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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

肌萎缩侧索硬化症 (ALS) 是一种运动神经元退行性疾病，会导致进行性进展虚弱和死亡。没有有效的治疗方法，给患者（和家人）带来了沉重的负担随着疾病的进展，会造成巨大的情感、身体和金钱影响。医生可以提供症状有所缓解，但无法治疗疾病而感到深深的挫败感，强调迫切需要确定新的治疗方法。参加过对外战争的退伍军人的比例明显更高 ALS 的发病率高于平民，因此需要研究疾病机制和新方法治疗途径，例如这里提出的，与退伍军人事务部的使命直接相关。越来越多的与 ALS 相关的基因表明疾病发生过程中涉及多种分子途径。然而，神经炎症是 ALS 中常见的下游因素，与疾病无关启动因子，可以调节疾病进展。小胶质细胞是神经炎症的主要成分在 ALS 中发挥双重作用：一方面延缓疾病早期的临床发作和进展，另一方面另一方面加速后期疾病的进展。这些角色的多样性反映了广泛和小胶质细胞的动态分子库。了解这一曲目的决定因素至关重要开辟新的治疗方法。在我们的初步数据和最近的出版物中，我们已经确定 RNA 结合蛋白 HuR 作为炎症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。通过对下游目标的调控，我们发现 HuR 驱动小胶质细胞激活的许多细胞特性，包括迁移、侵袭和其他免疫细胞的化学吸引。这一背景构成了我们假设的基础，即 HuR 发挥着通过促进小胶质细胞促炎激活的分子基础，在 ALS 中发挥关键作用抑制促进抗炎、延迟疾病表型的分子程序。我们提出三个具体目标来解决这一假设：1）确定亲的分子机制野生型和 ALS 中炎症细胞因子的减弱和抗炎细胞因子的增强 HuR 敲除后相关小胶质细胞，2) 表征 HuR 敲除对野生型和 ALS- 的影响响应炎症信号和化学吸引的相关小胶质细胞激活、迁移/侵袭其他免疫细胞的影响，3) 描述小胶质细胞中 HuR 敲除对 ALS 发病的影响和突变型 SOD1 小鼠的进展。我们最近开发了一种小鼠模型，其中 HuR 基因被从小胶质细胞中删除，这将极大地促进这些目标的完成。的长期目标该提案旨在描述转录后基因调控在控制分子和胶质细胞的细胞表型及其对 ALS 的影响。该提案的创新之处在于对后转录调控作为神经炎症的新途径以及 HuR 的原理验证研究作为 ALS 的治疗靶点。这一应用的意义不仅限于 ALS，因为小胶质细胞和神经炎症在调节其他中枢神经系统疾病（包括阿尔茨海默病、帕金森病、多发性硬化症、脊髓损伤和中风。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
作者：
通讯作者：

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

The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS.

DOI：
10.1186/s40478-021-01241-3
发表时间：
2021-08-13
期刊：
Acta neuropathologica communications
影响因子：
7.1
作者：
Kovacs M;Alamón C;Maciel C;Varela V;Ibarburu S;Tarragó L;King PH;Si Y;Kwon Y;Hermine O;Barbeito L;Trias E
通讯作者：
Trias E