Role of Klf15 in airway smooth muscle and the response to glucocorticoids

Klf15 在气道平滑肌中的作用以及对糖皮质激素的反应

• 批准号: 8298027
• 负责人: ANTHONY N GERBER
• 金额: $ 39.04万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298027
• 关键词: Acute; Address; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Architecture; Area; Asthma; Biology; Catabolism; Cell Cycle; Cells; Chronic; Data; Development; Disease; Disease model; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Growth; Health Expenditures; Homeostasis; Human; Hyperplasia; Inflammatory; Knock-out; Lead; Link; Lung; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Muscle; Muscle function; Output; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenocopy; Proteins; Publishing; Receptor Signaling; Repression; Research; Role; Signal Transduction; Site; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stress; Testing; Therapeutic; Tissues; United States; Viral; Wild Type Mouse; Work; Zinc Fingers; airway hyperresponsiveness; airway remodeling; allergic airway disease; allergic airway inflammation; asthmatic airway; base; chromatin immunoprecipitation; glucocorticoid-induced orphan receptor; in vivo; innovation; insight; mRNA Expression; muscle metabolism; novel; promoter; protein expression; respiratory smooth muscle; response; transcription factor

DESCRIPTION (provided by applicant): Inflammatory pathways that are repressed by glucocorticoid receptor (GR) signaling are strongly implicated in asthma pathogenesis and therapeutic responses to glucocorticoids (GCs). In parallel, GCs induce catabolic pathways that result in profound effects on metabolism, proliferation and tissue architecture. These catabolic consequences of GC signaling, which are relatively unexplored in the lung, may have relevance to the treatment of chronic asthmatic airway smooth muscle (ASM) remodeling, which is characterized by hyperplasia and hyperproliferation. Here we seek to define the function of a prototypical catabolic effector of GC signaling, a zinc-finger transcription factor termed Klf15, i ASM and allergic airway disease. Several lines of evidence strongly implicate Klf15 as both a key intermediary in responses to GCs and as a novel regulator of ASM biology. First, Klf15 mRNA and protein are strongly induced by GCs in culture human ASM. Second, Klf15 activity modulates the expresion of at least 5% of the GC-regulated transcriptome in murine lungs, establishing Klf15 as a major regulator of the downstream transcriptional effects of GCs. Third, Klf15 over- expression reduces human ASM proliferation and cel size, consistent with induction of pro-catabolic effects. Fourth, in a murine model of acute allergic airway disease, Klf15-/- mice develop allergic airway inflammation that is indistinguishable from wild type mice, but they have significantly decreased airway hyperresponsiveness, strongly implicating Klf15 in regulating airway function. However, the mechanistic basis for Klf15 as a target and intermediary of GCs in ASM, and in regulating airway responses in alergic airway disease are unknown. The goals of this proposal are: (1) to determine if GCs directly induce the GR to induce Klf15 expresion in ASM, thereby controlling downstream effects of GCs, (2) to determine mechanisms whereby Klf15 regulates gene expresion and proliferation in ASM, and (3) to test whether Klf15 activity specifically in ASM reduces airway hyperresponsivness and alters ASM remodeling in allergic airway disease models. This proposal will provide detailed insight into the mechanism of Klf15 and GR activity in ASM, and establish a molecular link between the activity of GCs in treating asthma and their potent pro-catabolic effects. This has broad implications for developing novel asthma therapeutics that selectively target catabolic pathways to treat severe airway remodeling. PUBLIC HEALTH RELEVANCE: In the United States, asthma afflicts over 20 million people and is associated with over 18 billion dollars in health care expenditures per annum. However, the molecular biology of the airway, which is the major site of asthma pathology, is not well understood, limiting development of new asthma therapies. By exploring the role of a gene termed Klf15 in the airway, and as a target of glucocorticoids, which are widely used to treat asthma, this grant will add to our knowledge of airway biology and therapeutics.

描述（由申请人提供）：受糖皮质激素受体（GR）信号传导抑制的炎症通路与哮喘发病机制和对糖皮质激素（GC）的治疗反应密切相关。与此同时，GC 诱导分解代谢途径，对代谢、增殖和组织结构产生深远影响。 GC 信号传导的这些分解代谢后果在肺部相对尚未被探索，可能与慢性哮喘气道平滑肌 (ASM) 重塑的治疗有关，其特征是增生和过度增殖。在这里，我们试图定义 GC 信号传导的原型分解代谢效应器、称为 Klf15 的锌指转录因子、i ASM 和过敏性气道疾病的功能。多项证据强烈表明 Klf15 既是 GC 反应的关键中介，又是 ASM 生物学的新型调节剂。首先，在人 ASM 培养物中，GC 强烈诱导 Klf15 mRNA 和蛋白。其次，Klf15 活性调节小鼠肺中至少 5% GC 调节的转录组的表达，从而确立 Klf15 作为 GC 下游转录效应的主要调节因子。第三，Klf15过度表达减少人ASM增殖和细胞大小，与促分解代谢作用的诱导一致。第四，在急性过敏性气道疾病的小鼠模型中，Klf15-/-小鼠 产生与野生型小鼠无法区分的过敏性气道炎症，但它们显着降低了气道高反应性，这与 Klf15 调节气道功能密切相关。然而，Klf15 作为 ASM 中 GC 的靶标和中介以及调节过敏性气道疾病的气道反应的机制基础尚不清楚。该提案的目标是：(1) 确定 GC 是否直接诱导 GR 诱导 ASM 中的 Klf15 表达，从而控制 GC 的下游效应，(2) 确定 Klf15 调节 ASM 中基因表达和增殖的机制，以及 (3) 测试 ASM 中特异的 Klf15 活性是否会降低气道高反应性并改变 ASM 过敏性气道疾病模型的重塑。该提案将详细了解 ASM 中 Klf15 和 GR 活性的机制，并建立 GC 治疗哮喘的活性与其强大的促分解代谢作用之间的分子联系。这对于开发选择性靶向分解代谢途径来治疗严重气道重塑的新型哮喘疗法具有广泛的意义。 公共健康相关性：在美国，哮喘困扰着超过 2000 万人，每年带来超过 180 亿美元的医疗保健支出。然而，作为哮喘病理学主要部位的气道的分子生物学尚不清楚，限制了新哮喘疗法的开发。通过探索 Klf15 基因在气道中的作用，以及作为广泛用于治疗哮喘的糖皮质激素的靶标，这笔资助将增加我们对气道生物学和治疗学的了解。