Allosteric Modulation of Cardiovascular Ion Channels

心血管离子通道的变构调节

• 批准号: 7488904
• 负责人: Arthur Karlin
• 金额: $ 165.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488904
• 关键词: Allosteric; Modulation; Cardiovascular; Ion; Channels

DESCRIPTION (provided by applicant): This Program Project Grant (PPG) proposal comprises 4 Projects and 3 Cores. The focus of the projects is to gain a better understanding of mechanisms modulating cardiovascular ion channels via allosteric effects. A central hypothesis is that allosteric modulators of ion channels play key roles in regulating cardiovascular physiology and are important novel therapeutic targets for major forms of heart disease including heart failure, arrhythmias and hypertension. We propose that perturbation of ion channel function, primarily by means of allosteric effects of subunit interactions and the actions of small molecules on the channel complexes, can regulate ion channels including K+ channels and the ryanodine receptor/Ca2+ release channel in the sarcoplasmic reticulum. We further propose that these allosteric modulations are key novel therapeutic targets that may alleviate many of the undesirable side effects of ion channel pore blockers. Therefore, the goal of this project is to use diverse approaches including biochemical, biophysical, chemical and in vivo testing to address the potential importance of allosteric modulation of cardiovascular ion channels in normal and pathologic functions. The 4 projects are integrally linked: 1) Overall and Project 1 PI - Arthur Karlin has 3 aims focused on identifying sites of interaction for allosteric modulations of ryanodine receptors and BKCa channels. 2) Project 2, PI - Andrew R. Marks has 3 aims focused on the functional characterization of the effects of allosteric modulation of the cardiac and skeletal ryanodine receptors. 3) Project 3 PI - Robert Kass has 3 aims focused on characterization of the allosteric modulation of KCNQ1/KCNE1. 4) Project 4 - PI Steven Marx has 3 aims focused on allosteric modulation of BKCa. Three Cores are: A) Administrative (A. Karlin and A.R. Marks); B) Chemical synthesis core- design and synthesis small molecules that will be used by all 4 projects. C) Animal Models and Tissue Culture Core- will generate and provide cell culture and genetic animal models of ion channel diseases to each project. As noted above all 4 projects are tightly linked. Animal models will be used by Projects 2, 3, and 4 to examine the effects on ion channel function and will be made available to outside investigators. Our group has generated substantial preliminary data to support all of the proposed aims and several publications, including several that are co-authored by members of the group.

描述（由申请人提供）： 该计划项目赠款（PPG）提案包括4个项目和3个核心。这些项目的重点是更好地了解通过变构效应调节心血管离子通道的机制。一个中心假设是，离子通道的变构调节剂在调节心血管生理学中起关键作用，并且是主要形式的心脏病，包括心脏衰竭，心律不齐和高血压的重要新型治疗靶标。我们提出，主要通过亚基相互作用的变构效应以及小分子对通道复合物的作用的扰动，可以调节包括K+通道在内的离子通道和ryanodine受体/Ca2+释放通道在肌浆网状中。我们进一步建议这些变构调节是主要的新型治疗靶标，可以减轻离子通道孔隙阻滞剂的许多不良副作用。因此，该项目的目的是使用多种方法，包括生化，生物物理，化学和体内测试，以应对正常和病理功能中心血管离子通道的变构调节的潜在重要性。这4个项目是整体链接的：1）总体和项目1 PI -Arthur Karlin具有3个目标，旨在识别Ryanodine受体和BKCA渠道变构调制的相互作用位点。 2）项目2，PI -Andrew R.标记的目标是3个目标，重点是心脏和骨骼瑞氨烷受体的变构调节作用的功能表征。 3）项目3 Pi -Robert Kass的目标是侧重于KCNQ1/KCNE1的变构调制的表征。 4）项目4 -Pi Steven Marx的目标是3个目标，重点是对BKCA的变构调节。三个核心是：a）行政（A. Karlin和A.R. Marks）； b）化学合成核心设计和合成小分子，所有4个项目都将使用。 c）动物模型和组织培养核心将为每个项目产生并提供离子通道疾病的细胞培养和遗传动物模型。如前所述，所有4个项目都紧密相关。项目2、3和4将使用动物模型来检查对离子通道功能的影响，并将提供给外部研究人员。我们的小组已经生成了大量的初步数据，以支持所有拟议的目标和几个出版物，其中包括该小组成员合着的几个。