Date of Award

Summer 2024

Language

English

Embargo Period

8-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Program

Biology

First Advisor

Melinda Larsen

Second Advisor

Thomas Begley

Third Advisor

Paolo Forni

Committee Members

Melinda Larsen, Thomas Begley, Paolo Forni, Yubing Xie

Keywords

Fibrosis, NOD/ShiLtJ, Saliva, MSC, Salivary Gland

Subject Categories

Biology

Abstract

Fibrosis is defined by the overgrowth, hardening, and scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. In the case of persistent injury or autoimmunity, as in Sjogren’s Disease, the ECM persists. Fibrosis can be studied in multiple animal models. Our lab has published the use of a mouse submandibular salivary gland partial resection model. In this procedure 40% of the left distal tip of the submandibular salivary gland (SMG) is excised. This leads to a chronic sustained fibrotic response in a localized region. The use of the non-obese diabetic mouse (NOD) has been widely used as a model for the research of Sjogren’s Disease (SjD) which develops secondary to Type 1 diabetes. The mouse develops progressive infiltrates in the salivary glands over time that are associated with loss of SMG function, leading to hyposalivation. The exact cause of hyposalivation is unknown. However, fibrosis has been shown to play an important role in the decreased function of many organs in various diseases. This includes hyposalivation in SjD, decreased lung function in Idiopathic Pulmonary Fibrosis (IPF) and decreased kidney function in chronic kidney disease (CKD). In these diseases fibroblasts migrate and differentiate into myofibroblasts. Some of the factors which promote a fibrotic response include the following: transforming growth factor (TGF)-β, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Epithelial-mesenchymal transition is promoted by TGF-β as well as the transition of fibroblasts to myofibroblasts. The use of antifibrotic drugs have been FDA approved for IPF. One of these drugs is the small molecule Nintedanib. Nintedanib targets multiple tyrosine kinases, including the platelet-derived growth factor receptors, vascular endothelial growth factor receptors 1 and 2, and fibroblast growth factor receptors 1–3. Mesenchymal Stromal/Stem Cells (MSCs) are multipotent cells that can self-renew and give rise to specialized cell types such as bone, cartilage, and muscles Tissue-resident MSCs are found in many locations throughout the body; here we extracted them from Submandibular Salivary Glands as part of a mixed stromal population. MSCs help maintain connective tissue during homeostasis. After injury or negative assault on tissue they are responsible for creating biologically active molecules to aid in regeneration and restoration. In previous work, mesenchymal stem cells have been shown to reduce fibrosis when implanted into multiple injury models in multiple tissues. By implanting them in the resection model, at the location of injury we hypothesized we would detect an increased healing response relative to an untreated injured gland. The efficacy of treatment for hyposalivation in mice can be measured by collecting and analyzing saliva. Determining the best collection method for reproducibility and survival is crucial. The saliva collected can also be analyzed using Raman Spectroscopy to detect minute molecular differences in healthy vs. disease model animals. This may allow for the detection of disease early, allowing for current treatments to be more effective and possibly extend the life of healthy tissues.

License

This work is licensed under the University at Albany Standard Author Agreement.

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Available for download on Sunday, August 09, 2026

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