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The Role of KCNMB1 and the Large Conductance Potassium (BK) Channel in Myofibroblast Differentiation and Pulmonary Fibrosis

KCNMB1 和大电导钾 (BK) 通道在肌成纤维细胞分化和肺纤维化中的作用

基本信息

批准号：
10171415
负责人：
STEVEN K HUANG
金额：
$ 51.03万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10171415
关键词：
Animal Model Biology Bladder Blood Vessels Calcium Calcium Signaling Cicatrix Code Contracts Cytoplasm DNA Methylation Data Development Disease Disease Progression Disease model Drug Targeting Epigenetic Process Exhibits Extracellular Matrix Fibroblasts Fibrosis Future Gene Expression Genes Genome Goals Grant Ion Channel Laboratories Lead Literature Lung Lung Inflammation Lung diseases Mediator of activation protein Mission Mus Myofibroblast Pathogenesis Pathogenicity Pathway interactions Patients Play Potassium Potassium Channel Public Health Publications Publishing Pulmonary Fibrosis Relaxation Role Signal Transduction Smooth Muscle Smooth Muscle Actin Staining Method Stimulus Testing Therapeutic Time United States National Institutes of Health Up-Regulation Work cell type clinical heterogeneity effective therapy fibrogenesis idiopathic pulmonary fibrosis in vivo interest large-conductance calcium-activated potassium channels lung injury novel novel therapeutic intervention response success targeted treatment treatment strategy wound

项目摘要

PROJECT SUMMARY Despite major advances in the understanding of the pathogenesis of pulmonary fibrosis, many of the therapies that target the most well-studied genes and pathways have not achieved universal success in reversing or even halting disease progression. This, along with the clinical heterogeneity of patients with idiopathic pulmonary fibrosis (IPF), suggest that consideration of other genes in models of disease pathogenesis may be useful. Fibroblasts from patients with IPF differ in the expression of many genes compared to normal fibroblasts, and this laboratory has had a longstanding interest in identifying epigenetic changes that account for these differences. KCNMB1 codes for the beta subunit of the large conductance (BK, Maxi-K, KCa1.1) potassium channel and was identified in our previous microarray study as the top differentially methylated gene in IPF fibroblasts. BK channels modulate potassium current and are well known to be important in vascular tone and smooth muscle biology, but its importance in fibrosis has never been examined. We recently showed in a publication that 1) KCNMB1 expression is increased in fibroblasts from IPF patients, 2) KCNMB1 contributes to increased BK channel activity, and 3) increased function of BK channels promote myofibroblast differentiation, a hallmark of IPF. How it does so and whether this is sufficient to promote or worsen pulmonary fibrosis in vivo is unknown. The objectives of this grant are to determine the mechanism of how BK channels contribute to myofibroblast differentiation and establish the importance of BK channels to animal models of pulmonary fibrosis. Our central hypothesis is that the epigenetic upregulation of KCNMB1 and increased BK channel activity in IPF fibroblasts contribute to pulmonary fibrosis by promoting calcium signaling in fibroblasts, which lead to myofibroblast differentiation. The First Aim is to establish the importance of BK channels to the development of pulmonary fibrosis in vivo, and localize its pathogenic actions to lung fibroblasts. The Second Aim is to delineate the mechanism by which BK channels contribute to myofibroblast differentiation, with the hypothesis that BK channels promote intracellular calcium signaling, which is necessary for differentiation into myofibroblasts. The Third Aim is to determine how expression of KCNMB1 is regulated in lung fibroblasts and how profibrotic stimuli modulates opening and closing of BK channels. This proposal is significant because it establishes BK channels as a novel, but important driver in the pathogenesis of pulmonary fibrosis. Accomplishing these aims will also identify a mechanism and role for BK channels in the differentiation of myofibroblasts that has never been previously described. Ultimately, these studies will serve to identify new targets for future IPF therapeutics.

项目总结