Type of Document Dissertation Author Madamanchi, Aasakiran URN etd-02092016-111936 Title α2β1 integrin in Retinopathy and Sprouting Angiogenesis Degree PhD Department Cancer Biology Advisory Committee
Advisor Name Title Dr. Jin Chen Committee Chair Dr. John S. Penn Committee Member Dr. John Stafford Committee Member Dr. Mary Zutter Committee Member Dr. Volker Haase Committee Member Keywords
- α2β1 Integrin
- Mathematical Models
Date of Defense 2014-07-11 Availability restricted AbstractAngiogenesis expands the vascular network during normal development and in response to angiogenic stress. Dysregulation of this dynamic process contributes to the pathogenesis of many diseases including retinopathies. The α2β1 integrin, a collagen and laminin receptor which is linked to risk of vascular retinopathy, plays an important yet incompletely understood role in angiogenesis. In this dissertation, I employ multidisciplinary approaches to examine the function of this integrin during both pathological and developmental angiogenesis in the retina.
The major goal is to contribute clinically relevant knowledge through mechanistic investigation of the link between α2β1 integrin in vascular retinopathies and careful exploration of this integrin’s role in angiogenesis. The central questions addressed in this thesis are, 1) does the α2β1 integrin contribute to the progression of retinopathies, and through what mechanism? And, 2) how does α2β1 integrin interface with the major angiogenesis pathways, and does that explain the divergent effects of α2-integrin deletion in different vascular beds?
Using the oxygen-induced retinopathy (OIR) model for retinopathy of prematurity (ROP) on wild type and α2-null mice, I elucidated the role of α2β1 integrin in both endothelial cells as well as in the retinal microenvironment. I uncover a novel, potentially mechanistically important role for the integrin in regulating retinal Müller cell function.
To clarify the role of α2β1 integrin in angiogenesis, I use in vitro, in vivo and in silico methods to characterize wild type and α2-null mice during postnatal development of the retinal vasculature. I develop a hybrid mathematical model to simulate cell signaling and vascular morphology in the developing postnatal murine retina. Using this model, I study how the VEGF-notch signaling system directs the development of morphological features including, retinal vascularization, plexus density, and plexus irregularity. I also use the model to predict how crosstalk to the VEGF-Notch axis from other angiogenic signals affects vascular phenotypes. Finally, I use the computational model as a platform for evaluating proposed signaling relationships between α2β1 integrin and the VEGF-Notch axis and present a molecular model which may explain how α2-integrin deletion causes disparate vascular phenotypes in different vascular microenvironments.
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