Allosteric Modulation of Cardiovascular Ion Channels

描述（由申请人提供）： 该计划项目补助金（PPG）提案包括4个项目和3个核心。该项目的重点是通过变构效应更好地了解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（包括心力衰竭、心律失常和高血压）的重要新治疗靶标。我们提出，离子通道功能的扰动，主要是通过亚基相互作用的变构效应和小分子对通道复合物的作用，可以调节离子通道，包括K+通道和Ryanodine受体/Ca 2+释放通道在肌浆网。我们进一步提出，这些变构调节是关键的新的治疗靶点，可以减轻离子通道孔阻滞剂的许多不良副作用。因此，本项目的目标是使用不同的方法，包括生物化学，生物物理，化学和体内测试，以解决心血管离子通道的变构调节在正常和病理功能的潜在重要性。这4个项目是整体联系在一起的：1）总体和项目1 PI -亚瑟卡林有3个目标，重点是确定兰尼碱受体和BKCa通道变构调节的相互作用位点。2)项目2，PI -安德鲁R。Marks有3个目标，重点是心脏和骨骼兰尼碱受体变构调节作用的功能表征。3)项目3 PI - Robert Kass有3个目标，专注于表征KCNQ 1/KCNE 1的变构调节。4)项目4 - PI Steven马克思有3个目标，重点是BKCa的变构调节。三个核心是：A）行政（A。卡林和A.R.标记）; B）化学合成核心-设计和合成将被所有4个项目使用的小分子。C）动物模型和组织培养核心-将为每个项目生成和提供离子通道疾病的细胞培养和遗传动物模型。如上所述，这四个项目是紧密相连的。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者。我们的小组已经产生了大量的初步数据来支持所有提出的目标和几个出版物，包括几个由小组成员共同撰写的出版物。

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.