Mechanisms of Steroid Resistance in Severe Asthma

描述(由申请人提供)： 严重哮喘的特点是对哮喘症状的控制不充分 和呼吸道生理学，尽管有很好的治疗，因此与 对哮喘治疗最有效的药物反应受损，即 吸入性皮质类固醇[ICS]糖皮质激素受体功能障碍 [GR]与SA相关，部分原因是高水平的 与Th2淋巴细胞活化相关的细胞因子，包括IL-4。近期 有证据表明，一氧化氮[NO]可能会放大大鼠体内IL-4的产生。 缺乏关键的抗炎细胞因子IL-10。我们已经证明了IL-10 在哮喘方面存在缺陷，这表明一氧化氮可能是哮喘的一个关键因素 调节IL-4。此外，核转录因子GATA-3是 对Th2淋巴细胞分化是必不可少的，它与DNA的结合是 被正常的GR抑制。为了定义SA的机制，我们建议(1) 描述SA炎症和重塑的标志物，并与 在ICS中控制的轻-中度哮喘，(2)建立 GR在SA和MMA中的作用及两种互补技术，(3)至 鉴定GATA-3在SA和MMA中的表达，(4)确定功能 糖皮质激素受体功能障碍对细胞因子产生和共刺激的影响 分子表达，以及(5)建立GR 功能障碍的发生，主要集中在Th2细胞因子、IL-10和NO。私家侦探有一个 建立了哮喘机械性研究的记录。二十 SA患者已经被确认，并与一家少数族裔诊所和 拥有27万份承保人寿的管理型医疗保健将增加我们的招聘人数 能力。我们向协作计划(1)提供已建立的 哮喘临床、转化和基础研究计划(2) 评估SA中GR功能障碍发展的机制研究，以及 (3)GATA-3在SA中表达的创新问题。

DESCRIPTION (provided by applicant): Severe asthma [SA] is characterized by inadequate control of asthma symptoms and airway physiology despite good therapy, and therefore is associated with impaired response to the most effective agents for asthma management, namely inhaled corticosteroids [ICS]. Dysfunction of the glucocorticoid receptor [GR] is associated with SA, and is in part a consequence of high levels of cytokines associated with Th2 lymphocyte activation, including IL-4. Recent evidence suggests that nitric oxide [NO] may amplify production of IL-4 in the absence of a key anti-inflammatory cytokine, IL-10. We have shown that IL-10 is deficient in asthma, suggesting that NO may be a critical factor in regulating IL-4. Further, the nuclear transcription factor GATA-3 is essential for Th2 lymphocyte differentiation, and its binding to DNA is inhibited by normal GR. To define the mechanisms of SA, we propose (1) to characterize markers of inflammation and remodeling in SA, and compare to mild-moderate asthma [MMA] which is controlled in ICS, (2) to establish the function of the GR in SA and MMA with two complementary techniques, (3) to characterize GATA-3 expression in SA and MMA, (4) to determine the functional consequences of GR dysfunction on cytokine production and co-stimulatory molecule expression, and (5) to establish the mechanisms by which GR dysfunction occurs, with focus on Th2 cytokines, IL-10, and NO. The PI has an established track record of mechanistic investigations in asthma. Twenty patients with SA are already identified, and links to a minority clinic and managed care with >270,000 covered lives will add to our recruitment capabilities. We offer to the collaborative program (1) an established program of clinical, translational, and basic research in asthma, (2) mechanistic studies to evaluate the development of GR dysfunction in SA, and (3) an innovative question of GATA-3 expression in SA.