Dual mTOR Signaling in Scleroderma Lung Disease

Glenn Rosen, MD
Stanford University School of Medicine

New Project Summary:

Based on their work in idiopathic pulmonary fibrosis (IPF), the Rosen lab, together with the lab of Dr. Robert West, will generate gene expression signatures from scleroderma lungs with interstitial lung disease (ILD). Lung biopsies and formalin-fixed, paraffin-embedded lung samples obtained through the Stanford ILD clinic and in collaboration with the laboratory of Dr. Carol Fegahli-Bostwick at the University of Pittsburgh will be analyzed by several methods. 3′-end sequencing for expression quantification (3SEQ) expression profiling will be used to generate a gene expression signature from scleroderma lung. Since 3SEQ profiling can be performed on precise areas of the lung (0.6mm core micro-dissections), this provides an opportunity to generate gene expression profiles from fibrotic foci (small group of cells) and abnormal vessels as well as from non-fibrotic areas of the scleroderma lung. By comparing the expression signatures of these areas to expression profiles from normal lung, the researchers hope to determine which signaling pathways are activated at discrete sites in scleroderma lung. Comparisons will also be made to fetal lung and cancerous lung expression signatures and will provide a useful comparison for genes involved in extracellular matrix production and its regulation. Additionally, the researchers will perform multidimensional molecular microscopic profiling (MMMP) using commercial antibodies or RNA in situ hybridization probes to identify the cells having altered signaling for the genes of interest identified in the gene expression profiling. This may provide an avenue for identifying which cell types have dysregulated signaling pathways and whether a temporal progression in dysregulation can be seen among the different cell types in the non-fibrotic areas, the abnormal vessels and the fibrotic areas of the lung. The 3SEQ and MMMP data will provide a basis for exploring biological mechanisms in scleroderma fibrotic lung. Additionally, the expression data will be correlated with clinical data to determine whether any candidates for biomarkers emerge. This project is complementary to the gene expression profiling performed by Dr. Michael Whitfield's laboratory in scleroderma skin and may reveal parallels between gene expression in two commonly affected organs in scleroderma.

What this project means for people with scleroderma:

Through the lab's planned analysis using 3SEQ profiling of gene expression in scleroderma lung, they hope to uncover genes with abnormal expression in areas of lung inflammation and scarring, which may both help with understanding the cause of scleroderma lung disease and identify targets for new treatments.

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