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Glucocorticoid receptor translational isoforms in asthma

哮喘中的糖皮质激素受体翻译亚型

基本信息

批准号：
8448648
负责人：
NICK LU
金额：
$ 35.58万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448648
关键词：
Adrenal Glands Adverse effects Animals Anti-Inflammatory Agents Anti-inflammatory Antigens Apoptosis Asthma Biological Models Bone Marrow CD4 Positive T Lymphocytes Cell Line Cell model Cells Data Dendritic Cells Development Disease Drug Targeting Drug or chemical Tissue Distribution Eukaryotic Initiation Factors Gene Expression Gene Expression Regulation Glucocorticoid Receptor Glucocorticoid-induced apoptosis Glucocorticoids Goals Helper-Inducer T-Lymphocyte Immune Immunity Immunosuppressive Agents Individual Inflammation Inflammatory Inflammatory Response Informatics Ligands Lipopolysaccharides Lung Mediastinal lymph node group Mediating Messenger RNA Metabolic syndrome Modeling Mus Odds Ratio Osteoblasts Osteoporosis Pattern Pharmaceutical Preparations Pituitary Gland Play Production Protein Isoforms Regulation Regulatory T-Lymphocyte Resistance Role Scanning Sentinel Staging Stimulus T-Lymphocyte T-Lymphocyte Subsets Testing Toll-like receptors Translations Work abstracting airborne allergen base cell type cytokine design improved killings pathogen respiratory risk benefit ratio selective expression stable cell line therapy development translation factor uptake

项目摘要

Abstract: Glucocorticoids are indispensable in the treatment of asthma and other inflammatory diseases although side effects such as hypothalamo-pituitary-adrenal suppression, metabolic syndrome, and osteoporosis limit their use. Our goal is to understand the mechanisms by which the glucocorticoid receptor (GR) mediates cell-specific functions, as this information may be useful in the development of treatments for asthma with improved efficacy/risk ratios. We have recently discovered that the GR has eight distinct translational isoforms expressed variably in a wide range of cell types. These GR isoforms have profoundly different effects on gene expression. We hypothesize that selective GR translational isoforms mediate distinct sensitivities to glucocorticoid-induced apoptosis and regulate cell-specific inflammatory responses in T cell and dendritic cell subsets that are crucial in asthma. We propose that inflammatory stimuli selectively regulate GR isoforms via translational mechanisms. To test these hypotheses, we will examine primary T cells and dendritic cells obtained from a murine asthma model, cell lines expressing individual GR isoforms, and bone marrow-derived dendritic cells. Studies in Aim 1 will determine in a murine asthma model the identity and function of GR translational isoforms in helper T cells that are sensitive and regulatory T cells (Tregs) that are resistant to glucocorticoid-induced apoptosis. Our preliminary data indicate that helper T cells express predominantly the proapoptotic GR-A isoform whereas Tregs have predominantly the GR-D isoforms that are incapable of inducing apoptosis in osteoblast and T cell model systems. We will determine the role of selective GR isoforms in T cell subset-specific functions and glucocorticoid sensitivities. Studies in Aim 2 will determine the identity and function of GR translational isoforms in immature and mature dendritic cells that also have distinct sensitivities to glucocorticoid-induced apoptosis. Our preliminary data indicate that immature dendritic cells switch from the GR-D isoforms to expressing the GR-A isoform after maturation. The role of GR isoforms in distinct glucocorticoid sensitivities of immature (insensitive) and mature (sensitive) dendritic cells and in maturational-stage specific functions will be determined. Studies in Aim 3 will determine the role of translation machinery in regulating the expression of selective GR isoforms. Our previous studies indicate that the GR translational isoforms are produced from a single species of mRNA via ribosomal leaky scanning and ribosomal shunting. Based on our preliminary results, we will focus on the role of eukaryotic initiation factors in selective expression of GR isoforms. These studies will improve our understanding of the cell-specific actions of GR translational isoforms in asthma. Selective GR isoforms are anticipated to mediate cell-specific sensitivities to glucocorticoids and regulate cell- specific functions. In addition, these studies may provide a basis for the development of anti- inflammatory drugs targeting or altering the expression of selective GR isoforms.

摘要：糖皮质激素在哮喘等炎症性疾病的治疗中是不可缺少的虽然副作用，如下丘脑-垂体-肾上腺抑制，代谢综合征，骨质疏松症限制了它们的使用。我们的目标是了解糖皮质激素受体 (GR)介导细胞特异性功能，因为这些信息可能有助于开发治疗哮喘，改善疗效/风险比。我们最近发现GR有八个不同的翻译异构体在广泛的细胞类型中表达。这些GR亚型具有深刻的对基因表达的不同影响。我们假设选择性GR翻译异构体介导对糖皮质激素诱导的细胞凋亡和调节细胞特异性炎症反应的不同敏感性 T细胞和树突状细胞亚群的反应在哮喘中至关重要。我们认为，刺激通过翻译机制选择性调节GR亚型。为了验证这些假设，我们将检测从小鼠哮喘模型获得的原代T细胞和树突状细胞，表达单个GR同种型和骨髓来源的树突状细胞。目标1中的研究将在小鼠中确定哮喘模型GR翻译亚型的身份和功能的辅助T细胞，是敏感的，调节性T细胞（Tcells）对糖皮质激素诱导的细胞凋亡具有抗性。我们的初步数据显示辅助性T细胞主要表达促凋亡GR-A同种型，而T细胞主要表达促凋亡GR-A同种型， GR-D同种型不能在成骨细胞和T细胞模型系统中诱导凋亡。我们将确定选择性GR亚型在T细胞亚群特异性功能和糖皮质激素敏感性中的作用。目标2中的研究将确定GR翻译异构体在未成熟和成熟细胞中的身份和功能。树突状细胞也对糖皮质激素诱导的凋亡具有不同的敏感性。我们的初步数据表明未成熟树突状细胞从GR-D同种型转变为表达GR-A同种型，成熟糖皮质激素受体亚型在未成熟（不敏感）和成熟的糖皮质激素敏感性中的作用（敏感的）树突细胞和成熟阶段的特异性功能将被确定。目标3中的研究将确定翻译机制在调节选择性GR亚型表达中的作用。我们以前的研究表明，GR翻译同种型是由单一种类的mRNA通过核糖体介导产生的。泄漏扫描和核糖体分流。根据我们的初步结果，我们将重点讨论真核生物起始因子在GR亚型选择性表达中的作用。这些研究将改善我们的了解哮喘中GR翻译亚型的细胞特异性作用。选择性GR 预期同种型介导细胞对糖皮质激素的特异性敏感性，并调节细胞对糖皮质激素的敏感性。具体功能。此外，这些研究可能为开发抗- 靶向或改变选择性GR同种型表达的炎性药物。