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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081172-05
Application #
8133509
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wang, Lan-Hsiang
Project Start
2007-09-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$1,049,461
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Zalk, Ran; Clarke, Oliver B; des Georges, Amédée et al. (2015) Structure of a mammalian ryanodine receptor. Nature 517:44-9
Marx, Steven O; Marks, Andrew R (2013) Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J Mol Cell Cardiol 58:225-31
Wan, Elaine; Kushner, Jared S; Zakharov, Sergey et al. (2013) Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice. FASEB J 27:1859-67
Goldklang, Monica P; Perez-Zoghbi, Jose F; Trischler, Jordis et al. (2013) Treatment of experimental asthma using a single small molecule with anti-inflammatory and BK channel-activating properties. FASEB J 27:4975-86
Wu, Roland S; Liu, Guoxia; Zakharov, Sergey I et al. (2013) Positions of ýý2 and ýý3 subunits in the large-conductance calcium- and voltage-activated BK potassium channel. J Gen Physiol 141:105-17
Niu, Xiaowei; Liu, Guoxia; Wu, Roland S et al. (2013) Orientations and proximities of the extracellular ends of transmembrane helices S0 and S4 in open and closed BK potassium channels. PLoS One 8:e58335
Morrow, John P; Katchman, Alexander; Son, Ni-Huiping et al. (2011) Mice with cardiac overexpression of peroxisome proliferator-activated receptor ? have impaired repolarization and spontaneous fatal ventricular arrhythmias. Circulation 124:2812-21
Wu, Roland S; Marx, Steven O (2010) The BK potassium channel in the vascular smooth muscle and kidney: ýý- and ýý-subunits. Kidney Int 78:963-74
Liu, Guoxia; Niu, Xiaowei; Wu, Roland S et al. (2010) Location of modulatory beta subunits in BK potassium channels. J Gen Physiol 135:449-59
Kushnir, Alexander; Betzenhauser, Matthew J; Marks, Andrew R (2010) Ryanodine receptor studies using genetically engineered mice. FEBS Lett 584:1956-65

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