Numerous studies have demonstrated the abundant expression and pleiotropy of CLC-3 in the heart. As a unique member of the CLC voltage-gated chloride (Cl-) channel superfamily, CLC-3 is suggested to function as not only a Cl- channel but also a Cl-/H+ antiporter or an anion transporter. Although CLC-3 has been implicated in the regulation of many cellular functions such as electrical activity, cell volume, proliferation, differentiation, migration, apoptosis and intracellular pH, the functional roles for CLC-3 Cl- channels in human heart disease remain unknown. The goal of the proposed research is to test the hypothesis that activation of CLC-3 in the heart is an important adaptive mechanism for both ionic and structural remodeling during pressure overload induced myocardial hypertrophy and it protects the cardiac myocytes against excessive cell volume increase and oxidative stress damage and also delays the decompensatory progression from hypertrophy to heart failure. To accomplish this goal, we will address the following Specific Aims: 1) To define the functional role of CLC-3 in cardiac electrophysiology and hemodynamics through a comparison of the properties of whole-cell Cl- current, action potentials, ECG, cardiac hemodynamics and function among the wild-type (Clcn3+/+), the heart-specific conditional (hsClcn3-/-) and doxycycline-inducible CLC-3 knockout (doxyhsClcn3-/-), and transgenic heart-specific CLC-3 over-expression (hsClCn3OE) mice; 2) To determine the functional role of CLC-3 in the ionic and structural remodeling during myocardial hypertrophy and heart failure by applying the transverse aorta-banding pressure-overload model to the Clcn3+/+, hsClcn3-/-, doxyhsClcn3-/-, and hsClcn3OE mice; 3) To delineate the molecular mechanisms underlying the adaptive effects of CLC-3 against excessive cell volume increase and oxidative stress damage inflicted during myocardial hypertrophy and heart failure. The significance is that this study will gain substantia knowledge on the novel function and molecular mechanisms of CLC-3 in the heart and significantly advance our understanding of the integrated physiology and pathophysiology of Cl- channels. The identification of CLC-3 as a novel molecular interventional target that mitigates pressure-overload-induced heart failure may reveal a previously unknown cardioprotective mechanism and set the stage for the development of new treatment strategies for this devastating heart disease.

Public Health Relevance

Heart diseases remain a major cause of human death. In every year over 600,000 Americans die of coronary heart disease and heart failure. Clinical care for heart diseases is usually intensive and involves long term hospitalization, which creates a significant burden on the healthcare system. This proposal is to use state-of- the-art techniques to study how activation of CLC-3 gene product in the heart can be protected the heart from damages caused by increased work load and stress. As a result, it will reveal previously unknown protective mechanisms and new information for better understanding of the cause of heart disease and of new drug targets for the treatment of heart diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113598-01A1
Application #
8446945
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$352,500
Indirect Cost
$102,500
Name
University of Nevada Reno
Department
Miscellaneous
Type
Organized Research Units
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
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