Potassium Channels and Control of Cardiovascular Function

钾通道与心血管功能的控制

• 批准号: 10335188
• 负责人: Colin G Nichols
• 金额: $ 91.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335188
• 关键词: ATP sensitive potassium channel complex; Address; Adult; Animal Model; Animals; Biochemical; Biological; Blood Circulation; Blood Vessels; Cantu syndrome; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Cells; Clinic; Data; Development; Genetically Modified Animals; Goals; Human; Individual; Ion Channel; Link; Lipids; Lymphedema; Metabolism; Molecular; Mutation; Myocardium; Nature; Pathologic; Pathology; Pericardial effusion; Pharmacology; Physiological; Polyamines; Potassium Channel; Proteins; Regulation; Research; Role; Site; Smooth Muscle; Testing; Work; cell motility; fetal; human disease; interest; neonatal death; novel

ABSTRACT My lab studies the mechanistic basis, and functional consequences, of ion channels, particularly background inward rectifier and ATP-sensitive potassium channels, that are found throughout the cardiovascular system. Our work integrates studies at multiple levels, from the fundamental molecular basis of channel activity to animal models of pathologies associated with human disease. We are interested in how channels are constructed and function, how they regulate individual smooth and cardiac muscles, and how altered channel function contributes to the pathological consequences of aberrant function in the cardiovascular system. Previously, we discovered that soluble cytoplasmic polyamines cause inward rectification and demonstrated their mechanism and sites of action in Kir channels. We have developed the capability to purify Kir and ATP-sensitive (KATP) channels and to analyze these proteins structurally, biochemically and functionally. This allows us to develop and address exciting new questions and hypotheses regarding the fundamental basis of Kir and KATP channel activity, including the molecular mechanisms by which lipids regulate gating and the dynamic structural changes that accompany gating. KATP channels link metabolism to electrical activity in cardiac and smooth muscle. Our recent findings regarding a causal role of KATP channel mutations in human Cantu Syndrome (CS) reveal multiple pathological consequences of underexcitability, including persistence of fetal circulation, pericardial effusion, lymphedema, decreased vascular compliance and decreased gut motility. Development of unique and novel genetically modified animals, as well as a unique research CS clinic, has allowed us to generate extensive preliminary data that begin to explain such features, and leads us to novel hypotheses which will be explored using multiple cell biological and physiological approaches in animals and humans to reach a full understanding of the nature and role of KATP dependent excitability in regulation of cardiovascular function. These studies will form the background to the testing of relevant pharmacological approaches to CS therapy in animal models and in humans, with the ultimate goal of developing a specific therapy for CS and related pathologies.

抽象的 我的实验室研究离子通道的机制基础和功能后果，特别是背景 内向整流器和 ATP 敏感钾通道，遍布整个心血管系统。 我们的工作整合了多个层面的研究，从通道活动的基本分子基础到 与人类疾病相关的病理学动物模型。我们感兴趣的是渠道如何 构造和功能，它们如何调节个体平滑肌和心肌，以及如何改变通道 功能导致心血管系统功能异常的病理后果。 此前，我们发现可溶性细胞质多胺会引起内向整流，并证明了它们的作用 Kir 通道的机制和作用位点。我们已经开发出纯化 Kir 和 ATP 敏感的能力 (KATP) 通道并从结构、生化和功能上分析这些蛋白质。这使我们能够 开发并解决有关 Kir 和 KATP 基础的令人兴奋的新问题和假设 通道活性，包括脂质调节门控的分子机制和动态结构 伴随门控的变化。 KATP 通道将新陈代谢与心肌和平滑肌的电活动联系起来。 我们最近关于 KATP 通道突变在人类坎图综合症 (CS) 中的因果作用的发现揭示了 兴奋性不足的多种病理后果，包括胎儿循环持续、心包 积液、淋巴水肿、血管顺应性降低和肠道蠕动降低。开发独特且 新颖的转基因动物以及独特的研究 CS 诊所使我们能够产生广泛的 初步数据开始解释这些特征，并引导我们提出将要探索的新假设 在动物和人类中使用多细胞生物学和生理学方法来充分了解 KATP 依赖性兴奋性在心血管功能调节中的性质和作用。这些研究将形成 在动物模型和实验中测试 CS 治疗相关药理学方法的背景 人类，最终目标是开发针对 CS 和相关病理的特定疗法。