Viral myocarditis (VM) is a significant contributor to heart failure. VM is an insidious disease that results in dilated cardiomyopathy and often requires cardiac transplantation. Furthermore, only supportive therapies currently exist for combating VM. Very little is known about the pathogenesis of the disease. It is becoming apparent that an excessive host immune response largely defines the progression of cardiomyopathy in patients with VM. Bioinformatics based analyses revealed Troponin I-interacting kinase (TNNI3K) to potentially regulate the immune response during VM. TNNI3K is a cardiomyocyte (CM) specific kinase that regulates the cardiac response to ischemia and pressure overload. The overall goal is to determine the validity of TNNI3K as a therapeutic target for combating VM. Our preliminary findings are the first to show that TNNI3K exacerbates the immune response during VM. Although immune cell infiltration is required for elimination of viral pathogen, there is a clear detrimental relationship between severity of acute inflammatory cell infiltrate and the development of cardiac dysfunction. As our preliminary findings reveal (1) Overexpression of CM-specific TNNI3K in a rodent model of VM results in an increased myocardial immune cell infiltration and (2) CM-specific deletion of TNNI3K conversely limits immune cell infiltration, we hypothesize that inhibition of TNNI3K will be protective in a setting f acute VM. Furthermore, as TNNI3K is a CM-specific kinase, it makes for a suitable therapeutic target. With 1) transgenic mice expressing wild-type, or kinase in-active TNNI3K, 2) conditional CM-specific TNNI3K knockout mice (cKO), and 3) a pharmacological TNNI3K inhibitor, we feel well equipped to dissect the role of TNNI3K in the immune response to cardiac injury. Using these tools, we intend to complete the following two specific aims: 1) Characterize the effect of TNNI3K on the immune response to VM. We will use flow cytometry and immunohistochemistry to characterize immune cell populations and hemodynamics to assess functional outcomes in mice with VM. 2) Examine the mechanism of TNNI3K in regulation of the immune response to cardiac injury. Using isolated adult CM from mice with VM, we will use molecular biology to investigate substrate interactions to determine their effect on the immune response. Overall, these findings will provide insight on the CM immune response to virus, provide novel TNNI3K direct interactions, and answer if TNNI3K is a suitable therapeutic target for combating VM.
Viral Myocarditis (VM) is an insidious disease that causes heart failure and often requires heart transplant. Our findings have assigned a novel function for Troponin I-interacting kinase (TNNI3K) in regulation of the immune response during VM. The proposed studies intend to assess the translational potential for targeting TNNI3K in combating VM as well as offer mechanistic insight on how a cardiac-specific kinase regulates the immune response to cardiac injury.
