Corticosteroid Insensitivity in the Neonatal and Pediatric Airway Diseases

描述（由申请人提供）：喘息和哮喘等气道疾病仍然是婴儿和儿童的重要临床问题，导致急诊室就诊和生活质量下降。哮喘的特征是慢性炎症导致气道增厚、过度收缩。虽然皮质类固醇在减少炎症方面是有效的，但大量儿童发展为皮质类固醇不敏感性伴哮喘控制不良。最近对其他疾病的研究强调了维生素D在减轻炎症，细胞增殖和纤维化方面的作用。在成人中，维生素D缺乏与哮喘增加相关，而维生素D补充剂可以增强皮质类固醇的有效性。然而，维生素D和皮质类固醇相互作用产生有益作用的机制，或维生素D在新生儿/儿科哮喘中的作用尚不清楚。我们的目标是确定与皮质类固醇不敏感性和维生素D相关的分子机制，在气道炎症的背景下。我们将使用一个发育中的人类气道的体外模型来检验以下假设：（1）炎症导致皮质类固醇不敏感，（2）维生素D增强皮质类固醇对炎症的钝化作用。这些研究将为临床前体内模型和皮质类固醇抵抗性哮喘儿童维生素补充的新治疗策略奠定基础。

DESCRIPTION (provided by applicant): Airway diseases such as wheezing and asthma remain a significant clinical problem for infants and children, leading to emergency room visits and reduced quality of life. Asthma is characterized by chronic inflammation resulting in a thickened, hypercontractile airway. Although corticosteroids are effective in reducing inflammation, a substantial cohort of children develops corticosteroid insensitivity with poorly-controlled asthma. Recent studies in other diseases highlight a role for Vitamin D in alleviating inflammation, cell proliferation, and fibrosis. In adults, Vitamin D deficiency correlates to increased asthma, while Vitamin D supplementation can enhance effectiveness of corticosteroids. However, the mechanisms by which Vitamin D and corticosteroids interact to produce beneficial effects, or the role of Vitamin D in neonatal/pediatric asthma, are not known. Our goal is to determine the molecular mechanisms related to corticosteroid insensitivity and Vitamin D in the context of inflammation in the developing airway. Using an in vitro model of developing human airways, we will test the hypothesis that (1) inflammation contributes to corticosteroid insensitivity, and (2) Vitamin D potentiates corticosteroid blunting of inflammation These studies will lay the foundation for pre-clinical in vivo models and novel therapeutic strategies for vitamin supplementation in children with corticosteroid-resistant asthma.