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.

项目概要尽管对肺纤维化发病机制的理解取得了重大进展，但许多治疗方法针对研究最充分的基因和途径的药物尚未在逆转或逆转方面取得普遍成功甚至阻止疾病进展。这以及特发性患者的临床异质性肺纤维化（IPF），表明在疾病发病机制模型中考虑其他基因可能是有用。与正常人相比，IPF 患者的成纤维细胞在许多基因的表达上存在差异成纤维细胞，该实验室长期以来一直对识别表观遗传变化感兴趣对于这些差异。 KCNMB1 编码大电导的 β 亚基（BK、Maxi-K、KCa1.1）钾通道，在我们之前的微阵列研究中被鉴定为顶级差异甲基化基因在 IPF 成纤维细胞中。 BK 通道调节钾电流，众所周知在血管中很重要张力和平滑肌生物学，但其在纤维化中的重要性从未被研究过。我们最近展示了在一篇出版物中指出：1) IPF 患者的成纤维细胞中 KCNMB1 表达增加，2) KCNMB1 有助于增加 BK 通道活性，3) BK 通道功能增强可促进肌成纤维细胞分化，IPF 的标志。它是如何做到这一点的以及这是否足以促进或恶化肺部疾病体内纤维化尚不清楚。这笔赠款的目标是确定 BK 渠道的机制有助于肌成纤维细胞分化并确定 BK 通道对动物模型的重要性肺纤维化。我们的中心假设是 KCNMB1 的表观遗传上调和 BK 增加 IPF 成纤维细胞中的通道活性通过促进成纤维细胞中的钙信号传导导致肺纤维化，从而导致肌成纤维细胞分化。第一个目标是确立 BK 渠道对体内肺纤维化的发展，并将其致病作用定位于肺成纤维细胞。第二个目的是描绘 BK 通道促进肌成纤维细胞分化的机制，其中假设 BK 通道促进细胞内钙信号传导，这是分化为细胞所必需的肌成纤维细胞。第三个目标是确定肺成纤维细胞中 KCNMB1 的表达是如何调节的促纤维化刺激如何调节 BK 通道的打开和关闭。这个提议很重要，因为它将 BK 通道确立为肺纤维化发病机制中新型但重要的驱动因素。实现这些目标还将确定 BK 渠道在差异化中的机制和作用。以前从未描述过的肌成纤维细胞。最终，这些研究将有助于确定新的未来 IPF 治疗的目标。