Enhancing Corticosteroid Sensitivity in Neonatal and Pediatric Lung Disease

增强新生儿和小儿肺部疾病中皮质类固醇的敏感性

基本信息

批准号：
9312919
负责人：
Rodney Britt
金额：
$ 15.03万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312919
关键词：
Adrenal Cortex Hormones Adult Adult asthma Agonist Allergens Anti-Inflammatory Agents Anti-inflammatory Area Asthma Binding CXCL10 gene Calcitriol Child Childhood Childhood Asthma Chronic Clinical Clinical Research Collagen Cytokine Signaling Data Deposition Development Disease Dose Epigenetic Process Exhibits Extracellular Matrix Extrinsic asthma Fetus Fibronectins Fluticasone propionate Foundations Gene Targeting Genes Glucocorticoid Receptor Glucocorticoids Goals Growth Healthcare Histology Histone Acetylation Human IL8 gene Immunology Impairment In Vitro Inflammation Inflammatory Interferon Type II Life Link Lung Lung diseases Lymphocyte Matrix Metalloproteinases Mediating Mentors Molecular Mus Muscle Cells Neonatal Newborn Infant Nuclear Translocation Pathway interactions Phase Play Pregnancy Publishing RANTES Receptor Signaling Recovery Research Research Personnel Resistance Respiratory physiology Role Signal Transduction Structure TNF gene Testing Therapeutic Therapeutic Uses Training Transactivation Vitamin D Vitamin D Deficiency Vitamin D supplementation Vitamin D3 Receptor Wheezing Work airway inflammation airway remodeling allergic airway inflammation asthmatic cell type clinically significant cytokine fetal improved in vitro Model in vivo inflammatory milieu laser capture microdissection mouse model muscle form muscle physiology neonate novel novel therapeutics programs promoter receptor expression respiratory smooth muscle response skills translational scientist

项目摘要

PROJECT SUMMARY/ABSTRACT The applicant's goals are to develop the necessary skills to become an independent translational researcher in the area of neonatal/pediatric asthma. Childhood asthma developing early in life is a major healthcare burden. Corticosteroids (CS) are used therapeutically, but compared to adults, children require higher CS doses, and some develop CS resistance with greater airway remodeling that is difficult to treat. The mechanisms underlying CS insensitivity in developing airway are largely unknown. Airway smooth muscle (ASM) is a key cell type in asthma, and exhibits hyperreactivity (AHR), proliferation, and remodeling in response to inflammation. There is currently little information on how developing ASM contributes to neonatal/pediatric asthma, or to CS resistance. The overall hypothesis is that Th1 inflammation (TNFα, IFNγ) induces CS insensitivity in developing airway by disrupting glucocorticoid receptor expression and signaling, leading to enhanced ASM proliferation and remodeling. In terms of potential therapy, there is increasing evidence for Vitamin D (VitD) enhancing CS sensitivity, but little to no information on underlying mechanisms, particularly in developing airway (a second focus of this proposal). Via 3 Aims, the applicant will progressively build towards research independence investigating CS insensitivity in neonatal/pediatric asthma: Aim 1 (K99 Phase): Using an in vitro model of Th1 induced CS insensitivity, determine mechanisms by which inflammation inhibits GR signaling and activity in developing human ASM. Aim 2 (K99/R00 Phases): Using an in vitro model of Th1 induced CS insensitivity determine mechanisms by which VitD enhances GR signaling in developing human ASM. Specific Aim 3 (R00 Phase): In novel CS-insensitive vs. –sensitive newborn mouse models of allergic airway inflammation, determine interactions between CS and calcitriol in alleviating AHR and remodeling. The mentored phase will examine how Th1 cytokines disrupt CS signaling in human fetal ASM (18-22 week gestation). The applicant will receive training in investigating cellular, molecular, and epigenetic mechanisms related to glucocorticoid receptor signaling via an in vitro model of neonatal CS insensitivity involving Th1 cytokines. Complementary didactic, intellectual, and professional training will help prepare the applicant for the R00 phase where he will examine mechanisms relating to how VitD may enhance CS sensitivity in developing ASM using in vitro and novel in vivo neonatal mouse models of CS insensitivity. Together, these novel studies will enhance current understanding of how inflammation early in life disrupts glucocorticoid receptor signaling, and will identify the potential for VitD to improve CS sensitivity. The applicant will be mentored by senior, established investigators with substantial expertise in ASM physiology, lung immunology, glucocorticoid signaling, and asthma. Importantly, this project will provide a foundation for the applicant to establish an independent research program in neonatal/pediatric airway disease.

项目概要/摘要申请人的目标是培养成为独立翻译人员所需的技能新生儿/小儿哮喘领域的研究人员，生命早期发生的儿童哮喘是一个主要的医疗保健问题。皮质类固醇 (CS) 用于治疗，但与成人相比，儿童需要更高的 CS 剂量，有些人会出现气道重塑严重的 CS 抵抗，而这背后的机制是难以治疗的。气道发育中的 CS 不敏感性很大程度上是未知的。哮喘，并表现出对炎症反应的高反应性（AHR）、增殖和重塑。目前关于 ASM 的发展如何导致新生儿/儿童哮喘或 CS 抵抗的信息很少。总体假设是 Th1 炎症（TNFα、IFNγ）通过以下方式诱导气道发育中的 CS 不敏感：破坏糖皮质激素受体的表达和信号传导，导致 ASM 增殖和重塑增强。就潜在疗法而言，越来越多的证据表明维生素 D (VitD) 可以增强 CS 敏感性，但几乎没有证据表明维生素 D (VitD) 可以增强 CS 敏感性。没有关于基本机制的信息，特别是在气道发育方面（该提案的第二个重点）。目标是，申请人将逐步建立研究独立性，调查 CS 不敏感性新生儿/小儿哮喘：目标 1（K99 阶段）：使用 Th1 诱导的 CS 不敏感体外模型，确定炎症抑制人类 ASM 发育过程中 GR 信号传导和活性的机制 (K99/R00. 阶段）：使用 Th1 诱导的 CS 不敏感机制的体外模型确定 VitD 的增强作用人类 ASM 中 GR 信号传导的发展（R00 阶段）：在新型 CS 不敏感与敏感中。过敏性气道炎症的新生小鼠模型，确定 CS 和骨化三醇之间的相互作用减轻 AHR 和重塑的指导阶段将研究 Th1 细胞因子如何破坏 CS 信号传导。人类胎儿 ASM（妊娠 18-22 周）申请人将接受细胞、分子和细胞研究方面的培训。通过新生儿 CS 不敏感体外模型研究与糖皮质激素受体信号传导相关的表观遗传机制涉及 Th1 细胞因子的补充性教学、智力和专业培训将有助于做好准备。 R00 阶段的申请人，他将研究 VitD 如何增强 CS 敏感性的机制使用 CS 不敏感的体外和体内新生小鼠模型开发 ASM。研究将增强目前对生命早期炎症如何破坏糖皮质激素受体的理解信号，并将确定 VitD 提高 CS 敏感性的潜力申请人将得到资深人士的指导。建立了在 ASM 生理学、肺免疫学、糖皮质激素信号传导方面具有丰富专业知识的研究人员，重要的是，该项目将为申请人建立独立研究奠定基础。新生儿/儿童气道疾病计划。