Corticosteroid Insensitivity in the Neonatal and Pediatric Airway Diseases

新生儿和儿童气道疾病中的皮质类固醇不敏感

基本信息

批准号：
8852482
负责人：
Rodney Britt
金额：
$ 3.1万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-07 至 2015-12-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852482
关键词：
2 year old Adrenal Cortex Hormones Adult Age Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Breathing Bronchoconstriction Cell Proliferation Cell model Cells Child Childhood Childhood Asthma Chronic Chronic lung disease Clinical Clinical Data Disease Dose Effectiveness Emergency department visit Extracellular Matrix Failure Fibrosis Fluticasone propionate Foundations Future Glucocorticoid Receptor Glucocorticoids Goals Growth HDAC2 gene Healthcare Histone Acetylation Histone Deacetylase Human Impairment In Vitro Infant Inflammation Inflammation Mediators Inflammatory Lead Lung Measures Molecular Neonatal Nuclear Translocation Oral Participant Pharmaceutical Preparations Phosphorylation Play Production Quality of life RANTES Recurrence Relative (related person)Resistance Resistance development Role Sampling Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Source Staging Steroid Resistance Steroid-resistant asthma Structure Supplementation System TNF gene Techniques Testing Therapeutic Vitamin D Vitamin D Deficiency Vitamin D2 Vitamin D3 Receptor Vitamins Wheezing age related airway inflammation asthmatic base chemokine cohort cytokine fetal fluticasone in vitro Model in vivo in vivo Model insight interest mouse model neonate novel novel therapeutics pre-clinical prednisolone premature public health relevance respiratory smooth muscle

项目摘要

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.

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一个重要临床问题，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。尽管皮质类固醇可有效减轻炎症，但仍有相当一部分儿童因哮喘控制不佳而出现皮质类固醇不敏感。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，而补充维生素 D 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/小儿哮喘中的作用尚不清楚。我们的目标是确定在气道发育炎症背景下与皮质类固醇不敏感和维生素 D 相关的分子机制。使用发育中的人类气道的体外模型，我们将检验以下假设：(1) 炎症导致皮质类固醇不敏感，以及 (2) 维生素 D 增强皮质类固醇对炎症的抑制作用。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补充维生素的新治疗策略。