Myocardial ischemia and reperfusion results in loss of viable myocardium leading to increased load on the remaining tissue. This change in load initiates reparative and compensatory signaling pathways, the success of which determines the extent of pathologic left ventricular remodeling following ischemia and reperfusion. Stress-activated cytokines including interleukin-1 participate in the early signaling events following ischemia and reperfusion. We identified an interleukin-1 receptor family member, T1/ST2, as a gene highly-induced by both mechanical strain and interdeukin-1 in cardiac myocytes. T1/ST2 has not previously been reported to be expressed in cardiac myocytes, but its growth and immune functions in cell types outside the cardiovascular system coupled with our novel findings in cardiac myocytes suggest that T1/ST2 may be an interface molecule between immune/inflammation responses and myocyte survival following ischemia and reperfusion.
The aims i n this proposal address critical questions regarding the function of this previously-classified immune function gene in stress-activated pathways during myocardial ischemia and reperfusion potentially affecting myocyte survival.
In specific aim 1 we will examine the induction and signaling of T1/ST2 and its coupling to myocyte survival during hypoxia/reoxygenation in cardiac myocytes in vitro.
In specific aim 2, TI/ST2 null mice will be subjected to myocardial ischemia and reperfusion to determine the role of TI/ST2 in myocyte survival and remodeling.
In specific aim 3, we will deliver the T1/ST2 gene directly into the myocardium of T1/ST2 null mice subjected to ischemia and reperfusion and examine myocyte survival and ventricular remodeling.
In specific aim 4 we propose to identify peptide ligands of T1/ST2 and their effects on the myocardium during ischemia and reperfusion.
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