The Ras activator RasGRP3 mediates diabetes-induced embryopathy and ET1-induced vessel morphogenesis

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  • March 22, 2019
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  • Randhawa, Paramjeet Kaur
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • Blood vessel formation is critical throughout the life of vertebrate organisms, and vessel dysfunction jeopardizes both fetal development and adult survival. Diseases such as diabetes disrupt vessel regulation and contribute to numerous vascular pathologies. Therefore, understanding blood vessel regulation in pathological conditions is essential to devising preventative treatments. The work presented in this dissertation aims to understand how perturbations in the Ras activator, Ras guanyl-releasing protein 3 (RasGRP3), mediate aberrant vessel morphogenesis. We have identified RasGRP3 as a downstream component in an endothelin-1 (ET1) signaling pathway. ET1 signaling is a primary mediator of vascular pathology in diabetes. I hypothesized that RasGRP3 mediates diabetes-induced embryopathy and changes in endothelial cell behavior and vessel morphology. Work by Joanna Fried and Jessica Heinz demonstrated that RasGRP3 is required for embryogenesis in diabetic conditions. In collaboration with Dr. Svetlana Rylova, I determined that activated RasGRP3 promotes Ras-ERK signaling, which can be induced by phorbol ester or endothelin-1 (ET1). Dr. Rylova demonstrated that overexpression of activated RasGRP3 is sufficient to induce Ras-ERK activation and perturb directional migration. In collaboration with Stephanie Kiser, I showed that RasGRP3 is required for ET1-induced Ras activation, proliferation and migration in endothelial cells. Using an embryonic stem cell model to simulate pathological angiogenesis, we also identified a role for RasGRP3 in ET1-induced vessel dysmorphogenesis. By identifying the molecular requirements that mediate RasGRP3-dependent effects, we can understand how changes in cellular or morphological processes induce vascular pathology. The data herein advance our understanding of RasGRP3-vessel pathology as they may pertain to diabetic conditions.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology."
Advisor
  • Bautch, Victoria
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
Date uploaded
  • March 18, 2013

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