Date of Award

Summer 2024

Language

English

Embargo Period

7-22-2024

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College/School/Department

Department of Biomedical Sciences

Program

Biomedical Sciences

First Advisor

Janice Pata

Second Advisor

Melinda Larsen

Committee Members

Nicholas Mantis

Keywords

Fibrosis, Salivary Glands, Pdgfra+/b+ Fibroblasts, TGFB Signaling, Inflammation

Subject Categories

Biomedical Informatics | Genetic Processes | Medical Cell Biology | Medical Genetics | Medical Immunology | Medical Molecular Biology | Medical Pathology | Oral and Maxillofacial Surgery | Oral Biology and Oral Pathology | Oral Medicine | Pediatric Dentistry and Pedodontics | Periodontics and Periodontology | Veterinary Pathology and Pathobiology

Abstract

Fibrosis is of significant concern to the medical community as numerous disease processes are characterized by progressive fibrosis leading to organ damage. We begin the process of examining the mechanism of fibrosis to salivary gland hypofunction and briefly consider Sjögren’s Disease (SjD). Method: We employed single-cell RNA sequencing data from a reversible mouse salivary gland injury model and from NOD/ShiLtJ mice, a model of secondary SjD. We performed treatment comparisons with the help of Seurat dotplots and UMAPS. Using differential gene expression analysis and the publicly available R packages: clusterProfiler, WikiPathways and Cytoscape, we identified the processes and pathways increased in the fibroblast population and the Pdgfra/b copositive population and visualized the hits from our dataset in a published fibrosis pathway network. Results: We determined that fibrosis of mouse salivary glands is orchestrated by a subtype of fibroblasts identified as Pdgfra/b copositive fibroblasts. This subtype expands in response to ligation injury likely through TGFB signaling. We highlight that fibrosis is a characteristic process of the fibroblasts in a Sjögren’s Disease mouse model. We show the molecules involved in the fibrosis process in the Pdgfra/b copositive fibroblasts. The reversible fibrosis mouse model is a relevant model showing concordance with the human ductal obstructive injury. Conclusions: Pdgfra/b copositive fibroblasts are a disease subtype that rise upon injury and are proliferative and fibrotic. Bioinformatics revealed five processes are increased in fibroblasts in response to injury: blood circulation, leukocyte migration, cell chemotaxis and extracellular matrix organization. G-coupled protein receptor signaling is the most significant pathway increased through Wnt signaling which give rise to the TGFB mediated fibrosis. This work paves the way for further targeted in-vivo and in-vitro analyses for the contribution of TGFB to this fibroblast disease sub-type.

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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