Peroxisome Proliferator-Activated Receptors (PPARs) are a family of conserved ligand activated nuclear receptor transcription factors heterogeneously expressed in mammalian tissues. PPARγ is recognized as a master regulator of adipogenesis, fatty acid metabolism, and glucose homeostasis, but genetic evidence also supports the concept that PPARγ regulates the cardiovascular system, particularly vascular function and blood pressure. There is now compelling evidence that the beneficial blood pressure lowering effects of PPARγ activation are due to its activity in vascular smooth muscle and endothelium, through its modulation of nitric oxide-dependent vasomotor function. Endothelial PPARγ regulates the production and bioavailability of nitric oxide, while PPARγ in the smooth muscle regulates the vasomotor response to nitric oxide. We recently identified retinol binding protein 7 (RBP7) as a PPARγ target gene that is specifically and selectively expressed in the endothelium. We will discuss the evidence that RBP7 is required to mediate the antioxidant effects of PPARγand mediate PPARγ target gene selectivity in the endothelium, as well as the work so far in determining the mechanism of RBP7:PPARγ interaction. (56)
Thesis
Role of PPARγ and retinol binding protein 7 in the vascular endothelium
University of Iowa
Master of Science (MS), University of Iowa
Autumn 2017
DOI: 10.17077/etd.jc7b1qli
Abstract
Details
- Title: Subtitle
- Role of PPARγ and retinol binding protein 7 in the vascular endothelium
- Creators
- Addison Wayne Woll - University of Iowa
- Contributors
- Curt D. Sigmund (Advisor)Frederick W. Quelle (Committee Member)Isabella M. Grumbach (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Molecular and Cellular Biology
- Date degree season
- Autumn 2017
- DOI
- 10.17077/etd.jc7b1qli
- Publisher
- University of Iowa
- Number of pages
- ix, 45 pages
- Copyright
- Copyright © 2017 Addison Wayne Woll
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 41-45).
- Public Abstract (ETD)
A goal of modern biomedical research is to advance the healthcare, lifespan, and quality of life for people. Many pharmaceuticals have off-target effects, aka side-effects. A goal of pharmacology is to identify druggable targets with fewer side-effects. Peroxisome proliferator-activated receptor gamma (PPARg) is a nuclear transcription factor, or a protein found in the nucleus of the cell which can turn on genes when activated by a signal. Flipping on PPARg leads to many beneficial effects; it was originally used an as anti-diabetic drug target which was also found to provide cardiovascular benefits. However, drugs targeting PAPRg also have negative side-effects such as weight gain and congestive heart failure.
Flipping on PPARg leads to a cascade of other proteins being made and/or activated. Retinol binding protein 7 (RBP7) is one such protein. Our lab has shown that global deletion of RBP7 was necessary for the beneficial effects of PPARg in the vascular endothelium, the layer of cells forming the inner-lining of cells in blood vessels. To study the mechanism of how PPARg and RBP7 interact, we changed key residues in the structure of RBP7, and predicted that RBP7 would no longer be able to interact with PPARg. I have generated a mouse model, where we can turn on RBP7, which will be used to determine the protective effects of increased RBP7 in mice. Since RBP7 is only found in endothelial cells, we predict that drugs targeting RBP7 might have fewer side-effects than existing drugs affecting PPARg action in many cell types.
- Academic Unit
- Interdisciplinary Graduate Program in Molecular Medicine
- Record Identifier
- 9983776612302771
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