Date of Award
Spring 6-30-2025
Document Type
Thesis (Master's)
Department or Program
Microbiology and Immunology
First Advisor
Patricia A. Pioli
Second Advisor
Michael L. Whitfield
Abstract
Abstract
Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by multiple-organ involvement and notably by fibrosis. Current therapies for SSc focus on symptom managements and treating specific organ related complications. However, heterogeneous nature of the disease further complicates treatment responses and hinders the development of new therapies. Therefore, there is a critical unmet need for the development of patient-specific therapeutics.
The objectives of this thesis were: (1) to evaluate the therapeutic potential of Bardoxolone Methyl (CDDO-Me) in both SSc fibroblasts and SSc macrophages. To achieve these goals, I utilized both wet-lab analysis tools and computational analysis.
As part of a drug-repurposing effort, I evaluated the potential therapeutic efficacy of Bardoxolone Methyl, also known as CDDO-Me, which was originally developed at Dartmouth College. CDDO-Me has been explored in other clinical manifestations including chronic kidney disease (CKD), PAH associated with connective tissue disease (PAH-CTD), pulmonary hypertension associated with ILD, Alport syndrome, and many other. CDDO-Me is a synthetic oleanane triterpenoid and a very strong activator of Nrf2 pathways. CDDO-Me activates Nrf2 downstream genes by modifying Nrf2 negative regulator, KEAP1 (E3 ligase adaptor Kelch-like ECH-associated protein 1). In Chapter 2, I confirmed the dual efficacy of CDDO-Me treatment in both lcSSc fibroblasts and lcSSc macrophages, which shows anti-fibrotic and immunomodulatory effect of CDDO-Me, respectively. CDDO-Me inhibited expression of pro-fibrotic markers in SSc fibroblasts, and downregulated expression and production of SSc immune-phenotypic markers in SSc macrophages. This study supports dual effect and the therapeutic potential of CDDO-Me by modulating two different effector cells in SSc.
Recommended Citation
Yang, Heetaek; morris, Emily A.; Wang, Chen-Yu; Orzechowski, Nicole M.; Whitfield, Michael; and Pioli, Patricia, "CDDO-Me Attenuates Fibroblast and Macrophage Activation in Limited Cutaneous Systemic Sclerosis" (2025). Dartmouth College Master’s Theses. 253.
https://digitalcommons.dartmouth.edu/masters_theses/253
