In excitable cells, voltage-gated K+ channels play an important role in regulating the duration of the action potential. The long-term objective of our research program is to elucidate the mechanisms that regulate cardiac cell excitation. We hypothesize that the cardiac myocytes can respond to prolongation of action potential duration (ADP) by turning on the expression of potassium channel genes that shorten the repolarization period. This compensatory response may be a key to limiting the extent of the prolongation of the ADP and QT intervals.
The aims of this proposal are to create mouse models to study electrical remodeling and elucidate the molecular mechanisms that control and regulation the expression of cardiac voltage-gated potassium channel genes. Specifically, the plan over the next five years is: (1) To create mouse models with combined deficiency of several outward potassium currents and to elucidate the molecular basis of the reentrant arrhythmias observed in mice over- expressing KV1.1N206Tag in the heart. (2) To elucidate the mechanisms which regulate the tissue-specific and the level of expression of Kv1.5. To characterize two novel transcription factors (KBF1 and KBF2) that bind to a silencer element (KRE) located in the promoter of Kv1.5. (3) To assess the biological role of KBF1 and KBF2 in the heart. In addition to contributing to our understanding of the basic mechanisms underlying cardiac excitation, these studies may be relevant to the development of new therapy to long QT syndrome and cardiac arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046005-10
Application #
6389163
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Spooner, Peter
Project Start
1991-08-08
Project End
2004-07-31
Budget Start
2001-04-01
Budget End
2002-07-31
Support Year
10
Fiscal Year
2001
Total Cost
$434,534
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Lau, Emily; Kossidas, Konstantinos; Kim, Tae Yun et al. (2015) Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling. PLoS One 10:e0122754
Kim, Tae Yun; Kunitomo, Yukiko; Pfeiffer, Zachary et al. (2015) Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1. Heart Rhythm 12:220-8
Terentyev, Dmitry; Rochira, Jennifer A; Terentyeva, Radmila et al. (2014) Sarcoplasmic reticulum Ca²? release is both necessary and sufficient for SK channel activation in ventricular myocytes. Am J Physiol Heart Circ Physiol 306:H738-46
Organ-Darling, Louise E; Vernon, Amanda N; Giovanniello, Jacqueline R et al. (2013) Interactions between hERG and KCNQ1 ?-subunits are mediated by their COOH termini and modulated by cAMP. Am J Physiol Heart Circ Physiol 304:H589-99
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Ziv, Ohad; Schofield, Lorraine; Lau, Emily et al. (2012) A novel, minimally invasive, segmental myocardial infarction with a clear healed infarct borderzone in rabbits. Am J Physiol Heart Circ Physiol 302:H2321-30
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Odening, Katja E; Choi, Bum-Rak; Liu, Gong Xin et al. (2012) Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm 9:823-32
Cooper, Leroy L; Odening, Katja E; Hwang, Min-Sig et al. (2012) Electromechanical and structural alterations in the aging rabbit heart and aorta. Am J Physiol Heart Circ Physiol 302:H1625-35
Biermann, Jurgen; Wu, Kezhong; Odening, Katja E et al. (2011) Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo. Eur J Pharmacol 650:309-16

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