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

• 批准号: 9977239
• 负责人: Rodney Britt
• 金额: $ 27.78万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977239
• 关键词: Adrenal Cortex Hormones; Adult; Adult asthma; Agonist; Airway Disease; Allergens; Anti-Inflammatory Agents; 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; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Healthcare; Histology; Histone Acetylation; Histone Deacetylase; Human; IL8 gene; Immunology; Impairment; In Vitro; Inflammation; Inflammatory; Interferon Type II; Life; Link; Lung; Lung diseases; Lymphocyte; Matrix Metalloproteinases; Mediating; Mentors; Molecular; Mus; Neonatal; Newborn Infant; Nuclear Translocation; Pathway interactions; Phase; Play; Pregnancy; Publishing; RANTES; Receptor Signaling; Recovery; Research; Research Personnel; Resistance; Respiratory physiology; Role; Signal Transduction; Smooth Muscle Myocytes; 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

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.

项目摘要/摘要 申请人的目标是发展必要的技能，成为独立的翻译 新生儿/小儿哮喘领域的研究人员。童年哮喘在生命的早期发展是主要的医疗保健 负担。皮质类固醇（CS）用于治疗，但与成年人相比，儿童需要更高的C剂量， 一些难以治疗的气道重塑的CS阻力。基础机制 CS在开发气道中的不敏感性在很大程度上是未知的。气道平滑肌（ASM）是关键单元格 哮喘并表现出对炎症的反应性（AHR），增殖和重塑。有 目前，关于发展ASM如何促进新生儿/小儿哮喘或CS耐药性的信息很少。 总体假设是，Th1注射（TNFα，IFNγ）在发育的气道中引起CS不敏感性 破坏糖皮质激素受体的表达和信号传导，从而增强ASM增殖和重塑。 在潜在疗法方面，有越来越多的证据表明维生素D（VITD）增强CS敏感性，但几乎没有 没有有关潜在机制的信息，特别是在开发气道方面（该提案的第二个重点）。通过3 目的，申请人将逐步建立研究独立性，以调查CS不敏感性 新生儿/小儿哮喘：AIM 1（K99期）：使用Th1诱导CS不敏感性的体外模型，确定 炎症会抑制人类ASM的GR信号传导和活性的机制。 AIM 2（K99/R00 阶段）：使用Th1诱导的CS不敏感性的体外模型决定了VITD增强的机制 发展人类ASM中的GR信号。特定目标3（R00阶段）：在新颖的CS不敏感与敏感的情况下 过敏性气道注射的新生小鼠模型，确定CS与钙三醇之间的相互作用 减轻AHR和重塑。修补阶段将检查Th1细胞因子如何破坏CS信号传导 人类胎儿ASM（妊娠18-22周）。申请人将接受调查细胞，分子和 通过新生儿CS不敏感性的体外模型与糖皮质激素受体信号相关的表观遗传机制 涉及Th1细胞因子。互补的教学，智力和专业培训将有助于准备 R00阶段的申请人，他将检查与VITD如何增强CS灵敏度有关的机制 使用体外和新型的CS不敏感性的体内新生小鼠模型开发ASM。这些小说在一起 研究将增强人们对生命早期炎症如何破坏糖皮质激素受体的理解 信号传导，并将确定VITD提高CS灵敏度的潜力。申请人将由高级考虑 已建立的研究人员在ASM生理学，肺免疫学，糖皮质激素信号传导方面具有丰富的专业知识， 和哮喘。重要的是，该项目将为申请人建立独立研究提供基础 新生儿/小儿气道疾病的计划。

项目成果

Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation.

• DOI: 10.3389/fphar.2022.855247
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Lewis, Brandon W.;Ford, Maria L.;Khan, Aiman Q.;Walum, Joshua;Britt, Rodney D., Jr.
• 通讯作者: Britt, Rodney D., Jr.