Dissertation
Examination of a model of systemic sclerosis, the Tight Skin 2 mouse: before, during and after fibrotic disease
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2012
DOI:
https://doi.org/10.17918/00008509
Abstract
Objective. The Tight Skin (Tsk) 2 mouse model of Systemic Sclerosis (SSc) has many features of human disease including tight skin, an altered extracellular matrix (ECM), and antinuclear antibodies (ANAs). The mutation that causes SSc-like disease in Tsk2/+ mice is unknown. Tsk2/+ mice were bred to identify the gene, investigate the role of ANAs and toll-like receptor 7 (TLR7) signaling in disease development and progression, and evaluate fibrotic ECM changes that are difficult to study in patients with SSc. Approach. Tsk2/+ mice were bred to a B6.chr 1-A/J background to fine-map Tsk2. Tsk2/+ mice were also bred to mice with an extra copy of Tlr7 (Yaa), or to mice deficient in Tlr7 (TLR7KO) to investigate the role of TLR7 in disease. Skin was examined for fibrosis and blood samples were examined for ANA production. Skin samples from B6. Tsk2/+ and WT mice at various ages were examined for ECM alterations, cellular infiltrates and fibrotic gene expression levels. Results. Genotyping narrowed the Tsk2 interval to less than 3 megabases, containing seven known genes: Gulp1, Col3a1, Col5a2, Wdr75, Slc40a1, Dnahc7b and Slc30a10. Skin fibrosis in Tsk2/+ mice occurred 8 weeks after the development of the 'tight skin' phenotype. Dermal collagen accumulation was significantly increased in Tsk2/+ mice only after 10 weeks of age, and at 17 weeks of age B6. Yaa. Tsk2/+ male mice had significantly more fibrosis compared to B6. Tsk2/+ and TLR7KO. Tsk2/+ male mice. ANA production was not observed until at least 14 weeks of age, and was not different between Tsk2/+ and WT littermates. In pre-fibrotic skin of Tsk2/+ mice, there was increased expression of genes associated with fibrosis, and a significant increase in elastic fibers. This abnormal elastic fiber phenotype was also observed in diseased tissue from two patients with SSc. Conclusions. The new Tsk2 interval includes two strong candidate genes, Col3a1 and Col5a2. TLR7 signaling and ANA production are important contributors to disease severity, but are not necessary for disease initiation. The disease state in the Tsk2/+ mouse is progressive, and therefore this model is valuable for the examination of early, pre-fibrotic pathology that is otherwise challenging to examine in SSc.
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Details
- Title
- Examination of a model of systemic sclerosis, the Tight Skin 2 mouse
- Creators
- Kristen Brooke Long
- Contributors
- Elizabeth P. Blankenhorn (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xx, 155 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888944204721