Role of Microglial Hur in promoting neuroinflammation and ALS disease progression

肌萎缩侧索硬化症（ALS）是一种运动神经元的退行性疾病，其导致进行性脊髓损伤。 软弱与死亡没有有效的治疗方法，使患者（和家庭）负担沉重， 随着疾病的发展，会产生巨大的情绪、身体和金钱上的影响。医生可以提供 症状有所缓解，但人们对无法治疗这种疾病深感沮丧， 强调了寻找新疗法的强烈需求。参加过海外战争的退伍军人 ALS的发病率比平民人口，从而调查疾病的机制和新的 治疗途径，如这里提出的，与VA使命直接相关。 越来越多的与ALS相关的基因表明疾病发生的分子途径广泛。 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，可以调节疾病的进展。小胶质细胞是神经炎症的主要成分， 在ALS中发挥双重作用：一方面延迟疾病早期的临床发作和进展， 另一方面加速疾病在后期的进展。这些角色的多样性反映了 小胶质细胞的动态分子库。了解这些剧目的决定因素至关重要 来开拓新的治疗方法。在我们的初步数据和最近的出版物中，我们发现 RNA结合蛋白HuR是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， 发现HuR驱动小胶质细胞活化的许多细胞特性，包括迁移、侵袭和细胞周期。 其他免疫细胞的化学吸引力。这一背景构成了我们假设的基础，即HuR在其中扮演了一个重要角色。 通过促进小胶质细胞中促炎激活的分子基础在ALS中发挥关键作用， 抑制促进抗炎、疾病延迟表型的分子程序。我们 提出了三个具体的目标来解决这一假设：1）确定前的分子机制， 野生型和ALS中炎性细胞因子减弱和抗炎性细胞因子增强， 2）表征HuR敲除对野生型和ALS的影响， 相关的小胶质细胞活化，响应炎症信号和化学吸引的迁移/侵袭 和3）表征小胶质细胞中HuR敲除对ALS发作的影响， 突变型SOD 1小鼠中的进展。我们最近开发了一种小鼠模型，其中HuR在基因上是 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 该建议是为了描述转录后基因调控在控制分子和 胶质细胞表型及其对ALS的影响。本文的创新之处在于对后危机的研究。 转录调节作为神经炎症的新途径和HuR的原理验证研究 作为ALS的治疗靶点。这种应用的意义超出了ALS作为小胶质细胞， 神经炎症在调节其它CNS疾病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.