Project 2
Leptin regulation of endothelial cell metabolism & vascular oxidative stress in diabetes-associated cardiovascular disease
Project 2 investigates endothelial dysfunction in type 1 diabetes (T1D), focusing on excessive activity of the PFKFB3/glycolysis–lactate–NOX1–ROS signaling pathway. It also explores leptin’s role in endothelial cell metabolism and sex differences (hormones and chromosomes) in the severity of vascular dysfunction.
Central Hypothesis
The central hypothesis is based on novel preliminary data indicating that disruption of endothelial leptin signaling promotes EC dysfunction via changes in metabolism and redox balance. The mechanisms involved include increased PFKFB3 driven glycolysis that enhances Nox1/ROS and inhibition of eNOS/NO to promote redox imbalance that impairs endothelial function in type1 diabetes (T1D). Sex differences in leptin biology are proposed to account for the increased susceptibility of female mice to EC dysfunction in T1D. Preliminary results also suggest that T1D contributes to endothelial dysfunction via enhanced PFKFB3-driven glycolysis induced oxidative stress mediated through NADPH oxidase NOX1. These preliminary data support the hypothesis that EC metabolism shapes EC function via sex-specific, Nox1 and leptin-dependent mechanisms. This hypothesis will be tested by performing the following specific aims.
Lead Bio
Dr. Eric Belin de Chantemele is a Professor of Medicine in the VBC at MCG/AU. He has more than 15 years of expertise investigating the interactions between altered metabolism and cardiovascular diseases and more specifically, has investigated the role of the adipokine leptin as a regulatory mechanism influencing endothelial function, oxidative stress, inflammation, and blood pressure regulation. Dr. Belin de Chantemele also has expertise in the role of sex differences in cardiovascular disease and has uncovered a novel link between female sex, leptin, aldosterone and blood pressure. Dr. Belin de Chantemele is well qualified to lead Project 2. Co-I for Project 2 is Dr. David Fulton, a Regents Professor and Director of the VBC at MCG/AU and a leading expert in the area of endothelial biology and NO/eNOS and NADPH oxidase in cardiovascular disease for the past twenty years. Dr. Fulton will serve as a Co-I and provide additional studies and mechanistic insight on how glycolysis and PFKFB3 regulate eNOS function and redox balance. Dr. Fulton will also serve as co-director of Core C
Project Team
Dr. Eric Belin de Chantemele
- Project Lead
Dr. David Fulton
- Co-Investigator
Simone Kennard
- Sr Research Tech
Benjamin Wall
- Research Assistant
Adam Salon
- Postdoc Fellow
Jing Ma
- Research Associate
Joseph Costello
- Sr Research Tech
Vijay Patel
- Consultant