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

• 批准号: 10408754
• 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
• 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/10408754
• 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 diseases; Mediator of activation protein; Mission; Mus; Myofibroblast; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Potassium; Potassium Channel; Public Health; Publications; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; 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

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.

项目摘要 尽管了解肺纤维化的发病机理的重大进展，但许多疗法 针对最深思的基因和途径，在逆转或 甚至停止疾病进展。这是特发性患者的临床异质性 肺纤维化（IPF），表明疾病发病机理模型中其他基因的考虑可能是 有用。来自IPF患者的成纤维细胞在许多基因的表达上与正常相比不同 成纤维细胞，该实验室对确定表观遗传变化有很长的兴趣 对于这些差异。 KCNMB1代码大型电导的β亚基（BK，Maxi-K，KCA1.1） 钾通道，并在我们以前的微阵列研究中被鉴定为顶部差异甲基化基因 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 语调和平滑肌肉生物学，但从未研究过其在纤维化中的重要性。我们最近显示 在1）IPF患者成纤维细胞中增加KCNMB1表达的出版物，2）KCNMB1 有助于增加BK通道活动，3）BK通道的功能增加促进肌纤维细胞 差异化，IPF的标志。这样做的方法以及这是否足以促进或恶化肺部 体内纤维化尚不清楚。这笔赠款的目标是确定BK通道的机制 有助于肌纤维细胞分化，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的表观遗传上调并增加了BK 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促进肺纤维化， 导致肌纤维细胞的分化。第一个目的是确定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 目的是描述BK通道有助于肌纤维细胞分化的机制 BK通道促进细胞内钙信号的假设，这对于分化为 肌纤维细胞。第三个目的是确定如何在肺成纤维细胞中调节KC​​NMB1的表达 纤维化刺激如何调节BK通道的打开和关闭。该提议很重要，因为它 在肺纤维化发病机理中建立BK通道是一种新颖但重要的驱动力。 实现这些目标还将确定BK渠道在区分中的机制和作用 以前从未描述过的肌纤维细胞。最终，这些研究将有助于确定新的 未来IPF治疗剂的目标。