Year of Award

2024

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Biochemistry & Biophysics

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Bruce Bowler

Commitee Members

Travis Wheeler, Stephen Lodmell, Jesse Hay

Keywords

Biased agonism, Biased signaling, Molecular dynamics, PPAR, RNA-sequencing, Selective modulators

Abstract

Peroxisome proliferator activated receptor gamma (PPARγ) is a nuclear receptor, a type of ligand dependent transcription factor heavily studied as pharmaceutical targets for a variety of medical conditions. Nuclear receptors bind enhancer regions of DNA and recruit coregulator proteins in a ligand dependent manner, thereby altering transcription. PPARγ has been studied as a treatment target for type II diabetes; however, severe side effects plague FDA-approved PPARγ agonists. This led to research into partial agonists, which have shown better outcomes in mice. Our lab’s recent research has discovered that partial agonists, as well as the experimental full agonist GW1929, induce a biased coactivator recruitment profile compared to the FDA-approved agonist rosiglitazone. Specifically, GW1929 recruits a particular class of coactivators more efficaciously than rosiglitazone while both recruit another class of coactivators with similar affinity.

The goal of this dissertation is to evaluate biased signaling in human cells, uncover the mechanism for biased agonism induced by GW1929, and determine how cellular context affects PPARγ signaling. Using RNA sequencing, we evaluated human adipocytes for signaling bias and found that, despite targeting the same receptor, GW1929 and rosiglitazone induce different transcriptomes leading to biased pathway signaling. Furthermore, we investigated the interactions between multiple ligands and PPARγ in the presence and absence of coregulators using molecular dynamics simulations. We found that GW1929 induces unique global changes to PPARγ, providing a potential mechanism for GW1929-induced biased agonism. Further RNA sequencing with a panel of 11 ligands uncovered a group of genes downregulated by agonists that are associated with a different suite of transcription factors than genes upregulated by agonists. These results test biased signaling for PPARγ ligands and highlight the potential to design biased PPARγ agonists based on PPARγ dynamics.

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Available for download on Sunday, August 27, 2028

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