Coxsackieviral infection of the heart is an important cause of cardiomyopathy in children and adults. However, little is known of the innate signaling mechanisms within the cardiac myocytes that control viral infection. A better understanding of these mechanisms may allow design of novel therapeutic strategies for viral heart disease. Recently, we have shown that inhibition of Janus kinase (JAK)- signaling transducer and activator of transcription (STAT) in the cardiac myocyte by expression of SOCS 1 has a marked effect on viral replication and viral-mediated cytopathic effects. Disruption of interferon alpha/beta receptors had no effect and disruption of interferon-gamma receptors had minimal effect on early viral replication in the heart. We, therefore, hypothesize that other, non-interferon mediated innate immune mechanisms are important within the cardiac myocyte to combat viral infection. These could include signaling through the glycoprotein (gp) 130 that also activates JAK-STAT signaling. We, therefore, propose the following specific aims: 1) Determine in CVB3 infected mice whether gp130, IFN-gamma signaling, or both are important for a) the induction of JAK-STAT-SOCS signaling in the heart and b) the innate immune defense against viral infection. 2) Identify mechanisms related to viral infection and replication by which forced expression of SOCS1 in the cardiac myocyte induces a marked cytopathic effect following CVB3 infection and determine whether transgenic SOCS3 expression will also affect the innate immune response in a manner similar to that observed in SOCS1 transgenic mice. 3) Determine the effect of cardiac-specific knockout of SOCS1 and SOCS3 on JAK-STAT signaling in cardiac myocytes and the cardiomyopathy associated with CVB3 infection.
These aims will provide a novel insight into the mechanisms by which JAK-STAT-SOCS activation within the cardiac myocyte regulates the innate anti-viral response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057365-07
Application #
7237297
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Schwartz, Lisa
Project Start
1998-12-05
Project End
2009-04-30
Budget Start
2007-08-01
Budget End
2009-04-30
Support Year
7
Fiscal Year
2007
Total Cost
$216,185
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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