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: 10421258
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421258
• 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.

肌萎缩性外侧硬化症（ALS）是运动神经元的退化性疾病，导致进行性疾病 软弱和死亡。没有有效的治疗方法，使患者（和家庭）负担 随着疾病的发展，压倒性的情绪，身体和金钱后果。医师可以提供 有些症状缓解，但无法治疗这种疾病，有一种深切的沮丧感 强烈需要识别新疗法。外国战争的退伍军人有明显更高 ALS比平民的发病率，因此对疾病机制和新颖的调查 治疗途径，例如这里提出的途径，与VA任务直接相关。 与ALS相关的基因的越来越多暗示疾病开始中的各种分子途径。 然而，神经炎症是ALS中常见的下游元素，与该疾病无关 引发因素可以调节疾病进展。小胶质细胞是神经炎症和 在ALS中扮演双重角色：一方面，在疾病早期延迟临床发作和进展 其他手在后期加速疾病进展。这些角色的多样性反映了广泛的和 小胶质细胞的动态分子曲目。了解此曲目的决定因素至关重要 开放新的治疗方法。在我们的初步数据和最新出版物中，我们已经确定了 RNA结合蛋白HUR是炎性细胞因子和趋化因子产生的主要启动子 小胶质细胞和抗炎细胞因子的抑制剂。通过调节下游目标，我们 发现HUR推动了小胶质激活的许多细胞特性，包括迁移，入侵和 其他免疫细胞的化学吸收。这种背景构成了我们假设hur扮演的假设的基础 通过促进小胶质细胞中促炎激活的分子基础，在ALS中的关键作用 抑制促进抗炎，疾病延迟表型的分子程序。我们 提出了三个特定的目的，以解决这一假设：1）确定促进的分子机制 野生型和ALS的炎症细胞因子衰减和抗炎细胞因子增强 HUR淘汰后相关的小胶质细胞，2）表征HUR敲除对野生型和ALS的影响 相关的小胶质激活，响应炎症信号的迁移/侵袭和趋化引诱 其他免疫细胞，以及3）表征小胶质细胞对ALS发作和 突变SOD1小鼠的进展。我们最近开发了一个鼠标模型，其中HUR是遗传学的 从小胶质细胞中删除，这将极大地促进这些目标的完成。长期目标的 该建议是为了表征转录后基因调节在管理分子和 胶质的细胞表型和对ALS的影响。该提案的创新是其对后的调查 转录调节是神经炎症的新途径和对HUR的原则研究证明 作为ALS的治疗靶标。本应用的重要性扩展到ALS作为小胶质细胞和 神经炎症在调节其他中枢神经系统疾病中起着关键作用，包括阿尔茨海默氏症，帕金森氏症， 多发性硬化症，脊髓损伤和中风。

项目成果

The vitamin D activator CYP27B1 is upregulated in muscle fibers in denervating disease and can track progression in amyotrophic lateral sclerosis.

维生素 D 激活剂 CYP27B1 在去神经疾病的肌纤维中表达上调，并且可以追踪肌萎缩侧索硬化症的进展。

• DOI: 10.1016/j.jsbmb.2020.105650
• 发表时间: 2020
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Si,Ying;Kazamel,Mohamed;Kwon,Yuri;Lee,Ikjae;Anderson,Tina;Zhou,Siyu;Bamman,Marcas;Wiggins,Derek;Kwan,Thaddaeus;King,PeterH
• 通讯作者: King,PeterH

The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack.

• DOI: 10.1016/j.addr.2021.114082
• 发表时间: 2022-03
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Guha A;Waris S;Nabors LB;Filippova N;Gorospe M;Kwan T;King PH
• 通讯作者: King PH

Smad8 Is Increased in Duchenne Muscular Dystrophy and Suppresses miR-1, miR-133a, and miR-133b.

• DOI: 10.3390/ijms23147515
• 发表时间: 2022-07-07
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis.

• DOI: 10.1038/s41598-020-73845-z
• 发表时间: 2020-10-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kwan T;Kazamel M;Thoenes K;Si Y;Jiang N;King PH
• 通讯作者: King PH

Targeting the HuR Oncogenic Role with a New Class of Cytoplasmic Dimerization Inhibitors.

• DOI: 10.1158/0008-5472.can-20-2858
• 发表时间: 2021-04-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Filippova N;Yang X;Ananthan S;Calano J;Pathak V;Bratton L;Vekariya RH;Zhang S;Ofori E;Hayward EN;Namkoong D;Crossman DK;Crowley MR;King PH;Mobley J;Nabors LB
• 通讯作者: Nabors LB