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.
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.
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