Abstract/Details

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


2011 2011

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Abstract (summary)

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.

Indexing (details)


Subject
Molecular biology;
Developmental biology
Classification
0307: Molecular biology
0758: Developmental biology
Identifier / keyword
Health and environmental sciences; Biological sciences; Angiogenesis; Diabetes; Diabetic embryopathy; Diacyclgycerol; Endothelial cells
Title
The Ras activator RasGRP3 mediates diabetes-induced embryopathy and ET1-induced vessel morphogenesis
Author
Randhawa, Paramjeet Kaur
Number of pages
143
Publication year
2011
Degree date
2011
School code
0153
Source
DAI-B 72/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124656397
Advisor
Bautch, Victoria L.
Committee member
Bautch, Victoria L.; Cheney, Richard; Conlon, Frank; Donaldson, Julie; Fanning, Alan; Rogers, Stephen
University/institution
The University of North Carolina at Chapel Hill
Department
Biology
University location
United States -- North Carolina
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3456296
ProQuest document ID
871427578
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/871427578
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