Project 3
Mitochondrial dynamics protein Drp1 regulation of endothelial metabolism, ROS, & ischemic vascular disease
The overall goal of Project 3 is to investigate a novel relationship between ROS (redox) signaling and EC glycolysis that is orchestrated by the mitochondrial dynamics protein, Drp1. Drp1 functions as a novel redox sensor that transmits VEGF-derived H2O2 signaling into behavioral changes in ECs to enhance angiogenesis.
Central Hypothesis
Excess ROS induced by cardiovascular risk factors such as diabetes can impair the balance between redox signaling and metabolism, resulting in endothelial dysfunction (e.g. impaired angiogenesis), which contributes to vascular disease, such as peripheral artery disease (PAD). Preliminary data support the hypothesis that VEGF/NOXderived H2O2 stimulates Cys oxidation of Drp1 to promote mitochondrial fission and mitoROS, which drives glycolysis and endothelial activation (e.g. angiogenesis) by oxidative activation of AMPK as well as increased PFKFB3 expression in ECs. By contrast, in disease conditions such as diabetes, this pathway is impaired due to hyperactivation of Drp1 via phosphorylation which promotes pathological mitochondrial fragmentation-excess mitoROS that leads to VEGFR2 degradation.
Lead Bio
Dr. Masuko Ushio-Fukai is a Professor of Medicine & Director of the Redox Signaling Program in the VBC at MCG/AU. She is a leading expert in ROS metabolism and redox signaling, with expertise on the crosstalk between NADPH oxidases (NOX) and mitochondria in ECs & in the role of this pathway in angiogenesis and ischemic vascular disease over the past twenty years.
Her laboratory has significant experience in measurements of mitochondrial metabolism & ROS signaling in ECs and was one of the first to demonstrate that H2O2 derived from NOX plays an essential role in reparative neovascularization using animal models of peripheral artery disease (PAD). In collaboration with Dr. Tohru Fukai, she has been investigating the role of Cu transport proteins in angiogenesis & has discovered a novel link between Cu transport proteins and ROS signaling that contributes to inflammation and angiogenesis.
Thus, she has extensive expertise in the area of ROS/redox imbalance, EC dysfunction & angiogenesis, and her laboratory is well equipped using various techniques to measure ROS in vitro & in vivo.
As the leader of Project 3, Dr. Ushio-Fukai will explore the role of endothelial mitochondrial dynamics protein, Drp1, in the interplay between NOX/mitoROS signaling, glycolysis, and ischemic vascular disease. Dr. Ushio-Fukai will serve as PPG Co-Director, Project 3 leader, & Co-I of Core A & Core C.
Project Team
Dr. Masuko Fukai
- Project Lead
Sudhahar Varadarajan
- Research Associate
Rajalakshmi Karmegam
- Sr Research Associate
Dipankar Ash
- Assistant Research Scientist
Sheela Nagarkoti
- Postdoc Fellow
Shikha Yadav
- Post Doc
Stephanie Spears
- Sr Research Associate
Kamarajan Rajagopal
- Postdoc Fellow
Leslie Poole
- Contributor
Kate Carroll
- Contributor
Vijay Patel
- Consultant