The focus of this research program since its inception has been variable repolarization in the heart, and its relation to abnormal cardiac rhythms, a continuing public health problem. Investigation of arrhythmia susceptibility in the intact heart has been greatly advanced by studies of monogenic arrhythmia diseases such as the congenital long QT syndromes or the Brugada Syndrome. A finding that is especially relevant to the present proposal is that mutation carriers may be phenotypically normal, and a number of mechanisms have been proposed to explain such variable penetrance. The present proposal will build on extensive preliminary data to test the hypothesis that variable cardiac sodium channel delivery to the cell surface can determine the clinical phenotype of sodium channel-linked forms of monogenic disease. A key feature of this proposal is that we will for the first time systematically extend studies we and others have conducted in vitro showing misprocessing of mutant long QT syndrome ion channels to the intact heart. This will be accomplished by implementing recombinase-mediated cassette exchange, a new technique that allows rapid and efficient generation of multiple mouse lines bearing mutant DMAs at a target locus. We have successfully targeted the sodium channel locus for cassette exchange in embryonic stem cells, and have now validated the method by generating mice-with normal sodium channel function-in which expression of the wild-type murine sodium channel gene has been ablated, and replaced by the human isoform.
Specific aim 1 will assess cell surface expression in vitro of LQT3 and Brugada Syndrome mutations chosen from domains of the channel predicted to exhibit specific secondary structures.
In specific aim 2, we will study whole heart phenotypes, including arrhythmia susceptibility, in mice we generate by cassette exchange to express humanized and epitope-tagged wild-type or mutant (LQT3 or Brugada Syndrome) channels.
Specific aim 3 will use these mouse models to manipulate cell surface sodium channel expression. The outcome of this research will not only advance our understanding of the pathophysiology of monogenic congenital arrhythmia syndromes, but also will point to more general approaches for therapeutic manipulation of ion channel expression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049989-16
Application #
7762714
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
1994-08-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
16
Fiscal Year
2010
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Roden, Dan M (2016) Predicting drug-induced QT prolongation and torsades de pointes. J Physiol 594:2459-68
Roden, Dan M (2016) Pharmacogenetics of Potassium Channel Blockers. Card Electrophysiol Clin 8:385-93
Wrobel, Eva; Rothenberg, Ina; Krisp, Christoph et al. (2016) KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting. Nat Commun 7:12795
Stroud, Dina Myers; Yang, Tao; Bersell, Kevin et al. (2016) Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart. J Am Heart Assoc 5:
Yang, Tao; Chun, Young Wook; Stroud, Dina M et al. (2014) Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current. Circulation 130:224-34
Roden, Dan M (2014) Personalized medicine to treat arrhythmias. Curr Opin Pharmacol 15:61-7
Weeke, Peter; Roden, Dan M (2014) Applied pharmacogenomics in cardiovascular medicine. Annu Rev Med 65:81-94
Roden, Dan M (2014) Pharmacology and Toxicology of Nav1.5-Class 1 anti-arrhythmic drugs. Card Electrophysiol Clin 6:695-704
Roden, Dan M; Knollmann, Björn C (2014) Dantrolene: from better bacon to a treatment for ventricular fibrillation. Circulation 129:834-6

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