Allosteric Modulation of Cardiovascular Ion Channels

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。一个中心假说是，离子通道的变构调节剂在调节心血管生理方面起着关键作用，是治疗包括心力衰竭、心律失常和高血压在内的主要形式心脏病的重要新靶点。我们认为，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体的作用，可以调节肌浆网中的离子通道，包括K+通道和兰尼定受体/钙释放通道。我们进一步提出，这些变构调节是关键的新的治疗靶点，可能会减轻离子通道孔道阻滞剂的许多不良副作用。因此，本项目的目标是使用包括生化、生物物理、化学和活体测试在内的多种方法来研究变构调节心血管离子通道在正常和病理功能中的潜在重要性。这4个项目是紧密相连的：1)总体和项目1，Pi-Arthur Karlin的3个目标集中于确定兰尼定受体和BKCa通道的变构调节的相互作用部位。2)项目2，Pi-Andrew R.Marks的3个目标集中在心脏和骨骼兰尼定受体的变构调节效应的功能表征上。3)项目3PI-Robert Kass的3个目标是表征KCNQ1/KCNE1的变构调节。4)项目4-PI史蒂文·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.Karlin和A.R.Marks)；B)化学合成核心--所有4个项目都将使用的设计和合成小分子。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，所有4个项目都紧密联系在一起。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，并将向外部研究人员提供。我们小组已经生成了大量初步数据，以支持所有拟议的AIMS和几份出版物，其中包括几份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.