knock-out; Link; MME gene; Mediating; Mediator of activation protein; Microglia; Mission; Molecular; Motor; Motor Neuron Disease; Multiple Sclerosis; Mus; Muscle; NOS2A gene; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Onset of illness; Paralysed; Parkinson Disease; Pathway interactions; Patients; Peripheral; Phenotype; Phosphodiesterase Inhibitors; Physicians; Play; Population; Post-Transcriptional Regulation; Process; Production; Property; Publications; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Regulator Genes; Research; Role; Signal Transduction; Signaling Molecule; Spinal cord injury; Stroke; TNF gene; Testing; Tissues; Toxic effect; Up-Regulation; Veterans; War; Work; attenuation; chemokine; cytokine; effective therapy; family burden; glial activation; in vivo Model; injured; innovation; macrophage; migration; mouse model; mutant; neuroinflammation; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; phase II trial; programs; promoter; recruit; response; small molecule inhibitor; superoxide dismutase 1; therapeutic target

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that leads to progressive weakness and death. There is no effective treatment, leaving the patient (and family) burdened with an overwhelming emotional, physical and monetary fallout as the disease progresses. The physician can provide some symptomatic relief, but there is a deep sense of frustration in not being able to treat the disease, underscoring a strong need to identify new treatments. Veterans of foreign wars have a significantly higher incidence of ALS than the civilian population, and thus investigations into disease mechanisms and novel therapeutic pathways, such as the one proposed here, are of direct relevance to the VA mission.The ever growing list of genes linked to ALS implicates a wide range of molecular pathways in disease initiation. Neuroinflammation, however, is a common downstream element in ALS that, independent of the disease initiating factor, can modulate disease progression. Microglia are a major component of neuroinflammation and play dual roles in ALS: on the one hand delaying clinical onset and progression early in the disease and on the other hand accelerating disease progression in later stages. The diversity of these roles reflects the broad and dynamic molecular repertoire of the microglial cell. Understanding the determinants of this repertoire is critical for opening up new therapeutic approaches. In our preliminary data and recent publication, we have identified the RNA binding protein HuR as a major promoter of inflammatory cytokine and chemokine production in microglia and a suppressor of anti-inflammatory cytokines. Through the regulation of downstream targets, we found that HuR drives many cellular properties of microglial activation including migration, invasion and the chemoattraction of other immune cells. This background forms the basis of our hypothesis that HuR plays a pivotal role in ALS by promoting the molecular underpinnings of pro-inflammatory activation in microglia and suppressing the molecular program that promotes an anti-inflammatory, disease delaying phenotype. We propose three specific aims to address this hypothesis: 1) determine the molecular mechanism of pro- inflammatory cytokine attenuation and anti-inflammatory cytokine augmentation in wild-type and ALS- associated microglia after HuR knockout, 2) characterize the impact of HuR knockout on wild-type and ALS- associated microglial activation, migration/invasion in response to inflammatory signals and on chemoattraction of other immune cells, and 3) characterize the impact of HuR knockout in microglia on ALS onset and progression in the mutant SOD1 mouse. We recently developed a mouse model in which HuR is genetically deleted from microglia and this will greatly facilitate the completion of these aims. The long term objective of this proposal is to characterize the role of post-transcriptional gene regulation in governing the molecular and cellular phenotype of glia and the impact on ALS. The innovation of this proposal is its investigation of post- transcriptional regulation as a novel pathway in neuroinflammation and a proof-of-principle investigation of HuR as a therapeutic target in ALS. The significance of this application extends beyond ALS as microglia and neuroinflammation play critical roles in modulating other CNS disorders including Alzheimer's, Parkinson's, multiple sclerosis ,spinal cord injury and stroke.

肌萎缩性侧索硬化症（ALS）是一种运动神经元退行性疾病，导致进行性