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

p38 MAPK 作为中枢神经系统自身免疫性疾病女性特异性药物靶点

• 批准号: 8286179
• 负责人: CORY TEUSCHER
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286179
• 关键词: Address; Adolescent; Affect; Animal Model; Autoimmune Diseases; Autoimmune Process; Blood - brain barrier anatomy; CD4 Positive T Lymphocytes; Cells; Central Nervous System Diseases; Chronic; Clinical; Controlled Environment; Crohn' s disease; Data; Demyelinations; Development; Disease; Disease Progression; Disease susceptibility; Drug Delivery Systems; Drug Kinetics; Drug effect disorder; Effector Cell; Exhibits; Experimental Autoimmune Encephalomyelitis; Female; Functional disorder; Gender; Gene Expression; Gonadal Steroid Hormones; Hormones; Immune; Immune response; Incidence; Individual; Inflammatory; Inflammatory Response; Interferons; Interleukin-17; Knock-in Mouse; MAPK14 gene; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinase Kinases; Mitogens; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurologic; Neurologic Dysfunctions; Pathogenesis; Pathway interactions; Phase II Clinical Trials; Play; Predisposition; Prevention; Production; Rheumatoid Arthritis; Role; SB 203580; Severities; Sex Characteristics; Stimulus; Stress; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; United States; base; cell type; cytokine; drug efficacy; drug metabolism; genetic manipulation; human MAPK14 protein; insight; macrophage; male; new therapeutic target; novel; novel strategies; patient population; prevent; protein expression; research study; response; sex; sexual dimorphism; therapeutic target; young adult

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.

描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统(CNS)炎症性疾病，以髓鞘丢失、不同程度的轴突损伤和进行性神经功能障碍为特征。MS是年轻人和青少年中最常见的致残性神经疾病，在美国影响约350,000人，在全球影响100多万人。目前的多发性硬化症疾病修正疗法(DMT)疗效有限，副作用大，强调了基于潜在疾病机制靶向的新方法的必要性。P38丝裂原激活激酶(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，目前临床上正在探索抑制p38 MAPK作为治疗这些疾病的DMT。然而，p38MAPK在多发性硬化(或多发性硬化模型)的病理生理学中的作用及其作为治疗靶点的潜力尚未被研究。利用MS的主要自身免疫模型-实验性变态反应性脑脊髓炎(EAE)，我们测试了抑制p38MAPK是否会影响EAE的易感性和疾病的进展。用药理上的p38 MAPK抑制剂SB203580治疗雌性小鼠，要么完全预防疾病，要么在出现临床症状时使用就能阻止疾病。令人惊讶的是，雄性小鼠对治疗完全没有反应。这些结果提示，性别特异性因素参与SB203580介导的p38MAPK活性抑制和EAE易感性。在这一应用中，我们建议：1)确定抑制p38 MAPK在EAE中作用的分子和细胞机制；2)确定SB治疗反应中性别二型性的基础。了解药物的作用机制可能会为MS的治疗提供新的、更特异的药物靶点。就SB203580的疗效而言，性别二分法特别重要，因为许多自身免疫性疾病，包括多发性硬化症，在疾病易感性方面表现出女性特有的性别二型性。SB203580完全能够选择性地抑制女性疾病的发现为一种独特的DMT提供了可能性，这种DMT选择性地针对不断增加的女性多发性硬化症患者群体。据我们所知，还没有研究评估DMT在MS中抑制p38 MAPK的潜力，尽管许多针对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第二阶段临床试验。此外，相对较少的研究集中在多发性硬化症或其模型治疗反应的性别差异上。抑制p38MAPK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，而且还可能通过发现新的治疗干预靶点，提供与开发更多的MS DMT相关的机械性见解。