p38 MAPK as a female-specific druggable target in CNS autoimmune disease

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的一种慢性炎症性疾病，其特征是髓磷脂丢失、不同程度的轴突损伤和进行性神经功能障碍。多发性硬化症是年轻人和青少年最常见的致残性神经系统疾病，在美国影响约35万人，在世界范围内影响超过100万人。目前的MS疾病修饰疗法（dmt）疗效有限且有不良毒性，因此需要基于潜在疾病机制的新方法。p38丝裂原活化激酶（MAPK）是类风湿性关节炎（RA）和克罗恩病等疾病自身免疫/炎症反应的中心分子，p38 MAPK的抑制目前正在临床探索作为这些疾病的DMT。然而，p38 MAPK在多发性硬化症（或多发性硬化症模型）病理生理中的作用及其作为治疗靶点的潜力尚未被研究。通过MS的主要自身免疫性模型——实验性变应性脑脊髓炎（EAE），我们测试了p38 MAPK的抑制是否会影响EAE的易感性和疾病进展。用药理学p38 MAPK抑制剂SB203580治疗雌性小鼠，如果在临床症状开始时给药，要么完全预防疾病，要么停止疾病。引人注目的是，雄性小鼠对治疗完全没有反应。这些发现表明，性别特异性因素参与了SB203580介导的p38 MAPK活性抑制和EAE易感性。在这项应用中，我们建议：1)确定EAE中p38 MAPK抑制的分子和细胞机制，2)确定SB治疗反应中性别二态性的基础。了解药物作用机制可能为MS治疗提供新的，更特异性的药物靶点。关于SB203580疗效的性别二分法尤其重要，因为许多自身免疫性疾病，包括多发性硬化症，在疾病易感性上表现出女性特异性的性别二态性。SB203580完全能够选择性地抑制女性疾病，这一发现为一种独特的DMT提供了可能性，这种DMT可以选择性地针对不断增加的女性MS患者群体。据我们所知，还没有研究评估DMT在MS中抑制p38 MAPK的潜力，尽管许多靶向这一途径的化合物已经被批准用于其他自身免疫性疾病的2期临床试验。此外，相对较少的研究关注MS或其模型中治疗反应的性别差异的基础。抑制p38 MAPK通路不仅可能提供一种新的DMT，选择性地针对不断增加的女性MS患者群体，而且可能通过发现治疗干预的新靶点，为MS的其他DMT的发展提供相关的机制见解。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by myelin loss, varying degrees of axonal damage, and progressive neurological dysfunction. MS is the most common disabling neurologic disease of young adults and adolescents affecting ~350,000 individuals in the United States and more than 1 million individuals worldwide. Current MS disease-modifying therapies (DMTs) have limited efficacy and untoward toxicities, underscoring the need for new approaches based on targeting underlying disease mechanisms. The p38 mitogen-activated kinase (MAPK) is a central molecule in autoimmune/inflammatory responses in diseases such as rheumatoid arthritis (RA) and Crohn's disease, and inhibition of p38 MAPK is currently being explored clinically as a DMT for these diseases. However, the role of p38 MAPK in the pathophysiology of MS (or MS models) and its potential as a therapeutic target has not been investigated. Using experimental allergic encephalomyelitis (EAE), the principal autoimmune model of MS, we tested whether inhibition of p38 MAPK can influence EAE susceptibility and disease progression. Treatment of female mice with the pharmacological p38 MAPK inhibitor, SB203580, either completely prevented disease or halted disease if administered at the onset of clinical signs. Strikingly, male mice were completely unresponsive to treatment. These findings suggest that sex-specific factors contribute to SB203580 mediated inhibition of p38 MAPK activity and EAE susceptibility. In this application, we propose to: 1) determine the molecular and cellular mechanisms targeted by p38 MAPK inhibition in EAE and 2) determine the basis of the sexual dimorphism in the therapeutic response to SB. Understanding the mechanisms of drug action is likely to provide novel, more specific drug targets for MS therapy. The gender dichotomy with regard to efficacy of SB203580 is particularly important, since many autoimmune diseases, including MS, exhibit a female-specific sexual dimorphism in disease susceptibility. The finding that SB203580 is fully capable of selectively inhibiting disease in females provides for the possibility of a unique DMT that selectively targets the increasing female MS patient population. No study to our knowledge has evaluated the DMT potential of inhibiting p38 MAPK in MS, despite the fact that many compounds targeting this pathway are already approved for phase 2 clinical trials in other autoimmune diseases. Further, relatively few studies focus on the basis of sex differences in therapeutic responses in MS or its models. Inhibition of the p38 MAPK pathway may not only provide a novel DMT which selectively targets the increasing female MS patient population, but also will likely provide mechanistic insight relevant to development of additional DMTs for MS, by uncovering new targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to explore a new molecular pathway which is likely to be important in the pathogenesis of multiple sclerosis (MS), and understanding of this pathway can yield new therapeutic targets for treatment of this devastating disease. Further, this proposal explores the bases for sexual dimorphisms in efficacy of drug treatment in autoimmune disease. This point is highly salient today given the increasing female incidence of MS.