The main goal of this research proposal is to identify the functional role of amphiregulin signaling in perioperative cardio-protection from myocardial ischemia. Transcriptional responses elicited by ischemia/hypoxia involve hypoxia inducible transcription factors (HIFs). Here, we set out to identify HIF- dependent target genes that could mediate cardio-protection. Studies in mice with conditional Hif2a deletion pointed us towards amphiregulin (AREG). Indeed, re-constitution of Hif2aloxP/loxP Myosin Cre+ mice with AREG was associated with a reversal of their phenotype and provided cardio-protection in wild-type mice. Therefore, we hypothesize that AREG production and signaling through its receptor ErbB1 conveys cardio-protection from acute ischemia. We propose to study the transcriptional control of AREG during myocardial ischemia, and test the relevance of this pathway on human disease by examining AREG transcript and protein levels in human cardiac tissues. Moreover, we will examine the functional role of AREG during myocardial ischemia in Areg-/- mice. Finally, we will study expression and function of the AREG receptor ErbB1 utilizing a mouse line with myocyte-specific deletion of ErbB1. These studies are significant for developing novel therapeutic approaches to prevent or attenuate ischemic tissue injury of the myocardium in patients undergoing major surgery.
Our studies are designed to lay the groundwork for novel therapeutic approaches for treating surgical patients who are suffering from acute myocardial ischemia. Our studies point towards a novel therapeutic role for amphiregulin signaling through its receptor ErbB1. We believe our studies are highly significant for the treatment of patients suffering from perioperative myocardial ischemia - one of the leading causes of morbidity and mortality of surgical patients.
|Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69|