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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08282015-120707 |
| Date | 28 August 2015 |
| Creators | Savage, Sara Renee |
| Contributors | David Robertson, Vsevolod Gurevich, Mary Zutter, John Penn, Joey Barnett |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08282015-120707/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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