Modification of the magnitude and kinetics of K+ currents has been shown to be proarrhythmic, in response to both genetic abnormalities as well as pharmacologic intervention. The relationship between channel defects and altered repolarization or arrhythmogenesis is a complex problem which cannot be addressed intuitively. Describing the kinetic consequences of a point mutation requires the development of detailed mathematical models of ion channels. However, the tools for relating mutations to kinetic behavior have been limited. The most advanced models of structure have not yet been put into kinetic equations that are useful to investigators working at higher levels of integration in the heart. The broad goal of this proposal is to develop a systematic mathematical approach to developing structurally-based Markov models of channel kinetic behavior from mutational data. A new analysis approach will be developed to use non-linear parameter estimation to quantify the impact of a mutation or other manipulation (e.g., changes in pH, [K+]o) on kinetic behavior. The effects of altered kinetic behavior will be examined in conjunction with other mutations using mathematical adaptations of Hammond energy shifts and mutant cycle analysis. We will produce a generalization of these approaches to complex multi-step gating processes which can be applied to non-equilibrium situations. We will use this approach to develop Markov models of channel kinetics with high predictive values through three Specific Aims: (1) Develop base Markov models of Kv1.4, Kv4.3, KvLQT1 and HERG gating based on known and hypothesized structure-function relationships and voltage clamp data. (2) Map base Markov models to structures using site directed mutagenesis analyzed with parameter sensitivity analysis, optimization, Hammond energy shifts and kinetically-based mutant cycle analysis. (3) Incorporate modulation by pH and [K+]o into these Markov models. (4) To translate the structurally based Markov models of gating from Aims 1-3 into models of native myocyte currents This study will develop Markov models of channels and repolarization which will be unique in the degree to which the major gating states have been identified with mutagenesis and mapped to specific rigid domains of each respective K+ channel. The long term goal is to predict clinical phenotype directly from channel defect.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062465-15
Application #
8207218
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
1998-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
15
Fiscal Year
2012
Total Cost
$349,025
Indirect Cost
$126,275
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Bett, Glenna C L; Kaplan, Aaron D; Rasmusson, Randall L (2016) Action Potential Shape Is a Crucial Measure of Cell Type of Stem Cell-Derived Cardiocytes. Biophys J 110:284-6
Lin, Bo; Li, Yang; Han, Lu et al. (2015) Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. Dis Model Mech 8:457-66
Gold, Daniel A; Kaplan, Aaron D; Lis, Agnieszka et al. (2015) The Toxoplasma Dense Granule Proteins GRA17 and GRA23 Mediate the Movement of Small Molecules between the Host and the Parasitophorous Vacuole. Cell Host Microbe 17:642-52
Kim, Jong J; Yang, Lei; Lin, Bo et al. (2015) Mechanism of automaticity in cardiomyocytes derived from human induced pluripotent stem cells. J Mol Cell Cardiol 81:81-93
Rasmusson, Randall L; Anumonwo, Justus M (2015) Activation of HERG channels: opening new applications for the biophysics of antiarrhythmic therapy. Biophys J 108:1309-11
Han, Lu; Li, Yang; Tchao, Jason et al. (2014) Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells. Cardiovasc Res 104:258-69
Parikh, Ashish; Patel, Divyang; McTiernan, Charles F et al. (2013) Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 113:313-21
Bett, Glenna C L; Kaplan, Aaron D; Lis, Agnieszka et al. (2013) Electronic "expression" of the inward rectifier in cardiocytes derived from human-induced pluripotent stem cells. Heart Rhythm 10:1903-10
Zhou, Qinlian; Bett, Glenna C L; Rasmusson, Randall L (2012) Markov models of use-dependence and reverse use-dependence during the mouse cardiac action potential. PLoS One 7:e42295
Bett, Glenna Cl; Lis, Agnieszka; Wersinger, Scott R et al. (2012) A Mouse Model of Timothy Syndrome: a Complex Autistic Disorder Resulting from a Point Mutation in Cav1.2. N Am J Med Sci (Boston) 5:135-140

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