Regulation of Positional Identity in Scleroderma Skin

Howard W. Chang, MD, PhD
Stanford University

Project Summary:

Scleroderma is a disease characterized by excess fibrosis (hardening) in skin and other organs, but this fibrosis often occurs in specific places on the body, such as the fingers, hands and face. Dr. Chang hypothesizes that site-specific differences in fibroblasts may explain, in part, the tendency of scleroderma-related fibrosis to occur in these specific locations. His laboratory has shown that fibroblasts, the cells responsible for fibrosis (and more generally, the maintenance of the extracellular matrix), isolated from different anatomic sites, are distinguishable from each other by the pattern of genes that are activated within them. This "positional identity" of adult fibroblasts is dependent on their continuing appropriate expression of key master regulatory genes (HOX genes and noncoding RNAs). Further, Dr. Chang hypothesizes that fibroblasts are master regulatory cells in determining the organization of cells within the surrounding tissue. Thus if the positional identity of fibroblasts is lost in scleroderma, this might further support a microenvironment favorable for the progression of fibrosis.

Additionally, Dr. Chang is collaborating with clinical investigators to evaluate imatinib mesylate-a pharmaceutical agent that inhibits a type of enzyme called tyrosine kinases-- in scleroderma.

Research Update:

Researchers in Dr. Chang's lab have discovered that a specific type of RNA molecule, called a lincRNA, controls the expression of HOX genes in fibroblasts. To determine how this plays a role in scleroderma, they performed a microarray (see Dr. Michael Whitfield's project summary to learn more about microarrays) analysis of HOX RNA from scleroderma and normal skin biopsy samples and found that a distinct subset of lincRNAs are overexpressed in scleroderma skin. They have also made significant progress in characterizing the function of these overexpressed lincRNAs. In collaboration with Dr. Radhika Atit's lab, Dr, Chang is exploring the hypothesis that Wnt (a complex network of proteins responsible for multiple physiological processes) signaling is controlled by HOX gene expression in the skin and that its disruption in scleroderma skin contributes to fibrosis. 

What this project means for people with scleroderma:

In scleroderma patients, the hardening of skin occurs in some places more than others. Understanding what gives skin from different anatomic sites their sensitivity or resistance to scleroderma could lead to new treatment strategies for scleroderma.

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