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Development and study of specific Kir channel inhibitors

特异性Kir通道抑制剂的开发与研究

基本信息

批准号：
7586210
负责人：
ZHE LU
金额：
$ 22.74万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586210
关键词：
Action Potentials Affect Affinity Animals Anthelmintics Anti-Arrhythmia Agents Arrhythmia Bees Biochemistry Cardiac Chimera organism Complement Development Electrolyte Balance Electrophysiology (science)Engineering Evolution Exhibits Future Gene Deletion Genetic Glutamates Goals Heart Diseases Hereditary Disease Honey Immunoglobulin Variable Region Individual Ion Channel Kidney Kir2.1 channel Length Libraries Medicine Molecular Biology Mus Mutate Mutation Outcome Perception Physiological Physiology Piperazines Play Polyamines Potassium Channel Preparation Property Proteins Refractory Research Research Design Research Personnel Resolution Role Safety Shapes Specificity Structure Syndrome System Testing Therapeutic Therapeutic Agents Tissues Toxin Uncertainty base cell type heart electrical activity inhibitor/antagonist mutant programs prototype tertiapin therapeutic target

项目摘要

The long-term goals of our research are to develop inhibitors specifically targeting individual subtypes of ion channels, to determine inhibitor-channel interaction mechanisms, and to use the inhibitors to examine channel physiology and demonstrate certain therapeutic concepts. Since inward-rectifier K+ (Kir) channels play many vital physiological roles and represent increasingly important therapeutic targets, subtype-specific Kir channel inhibitors are experimentally and therapeutically valuable. The studies proposed below will be carried out with a combined approach of electrophysiology, biochemistry, and molecular biology. Previously, we discovered that a 21-residue honey bee toxin, tertiapin (TPN), inhibits renal Kir1.1 and cardiac Kir3.1/3.4 channels with nanomolar affinity. In Aim#1, we will create inhibitors specific for Kir1.1 or Kir3.1/3.4. Our preliminary studies have not only identified the channel sequence that will allow the selective targeting of various Kir subtypes but also established the prototype for such a subtype-specific inhibitor. The resulting specific inhibitors can be used in future studies to help prove the concept of new classes of medicine for treating certain cardiac diseases. Additionally, we found that piperazine - a very safe and inexpensive anthelmintic which has been shown to be anti-arrhythmic in some animal preparations - selectively inhibits strongly rectifying Kir channels such as Kir 2.1. The selectivity and safety of piperazine make it (or its derivatives) a promising candidate agent for treating certain cardiac arrhythmias. Because of this potential therapeutic value we will, in Aim#2, investigate the mechanisms by which piperazine interacts with the channel through a combination of energetic and structural studies. Furthermore, as the first step toward proving the concept, we will demonstrate that certain blocking properties of piperazine can be exploited for treating a form of short QT syndrome caused by a mutation in Kir2.1. The outcome of the proposed studies will significantly enhance our ability to decipher the physiological functions of Kir channels in a given cell type or tissue, and help in the development of effective therapeutic agents.

我们研究的长期目标是开发专门针对个体亚型的抑制剂离子通道，确定抑制剂-通道相互作用机制，并使用抑制剂来检查引导生理学并展示某些治疗概念。由于内向整流器 K+ (Kir) 通道发挥许多重要的生理作用，并代表日益重要的治疗靶点、亚型特异性 Kir 通道抑制剂具有实验和治疗价值。下面提出的研究将是采用电生理学、生物化学和分子生物学的综合方法进行。此前，我们发现一种含有 21 个残基的蜜蜂毒素特硫平 (TPN) 可抑制肾 Kir1.1 和具有纳摩尔亲和力的心脏 Kir3.1/3.4 通道。在 Aim#1 中，我们将创建针对 Kir1.1 或 Kir3.1/3.4。我们的初步研究不仅确定了允许选择性的通道序列不仅针对各种 Kir 亚型，还建立了这种亚型特异性抑制剂的原型。这由此产生的特异性抑制剂可用于未来的研究，以帮助证明新类别的概念治疗某些心脏病的药物。此外，我们发现哌嗪 - 一种非常安全且廉价的驱虫药，已被证明在某些动物制剂中具有抗心律失常作用 - 选择性抑制强烈的整流 Kir 通道，例如如基尔2.1。哌嗪的选择性和安全性使其（或其衍生物）成为有前途的候选药物用于治疗某些心律失常。由于这种潜在的治疗价值，我们将在目标#2中，研究哌嗪通过以下组合与通道相互作用的机制能量和结构研究。此外，作为证明这一概念的第一步，我们将证明哌嗪的某些阻断特性可用于治疗某种形式的短 QT Kir2.1 突变引起的综合征。拟议研究的结果将显着增强我们破译生理学的能力 Kir 通道在给定细胞类型或组织中的功能，并有助于开发有效的治疗药物代理。