Functional characterization of systemic sclerosis transcriptome.

摘要

Systemic sclerosis (SSc) is a rare autoimmune condition that is characterized by extensive fibrosis of the skin, vascular dysfunction and internal organ involvement such as pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH) and scleroderma renal crisis. There are no FDA-approved therapies available and the understanding of the disease pathogenesis is limited. We have identified four gene expression subsets in SSc.;A focus of the research presented here is to understand which animal models best represent human SSc, and which subset they best approximate. Among those models is the Tsk2/+ mouse model. The Tsk2/+ mouse model has been used for studying fibrosis, but its underlying causative mutation has been unknown. The identification of the causative mutation for Tsk2/+ is the focus of Chapter 2.;Recent work by Whitfield et al has greatly accelerated the understanding of global gene expression changes in SSc. I have investigated the genome wide changes of the SSc using RNA-Sequencing (RNA-Seq). We show that we can rebuild the SSc transcriptome at single base pair resolution. We demonstrate potential environmental triggers and identify genetic changes that may contribute to the SSc pathogenesis In Chapter 3, we will show that the common allele Rs2723187 in IL37 gene leads to over-reactive immune response upon CpG oligodeoxynucleotides stimulation.;Finally, we show the comparison between eight different animal models of SSc (Tsk1, Tsk2/+, SclGVHD, Bleomycin-induced fibrosis, Snail transgenic mouse, kinase-deficient type II Tgf-beta receptor (TbRIIDk-fib) mouse, B-catenin/Wnt model and PTEN knockout model) and human SSc. Our interspecies comparisons suggest the Tsk2/+ mouse at 4 and 12-week of age and Snail transgenic mouse approximate the fibroproliferative SSc; SclGVHD and TbRIIDk-fib mouse resemble the inflammatory SSc; other mouse models do not resemble SSc on the molecular level.