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

描述(申请人提供)：由糖皮质激素受体(GR)信号抑制的炎症通路与哮喘的发病机制和糖皮质激素(GC)的治疗反应密切相关。同时，GCs诱导分解代谢途径，对新陈代谢、增殖和组织结构产生深远的影响。这些GC信号的分解代谢效应在肺中相对未知，可能与以增殖和过度增殖为特征的慢性哮喘气道平滑肌(ASM)重构的治疗有关。在这里，我们试图定义一个典型的GC信号分解代谢效应因子，一个被称为Klf15的锌指转录因子，I ASM和过敏性呼吸道疾病。有几条证据强烈表明Klf15既是GCs反应的关键中介，也是ASM生物学的新调节因子。首先，在体外培养的人ASM中，GCs能强烈诱导Klf15基因的表达。其次，Klf15活性调节至少5%的GC调节的转录组在小鼠肺中的表达，使Klf15成为GC下游转录效应的主要调节因子。第三，Klf15的过度表达减少了人类ASM的增殖和细胞大小，这与诱导促分解代谢的作用一致。第四，在急性过敏性呼吸道疾病的小鼠模型中，KLF15-/-小鼠 发生过敏性呼吸道炎症，与野生型小鼠难以区分，但它们显著降低了呼吸道高反应性，强烈暗示KLF15在调节气道功能中的作用。然而，KLF15作为糖皮质激素在ASM中的靶点和中介，以及在调节过敏性呼吸道疾病的呼吸道反应中的机制基础尚不清楚。这项建议的目的是：(1)确定GCs是否直接诱导GR诱导ASM中KLF15的表达，从而控制GCs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中的KLF15活性是否降低了过敏性呼吸道疾病模型中的气道高反应性并改变ASM的重塑。这一建议将提供对ASM中KLF15和GR活性的详细了解，并建立GCs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。这对于开发新的哮喘治疗药物具有广泛的意义，这些药物选择性地针对分解代谢途径来治疗严重的气道重塑。

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.