Role of Microglial Hur in promoting neuroinflammation and ALS disease progression

肌萎缩侧索硬化症(ALS)是一种运动神经元退行性疾病，导致进行性 软弱和死亡。没有有效的治疗方法，让患者(和家人)背负着 随着疾病的发展，巨大的情感、身体和金钱后果。医生可以提供 症状有所缓解，但无法治疗这种疾病让人深感沮丧， 强调了确定新治疗方法的强烈需要。参加过海外战争的老兵有明显更高的 ALS的发病率高于平民人群，从而研究了ALS的发病机制和新颖 治疗途径，如这里提出的，与退伍军人管理局的任务直接相关。 越来越多与肌萎缩侧索硬化症相关的基因表明，在疾病的发生过程中涉及到一系列广泛的分子途径。 然而，神经炎症是肌萎缩侧索硬化症的常见下游因素，与疾病无关 启动因子，可以调节疾病的进展。小胶质细胞是神经炎症的主要成分， 在肌萎缩侧索硬化症中扮演双重角色：一方面延缓疾病早期的临床发病和进展，另一方面 另一方面，在后期加速疾病的发展。这些角色的多样性反映了广泛和 小胶质细胞的动态分子谱系。理解这个曲目的决定因素是至关重要的 开辟了新的治疗方法。在我们的初步数据和最近的出版物中，我们已经确定 作为炎性细胞因子和趋化因子产生的主要启动子的RNA结合蛋白HUR 小胶质细胞和抗炎细胞因子的抑制因子。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 其他免疫细胞的趋化性。这一背景形成了我们假设Hur扮演一个 在ALS中的关键作用通过促进小胶质细胞和 抑制促进抗炎、延缓疾病表型的分子程序。我们 针对这一假说，提出了三个具体的目标：1)确定PRO的分子机制。 野生型和肌萎缩侧索硬化症患者的炎性细胞因子减弱和抗炎细胞因子增强 HUR基因敲除后相关的小胶质细胞，2)表征HUR基因敲除对野生型和ALS的影响 炎症信号和化学吸引反应中相关的小胶质细胞激活、迁移/侵袭 以及3)小胶质细胞中HUR基因敲除对ALS发病和 突变型SOD1小鼠的研究进展。我们最近开发了一种小鼠模型，在这种模型中，Hur是遗传的 从小胶质细胞中删除，这将大大促进这些目标的完成。的长期目标是 这项建议是为了表征转录后基因调控在调控分子和 胶质细胞表型及其对ALS的影响。这一建议的创新之处在于它对后苏联的调查。 转录调控是神经炎性反应的新途径和Hur的原则验证研究 作为ALS的治疗靶点。这项应用的意义超出了ALS作为小胶质细胞和 神经炎症在调节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。

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.