The goal of this proposal is to develop the principal investigator (PI) into an independent physician- scientist in the field of cardiovascular research. The PI has already undergone both intensive PhD training in the basic science field of immunology and significant additional training in cardiovascular research, both basic science and translational in nature. The PI has completed clinical training in internal medicine and is currently completing the final year of cardiology subspecialty training. The following 5-year career development plan will provide further refinement and training for the PI in order to gain research independence at the conclusion of the award. Dr. Douglas Mann, Chief of Cardiology at Washington University, will mentor the PI. Dr. Mann is a recognized leader in myocardial inflammation and has a tremendous breadth of experience, from defining the role of pro-inflammatory cytokines in heart failure to taking that knowledge and spearheading a clinical trial based on his results. As such, he serves as a perfect example of a successful physician-scientist that is able to translate basic science research into the clinical arena. The PI will tak advantage of this mentorship and the enormous basic science and clinical resources available at Washington University, one of the nation's premier academic institutions, in order to define a new area of clinically relevant basic science research. Myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States and our understanding of the underlying mechanisms remains incomplete. Monocytes are the dominant cell type infiltrating the myocardium in the first week following MI. Unfortunately, little is known about the regulatory factors governing monocyte recruitment despite the fact that excessive recruitment leads to impaired infarct healing. Recent evidence suggests that pathological activation of angiotensin II (AngII) is directly involved in monocyte recruitment following ischemic injury. Angiotensin converting enzyme 2 (ACE2) is a critical endogenous AngII counter-regulator and acts not only to degrade AngII, but produces Ang1-7, a biologically active peptide that binds the Mas receptor (MasR). Enhancing the activity of any component of the ACE2 / Ang1-7 / MasR axis limits myocardial ischemic injury, however the interplay between the ACE2 axis and monocyte recruitment has not been assessed. We hypothesize that a monocyte-localized ACE2 / Ang1-7 / MasR axis exists, and is required to prevent both excessive monocyte recruitment and subsequent monocyte-mediated cardiac dysfunction following myocardial ischemia. By utilizing knockout and transgenic animals that target each member of the ACE2 / Ang1-7 / MasR axis, we will answer important mechanistic questions that define how the ACE2 axis governs monocyte recruitment and how altered recruitment impacts infarct healing. The answers to these questions may have broad clinical implications to the treatment of ischemic heart disease.
This career development proposal has two important components that will benefit public health. The first is the development of the principle investigator into a physician-scientist, which is a uniquely trained medical doctor who by treating patients, identifies critical gaps in our medical knowledge and subsequently investigates new treatment options. The second is the further characterization of a newly identified pathway that is able to prevent immune cell-mediated damage following heart attacks, potentially opening a novel therapeutic avenue for those who suffer from coronary artery disease.
|Clemente-Casares, Xavier; Hosseinzadeh, Siyavash; Barbu, Iulia et al. (2017) A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis. Immunity 47:974-989.e8|
|Epelman, Slava; Lavine, Kory J; Beaudin, Anna E et al. (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91-104|
|Shao, Zhili; Shrestha, Kevin; Borowski, Allen G et al. (2013) Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure. J Card Fail 19:605-10|
|Epelman, Slava; Mann, Douglas L (2012) Communication in the heart: the role of the innate immune system in coordinating cellular responses to ischemic injury. J Cardiovasc Transl Res 5:827-36|
|Epelman, Slava; Tang, W H Wilson (2012) H(2)S--the newest gaseous messenger on the block. J Card Fail 18:597-9|