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Title page for ETD etd-08282015-120707


Type of Document Dissertation
Author Savage, Sara Renee
URN etd-08282015-120707
Title The role of PPARβ/δ in diabetic retinopathy
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Joey Barnett Committee Chair
David Robertson Committee Member
John Penn Committee Member
Mary Zutter Committee Member
Vsevolod Gurevich Committee Member
Keywords
  • diabetic retinopathy
  • inflammation
  • transcription factor
  • angiogenesis
Date of Defense 2015-08-21
Availability unrestricted
Abstract
Diabetic retinopathy (DR) is disease of microvascular complications and is a leading cause of blindness in working age adults. DR consists of two main stages: the early non-proliferative stage is driven primarily by inflammation while the later proliferative stage is characterized by pre-retinal neovascularization. The peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is a transcription factor with known functions in lipid metabolism and glucose homeostasis. The role of PPARβ/δ in inflammation and angiogenesis, however, is not yet defined. To determine the action of PPARβ/δ in processes related to DR, rna-sequencing was first used to evaluate the effect of the PPARβ/δ antagonist GSK0660 on TNFα-induced inflammation in retinal endothelial cells. It was discovered that GSK0660 regulates TNFα-induced chemokine expression and subsequent leukocyte adhesion to endothelial monolayers via a mechanism involving inhibition of both ERK activation and NF-κB translocation. Further studies determined activation of PPARβ/δ with the agonist GW0742 increased expression of the angiogenic protein ANGPTL4 from retinal cells, increased endothelial cell tube formation, and promoted retinal neovascularization. GSK0660 was anti-angiogenic as it reduced expression of ANGPTL4 from retinal cells, inhibited endothelial cell proliferation and tube formation, and ultimately mitigated retinal neovascularization. Taken together, inhibition of PPARβ/δ was both anti-inflammatory and anti-angiogenic, resulting in reduced chemokine secretion, leukostasis, and retinal angiogenesis.
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