Steroid resistance of airway ILC2s

气道 ILC2 的类固醇抵抗

基本信息

批准号：
9914206
负责人：
Rafeul Alam
金额：
$ 45.4万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914206
关键词：
Abbreviations Acute Address Affect Airway Resistance Allergens Animal Model Antibodies Asthma Autoimmune Process B-Cell Lymphomas BMI1 gene Biological Blood Bronchoalveolar Lavage Cell Nucleus Cells Chronic Clinical Clinical Trials Complex Cytosol Development Dexamethasone Disease Epithelial Epithelium Exposure to Flow Cytometry Frequencies Genes Genetic Transcription Genomic approach Glucocorticoid Receptor Glucocorticoids Growth Factor Homologous Gene Human IL5 gene IL7 gene Immune response Immunodeficient Mouse In Vitro Inflammatory Interleukin-13 Leukemic Lymphocyte Lung Lymphoid Cell MAP Kinase Gene MAPK3 gene MEKs Mediator of activation protein Medical Care Costs Modality Modeling Molecular Moloney Leukemia Virus Mus Paper Pathway interactions Patients Phosphotransferases Play Polycomb Public Health Reporting Repressor Proteins Resources Retinoids Rhinovirus Role STAT protein Signal Pathway Signal Transduction Signaling Molecule Societies Source Steroid Receptors Steroid Resistance Steroid-resistant asthma Steroids Subgroup T-Lymphocyte TSLP gene Testing Th2 Cells Therapeutic Therapeutic Agents Therapeutic Intervention Thyroid Hormone Receptor Tumorigenicity Up-Regulation Virus Diseases Western Blotting airway hyperresponsiveness asthma model asthmatic patient base cost cytokine experimental study fMet-Leu-Phe receptor functional genomics genetic corepressor high risk human disease humanized mouse in vivo inhibitor/antagonist member mouse model neoplastic novel novel therapeutics preclinical study preclinical trial public health relevance receptor recruit resistance gene

项目摘要

Abstract: The glucocorticoid-type steroids are the mainstay of asthma therapy. A subgroup of asthmatic patients develops steroid resistance, which becomes a major therapeutic challenge and imposes a high cost to the society. An understanding the mechanism of steroid resistance is important. Asthma is driven by the type 2 immune response. Type 2 innate lymphoid cells (ILC2s) are an important source of type 2 cytokines. Two epithelial cytokines—IL33 and TSLP promote the development and function of ILC2s. We have recently reported that airway ILC2s, as compared to blood ILC2s, from a subgroup of asthmatic patients are steroid resistant in a TSLP (thymic stromal lymphopoietin)-dependent manner. Blood ILC2s become steroid resistant when exposed to TSLP but not IL33. We have uncovered a mechanism for this dichotomous effect. Steroids upregulate (protagonize) the receptors for TSLP but not IL33. By upregulating the receptors steroids lower their activation threshold. Steroids still antagonize many inflammatory pathways in these cells but, surprisingly, protagonize the pathways that directly interfere with the formation of the glucocorticoid receptor repressor complex. Consequently, these pathways upregulate type 2 cytokines unabated in the presence of steroids, which results in steroid resistance. Based upon these findings we hypothesize that activation of steroid protagonized receptors induces steroid resistance through upregulation of select signaling pathways that disrupt the formation of the glucocorticoid receptor (GR) repressor complex. We propose 3 specific aims to test the foregoing hypothesis. Under specific aim 1 we will study the molecular mechanism of TSLP-induced steroid resistance of ILC2s. We will examine how a novel signaling pathway involving MEK2-CBX7-PRC1, identified in preliminary experiments, hinders the organization of the GR repressor complex. We will use human blood and lung ILC2s to maintain human disease relevance. Specific aim 2 is devoted to mechanistic and preclinical studies in mice. We will examine how repetitive exposure to allergens and rhinovirus contributes to the development of steroid resistance. We will use genetically modified mice to validate the importance of steroid resistant pathways. We will perform preclinical trials with pathway inhibitors in a humanized mouse model of steroid resistant asthma. Under specific aim 3 we will establish the relevance of TSLP and TSLPR signaling molecules for steroid resistance by studying bronchoalveolar lavage ILCs and T cells from steroid resistant and steroid sensitive asthmatic patients. We will evaluate pathway inhibitors for reversal of steroid resistance of airway lymphoid cells. We have all the necessary expertise, resources and collaborators to accomplish this project. The proposal is important because it addresses an unresolved clinical problem that affects not only asthma but also many chronic inflammatory, autoimmune and neoplastic diseases where steroid resistance is a therapeutic challenge. A successful completion of this project will help develop novel therapeutic modalities targeting steroid resistance, in general.

抽象的：糖皮质激素类固醇是哮喘患者的主要治疗方法。产生类固醇耐药性，这成为主要的治疗挑战并给患者带来高昂的成本了解类固醇耐药的机制很重要。 2 型先天淋巴细胞 (ILC2) 是 2 型细胞因子的重要来源。上皮细胞因子——IL33 和 TSLP 促进 ILC2 的发育和功能。报道称，与血液 ILC2 相比，来自哮喘患者亚组的气道 ILC2 属于类固醇以 TSLP（胸腺基质淋巴细胞生成素）依赖性方式产生耐药性血液 ILC2 变得对类固醇耐药。当暴露于 TSLP 而不是 IL33 时，我们发现了这种二分效应的机制。上调（主导）TSLP 受体，但不上调 IL33 受体。它们的激活阈值仍然拮抗这些细胞中的许多炎症途径，但令人惊讶的是，主导直接干扰糖皮质激素受体阻遏物形成的途径经过测试，这些途径在类固醇存在的情况下上调 2 型细胞因子，这会导致类固醇抵抗。根据这些发现，我们捕获了类固醇的激活。主角受体通过上调选择的信号通路诱导类固醇抵抗破坏糖皮质激素受体 (GR) 阻遏复合物的形成我们提出了 3 个具体的测试目标。在具体目标1下，我们将研究TSLP诱导的分子机制。我们将研究涉及 MEK2-CBX7-PRC1 的新信号通路，初步实验中发现，它会阻碍 GR 阻遏物复合体的组织。人类血液和肺 ILC2 维持人类疾病相关性具体目标 2 致力于机制。我们将研究小鼠如何重复接触过敏原和鼻病毒。有助于类固醇耐药性的发展，我们将使用转基因小鼠来验证。我们将使用途径抑制剂进行临床前试验。在具体目标 3 下，我们将建立类固醇抵抗性哮喘的人源化小鼠模型。通过研究支气管肺泡灌洗 ILC 和 T 来研究类固醇抵抗的 TSLP 和 TSLPR 信号分子我们将评估来自类固醇抗性和类固醇敏感性哮喘患者的细胞。我们拥有所有必要的专业知识、资源和逆转气道淋巴细胞的类固醇耐药性。该提案很重要，因为它解决了一个未解决的临床问题。这个问题不仅影响哮喘，还影响许多慢性炎症、自身免疫和肿瘤疾病类固醇耐药性是治疗挑战的疾病，该项目的成功完成将有所帮助。一般来说，开发针对类固醇耐药性的新治疗方式。