The proposed K08 Mentored Career Development Award will enable me to develop into an established and independent researcher with expertise on the role of vascular ion channels in heart failure (HF) and other cardiovascular diseases associated with vascular dysfunction, such as hypertension and diabetes. I am a clinical cardiologist, cardiac electrophysiologist, as well as experienced basic and translational researcher whose long-term goal is to understand the electrophysiologic remodeling of the vasculature in cardiovascular diseases to develop new therapies for the treatment of HF and vascular dysfunction. However, further career development and research training is necessary for me to reach this goal. I have a long-standing, productive relationship with my mentor, Dr. Steven Marx, an experienced ion channel researcher, with whom I published the finding that resistance vessels in HF undergo electrical remodeling of the vasculature; specifically, the vascular smooth muscle (VSM) cell membrane potential is depolarized, cytosolic [Ca2+] is elevated, and the expression and activity of vascular large conductance, Ca2+ activated potassium channels (BK channels) are markedly reduced compared to mice without heart failure. I plan to elucidate the ion channels responsible for this vascular dysfunction. The centra hypothesis of this application is that abnormal vascular ion channel activity may be one of the molecular mechanisms that causes vascular dysfunction. I have arranged a multidisciplinary board of established investigators (Dr. Donna Mancini, Dr. Andrew Marks, Dr. Paolo Colombo, Dr. Robert Kass, Dr. Shunichi Homma) and career development mentor (Dr.
J aim e Rubin), to help me attain the goals of (1) obtaining comprehensive basic cellular electrophysiologic training, (2) acquiring skills in molecular cardiology to generate and phenotype new mouse models of human congestive heart failure and study possible therapies to reverse vascular dysfunction and heart failure, and (3) conducting ethical research, while acquiring the necessary skills for effective research presentation and publication. I plan to use data and skills acquired during this award to develop new therapies to treat HF and vascular disease.
Congestive heart failure is one of the leading diagnoses of hospital admissions today. It is a clinical syndrome resulting from decreased cardiac function and hence decrease perfusion to vital organs, causing concomitant vascular dysfunction, namely vasoconstriction and increased resistance to endothelial mediated relaxation. This is a result of abnormalities in the vascular smooth muscle cells, which hinders cardiac output and results in further adverse cardiac remodeling. This proposal focuses on understanding the role of vascular smooth muscle ion channels in controlling blood vessel contractility, with the goal of developing novel therapeutic approaches to treat heart failure and vascular dysfunction after myocardial infarction.
| Wan, Elaine; Boyden, Penelope A (2015) Matter of Fat: Are Lipids Antiarrhythmic? Circ Arrhythm Electrophysiol 8:1313-5 |
