Dissertation/Thesis Abstract

Characterization of molecular subsets of scleroderma using pathway analysis and animal models
by Sargent, Jennifer L., Ph.D., Dartmouth College, 2009, 161; 3356378
Abstract (Summary)

Scleroderma (systemic sclerosis; SSc) is a devastating autoimmune disease of unknown etiology for which there is no cure, and no truly effective therapies available. Immune dysfunction, fibrosis and vasculopathy are the three major features of the disease, however the interactions between these components are poorly understood. Highly heterogeneous clinical presentation of scleroderma has marred the advancement our understanding of causes and mechanisms of pathogenesis. Furthermore, with no molecular markers of disease activity and severity, development of appropriate animal models of scleroderma is extremely challenging.

Recently, Milano et al. [1] examined gene expression patterns in skin biopsies from morphea, diffuse and limited scleroderma patients and from healthy controls. They found that biopsies clustered together based on their gene expression and not strictly by traditional classifications nor by disease duration. These groupings, termed the molecular subsets of scleroderma’, represent unique subsets of disease each with significant associations to a distinct array of clinical parameters.

The work presented here seeks to address two major questions: What molecular mechanisms and signaling pathways underlie the molecular subsets of scleroderma? And, are any of the molecular subsets of scleroderma recapitulated in skin of animal models of the disease? We have used a hypothesis-driven approach to determine the relative contribution of pro-fibrotic cytokines TGFβ, IL13 and IL4 to gene expression in scleroderma biopsies. We report that TGFβ signaling underlies the diffuse-proliferation subset and that IL13 and IL4-associated signaling is enriched in the inflammatory subset of scleroderma. We have used to genome-wide profiling and interspecies comparative methods to determine which animal models of scleroderma best reflect the scleroderma subsets at a gene expression level. We report that IL13 signaling is required for manifestation of disease in cGVHD mice and that gene expression in skin from these animals recapitulates that of the inflammatory subset. Furthermore we report that skin from TSK2 mice shares gene expression features, including enrichment of a TGFβ-responsive signature, with the diffuse-proliferation subset. Thus we have shown that distinct signaling pathways underlie the subsets of scleroderma and that the cGVHD and TSK2 models of scleroderma best reflect gene expression of two subsets of human disease.

Indexing (document details)
Advisor: Whitfield, Michael L.
Commitee: Gorham, James D., Moore, Jason H., Varga, John
School: Dartmouth College
Department: Genetics
School Location: United States -- New Hampshire
Source: DAI-B 70/05, Dissertation Abstracts International
Subjects: Genetics, Bioinformatics, Immunology
Keywords: Gene expression, Microarray, Scleroderma, Systemic sclerosis
Publication Number: 3356378
ISBN: 978-1-109-16622-4
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