Author ORCID Identifier
https://orcid.org/0000-0002-1986-6491
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemical Biology
First Advisor
Maria E. Teves
Abstract
Systemic sclerosis (SSc) is a severe autoimmune disease characterized by progressive fibrosis of the skin and internal organs, leading to high morbidity and mortality. Fibrosis in SSc is driven by persistent activation of myofibroblasts, which produce excessive extracellular matrix and collagen. Although several profibrotic signaling pathways have been implicated in SSc, the molecular mechanisms regulating these pathways remain incompletely understood. The primary cilium functions as a critical signaling hub for pathways involved in fibrosis, including Hedgehog, Wnt, and transforming growth factor beta (TGF-β). Emerging evidence suggests that cilia-associated genes may be dysregulated in SSc, yet their role in disease pathogenesis remains largely unexplored.
This study investigates the role of sperm-associated antigen 17 (SPAG17), a cilia-associated protein, in regulating fibrotic signaling. Analysis of human SSc samples demonstrated reduced SPAG17 expression. Using murine knockout models and CRISPR/Cas9-mediated deletion in human cells, loss of SPAG17 was shown to promote a profibrotic phenotype characterized by increased α-smooth muscle actin expression, enhanced collagen type I production, and activation of TGF-β signaling. Furthermore, SPAG17 deficiency resulted in shortened primary cilia and disrupted localization of key ciliary signaling proteins. These alterations were associated with increased myofibroblast differentiation and fibrosis. Structural modeling and expression studies further characterized murine SPAG17 protein. Collectively, these findings identify SPAG17 as a previously unrecognized regulator of primary cilium function and fibrotic signaling. Reduced SPAG17 expression may contribute to the pathogenesis of SSc by promoting aberrant cilia-mediated signaling and persistent myofibroblast activation.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-6-2026
Included in
Disease Modeling Commons, Molecular Biology Commons, Rheumatology Commons, Skin and Connective Tissue Diseases Commons