The Role of Glycosyl Ceramides in Heart Failure and Recovery

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PROJECT SUMMARY/ABSTRACT Candidate: Eleni Tseliou, MD, PhD is cardiology fellow at the University of Utah (UU) in Salt Lake City as part of the Physician Scientist Training Program (PSTP) and currently a T32 research fellow at Dr. Drakos laboratory at the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI). Dr. Tseliou’s research project is focused on the impact of fatty acid (FA) metabolism on cardiac remodeling and myocardial recovery. Dr. Tseliou’s long-term goal is to independently direct an extramurally funded laboratory with research focused on metabolic mechanisms that affect cardiac heart failure (HF) and recovery. Career Development: This award will support Dr. Tseliou’s career development by building on her existing training in cardiovascular (CV) health and disease. Dr. Tseliou will receive extensive training in the planning and execution of studies investigating myocardial FA metabolism in humans, animal models and in vitro. The career development plan outlines a coordinated effort to train the candidate in areas including mass-spectrometry based lipidomic and metabolomic assessment of serum and tissue in HF; development and phenotyping of animal transgenic models of HF. Hands- on learning and mentoring opportunities will be complimented by broader training in current topics by regular attendance of didactic courses (research training, research interactions, career guidance, publications, research ethics and grant writing) molecular cardiology seminars and conferences. Environment: The University of Utah is an ideal environment for Dr. Tseliou’s career development. The CVRTI is a freestanding research institute located at the UU Health Sciences Center with a long-standing commitment to the promotion and advancement of early-career investigators in the field of CV biology. CVRTI faculty is well-funded and have excellent track records in mentoring junior physician-scientists to become independent investigators. This environment has a long and very rich history of excellence in basic and translational CV research and will provide Dr. Tseliou with the opportunity of collaboration across different specialties and the resources needed to complete the proposed studies. Moreover, the UU and Dr. Drakos integrated basic science and clinical research team will provide Dr. Tseliou with the unique opportunity to phenotype left ventricular assist devices (LVAD) patients with and without myocardial recovery, who are the source of precious serial human myocardial tissue and serum before and after the therapeutic intervention. Research: The central hypothesis of this project is that reduced cardiac specific expression of UGCG (UDP-glucose ceramide glucosyltransferase, a gene that catalyzes the glycosylation of ceramide) leads to the deregulation of FA metabolism and predisposes to HF. We seek to understand the mechanisms responsible for these phenomena. While several mechanisms of FA metabolism have been described, we contend that there are unexplored pathways influenced by altered ceramide:GlcCer balance as they relate to CV health and disease. Specifically, we hypothesize that UGCG overexpression in HF may help reverse cardiac hypertrophy and ventricular dilation, improve cardiac function and restore CV health.