Mechanisms of Steroid Resistance in Severe Asthma

描述（由申请人提供）： 严重哮喘[SA]的特点是哮喘症状控制不足 和气道生理学，因此与 对最有效的哮喘管理药物的反应受损，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，部分是高水平的 与Th 2淋巴细胞活化相关的细胞因子，包括IL-4。最近 有证据表明，一氧化氮[NO]可能会放大IL-4的产生， 缺乏关键的抗炎细胞因子IL-10。我们已经证明IL-10 在哮喘中是缺乏的，这表明NO可能是哮喘的关键因素。 调节IL-4。此外，核转录因子加塔-3是 对Th 2淋巴细胞分化至关重要，其与DNA的结合是 为明确SA的机制，我们建议（1） 表征SA中炎症和重塑的标志物，并与 轻度-中度哮喘[MMA]，在ICS中得到控制，（2）建立 GR在SA和MMA中的功能，采用两种互补技术，（3） 表征SA和MMA中的加塔-3表达，（4）确定SA和MMA中的功能性GATA-3表达。 GR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 发生功能障碍，重点是Th 2细胞因子，IL-10和NO。PI具有 建立了哮喘机制研究的跟踪记录。二十 已经确定了SA患者，并与少数民族诊所和 拥有超过270，000个覆盖生命的管理式医疗将增加我们的招聘 能力的我们为合作计划提供（1）一个既定的 哮喘的临床、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)加塔-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.