equipment and instrumentation necessary for organic synthesis and small molecule characterization including a Shimadzu LC-Mass spectrometer, a Varian 300-MHz 'H(13C, I5N, 31P)-nmr spectrometer and a Biacore plasmon resonance detector. The small molecules to be synthesized for each project will.be based on known parent compounds with previously demonstrated activity. The parent compounds include JTV-519 for the Marks project, rottlerin for the Marx project, R-L3 and acrylamide derivatives for the Kass project, and JTV ?derivatives and agents to cross-link and label proteins for the Karlin project. As required for each project, the Core will prepare specific classes of derivatives that will serve as tools to define structure and activity. The range of classes will include tethered analogs for affinity purification, radio-labeled analogs for binding studies, and analogs for photoaffmity labeling that contain a radiolabel or a tether for affinity purification. The Core will also produce selected parent compounds and analogs on a preparative scale for in vivo testing in the Animal Core Facility of the PPG. The ability to tailor molecules in response to biological and biochemical activity provides a potent tool for investigating the allosteric modulation of ion channels. JTV Rottlerin JTV R-L3 Class of Molecule to be prepared: (Marks) (Marx) (Karlin) (Kass) Parent Compound X X X Analogs for Structure-Activity II. Studies X X 3H- Labeled Analogs X IV. Tethered Analogs for Affinity Purification or Biacore Assay X V. Radiolabeled Photoaffinity Analogs X VI. Photoaffinity Analogs Tethered for Affinity Purification X PHS 398/2590 (Rev. 09/04) Page 2~ Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081172-05
Application #
8281525
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$147,370
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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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
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
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
Wu, Roland S; Liu, Guoxia; Zakharov, Sergey I et al. (2013) Positions of ?2 and ?3 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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