Dissecting and Targeting Deregulated Endothelial Metabolism in Diabetes-Induced Microvasculopathy

This Award will provide Dr. Ibrahim with training and experience necessary to become an independent investigator in microvascular research. The proposed career plan includes focused coursework and mentorship from a multi-disciplinary group of established researchers and professional educators. The training plan focuses on four training objectives: (1) Academic training in neurovascular biology. (2) Hands on training in confocal imaging and bioenergetic profile measurements. (3) Professional development and grant writing (4) Participation in scientific community services and networking. Dr. Al-Shabrawey will serve as the primary mentor and will oversee the training plan. Dr. Abel has extensive experience in glucose metabolism and transport in cardiovascular system. Dr. Yeudall and Dr. Jones will provide mentorship for professional development. The long-term goal of the proposed research is to identify novel targets to treat or prevent Diabetes-induced microvasculopathy (DIM) in those who are at high risk for developing microvascular complications in the heart, brain, eye, and kidney. Although endothelial activation is a common underlying causative factor, the molecular basis of such activation remains a big gap in our knowledge. With the advantage of retinal accessibility for live animal imaging to monitor pathological changes in vasculature; this proposal will address this gap in knowledge using Diabetic retinopathy (DR) as the disease model. Tissue hypoxia is the most common risk factor associated with DIM. Thus, the central hypothesis is that in DR, hypoxia triggers the energy sensor AMPK to shift the metabolism of endothelial cells (ECs) towards Glut1-mediated glycolysis. This metabolic shift activates endoplasmic reticulum (ER) stress and switching EC from quiescent to angiogenic phenotype. We will test the hypothesis by following aims: Aim1 will determine the role of endothelial AMPK in shifting bioenergetic metabolism and switching EC from quiescent to angiogenic phenotype in DR; Aim2 will test if targeting endothelial Glut1 effectively inhibits EC switch to angiogenic phenotype to prevent microvascular dysfunctions in DR; and Aim3 will determine how alteration in glucose metabolism induces ER stress, leading to endothelial dysfunctions. The successful completion of the proposed research and training plan will provide the knowledge and experience necessary to compete successfully for an R01 and achieve my goal of becoming an independent investigator. (AHA Program: Career Development Award)