Ionic currents in gastrointestinal smooth muscle

胃肠平滑肌中的离子电流

• 批准号: 7929151
• 负责人: HAMID I AKBARALI
• 金额: $ 10.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929151
• 关键词: ATP sensitive potassium channel complex; Affect; Binding; Binding Sites; Biochemical; Calcium; Calcium Channel; Cells; Clinical; Colitis; Colon; Data; Disease; Down-Regulation; Experimental Models; Functional disorder; Funding; Gene Expression Profile; Gene Expression Regulation; Goals; Inflammation; Inflammatory Bowel Diseases; Ion Channel; Kinetics; Molecular; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Muscle; Phosphoric Monoester Hydrolases; Potassium Channel; Property; Protein Isoforms; Protein Tyrosine Kinase; Proteins; Recurrence; Regulation; Role; Smooth Muscle; Smooth Muscle Myocytes; Sodium Dextran Sulfate; Testing; Therapeutic Agents; Tissues; Ulcerative Colitis; Up-Regulation; base; cell motility; gastrointestinal; mRNA Expression; novel therapeutics; protein-tyrosine kinase c-src; receptor coupling

DESCRIPTION (provided by applicant): The long-term goals of this study are to define the changes in ion channel activity in colonic inflammation. Ulcerative colitis is an inflammatory bowel disease characterized by recurrent episodes of colonic inflammation and tissue degeneration. The main hypothesis to be tested is that inflammation induces specific changes in ion channels within the circular smooth muscle cells resulting in decreased cell excitability and contraction. Preliminary data demonstrate down-regulation of L-type calcium currents and an up-regulation of the ATP-sensitive potassium channels in the murine colonic smooth muscle myocytes from the dextran sulphate -sodium (DSS) model of experimental colitis. Specific Aim 1 is to define the cellular basis of altered calcium channel function in the DSS -treated mice colon. In this aim, we will determine the changes in the biophysical properties, protein and gene expression and regulation by tyrosine kinase of the calcium channels with inflammation. We will also define the minimal binding domain for c-src kinase on the carboxy-terminus of the calcium channel. In specific aim, 2 we will determine the mechanisms associated with the enhanced activity of the ATP-sensitive potassium channel. We will identify the isoforms comprising this channel and define the changes in isoform expression levels with inflammation. Specific Aim 3 is to determine the functional effects of altered ion channel activity in whole tissue segments. This aim will integrate the findings of single channel modulation on whole tissue function following inflammation. Preliminary data indicate that enhanced sensitivity to the potassium channel openers observed in single channel studies correlate with increased hyperpolarization of whole tissue segments of colonic smooth muscle. The information obtained from these studies will increase our understanding of the potential changes in ion channel activity with inflammation and help identify novel therapeutic agents in the treatment of motility disturbances in the pathophysiology of the colon.

描述（由申请人提供）：本研究的长期目标是确定结肠炎症中离子通道活性的变化。 溃疡性结肠炎是一种炎症性肠病，其特征是反复发作的结肠炎症和组织变性。 要测试的主要假设是炎症会引起圆形平滑肌细胞内离子通道的特定变化，导致细胞兴奋性和收缩性降低。 初步数据表明，实验性结肠炎的葡聚糖硫酸钠 (DSS) 模型中，小鼠结肠平滑肌细胞中 L 型钙电流下调，ATP 敏感钾通道上调。 具体目标 1 是确定 DSS 处理的小鼠结肠中钙通道功能改变的细胞基础。 为此，我们将确定炎症过程中钙通道的生物物理特性、蛋白质和基因表达以及酪氨酸激酶的调节的变化。 我们还将定义钙通道羧基末端 c-src 激酶的最小结合域。 具体目标 2 我们将确定与 ATP 敏感钾通道活性增强相关的机制。 我们将鉴定包含该通道的同种型，并定义同种型表达水平随炎症的变化。 具体目标 3 是确定整个组织片段中离子通道活性改变的功能影响。 这一目标将整合单通道调节对炎症后整个组织功能的研究结果。 初步数据表明，在单通道研究中观察到的钾通道开放剂敏感性增强与结肠平滑肌整个组织片段的超极化增强相关。 从这些研究中获得的信息将增加我们对离子通道活性随炎症的潜在变化的理解，并有助于确定治疗结肠病理生理学运动障碍的新治疗药物。