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: 8459449
• 负责人: ANTHONY N GERBER
• 金额: $ 37.53万
• 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/8459449
• 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 Expression Profiling; 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.

描述（由申请人提供）：被糖皮质激素受体（GR）信号抑制的炎症通路与哮喘发病机制和糖皮质激素（GCs）的治疗反应密切相关。同时，GCs诱导分解代谢途径，对代谢、增殖和组织结构产生深远影响。这些GC信号的分解代谢结果在肺中相对未被探索，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信号的一个原型分解代谢效应，一个锌指转录因子Klf15，在ASM和过敏性气道疾病中的功能。一些证据强烈暗示Klf15既是对GCs反应的关键中介，也是ASM生物学的新调节剂。首先，在培养的人ASM中，GCs强烈诱导Klf15 mRNA和蛋白表达。其次，Klf15的活性调节了小鼠肺中至少5%的gc调控转录组的表达，这表明Klf15是gc下游转录效应的主要调节因子。第三，Klf15过表达降低人ASM增殖和细胞大小，与诱导促代谢作用一致。第四，在小鼠急性过敏性气道疾病模型中，Klf15-/-小鼠