The goal of this proposed clinical-translational study is to not only advance nursing science, but also the skin fibrosis field by (1) elucidating crucial molecular pathways driving fibrosis and (2) correlating them with patient-centric outcome measures of disease severity. Because scleroderma or systemic sclerosis (SSc) is an extreme phenotype of fibrosis, extensively related to skin, it presents an opportunity to translate the methods and results of animal studies of skin fibrosis and wound healing for use in human studies. Capitalizing on existing microarray gene expression data and matching clinical assessment data from (1) SSc patients and (2) normal and SSc patient skin fibroblasts, our multidisciplinary team proposes to apply high-throughput genomic technologies to investigate the interplay between chemokines and extracellular pathways. Our three specific aims are as follows: (1) To identify the genes involved in chemokine-modulated progression of fibrosis, we propose to (a) identify differentially expressed genes between fibrotic stimulated fibroblasts treated with chemokine cocktails and (b) validate gene expression profiles by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry; (2) To identify the genes that participates in chemokine modulation within the context of fibrotic severity (we predict that chemokines modulate the change the fibrotic process in fibroblast and hypothesize a direct correlation between distinct chemokine profiles and degree of fibrotic), we propose to (a) use a global approach to measure the changes in the gene expression profile before and after chemokine cocktail treatment of SSc patients fibroblast and (b) correlate the profiles with modified Rodnan skin score (mRSS), which is the clinical assessment of severity of skin thickening; (3) To explore the genes in the chemokine pathway that differentiate severity of fibrosis in SSc tissue biopsies (we postulate unique chemokine gene signatures that not only regulate fibrosis, but also influence disease severity), we propose to (a) investigate possible relationships between chemokine gene alterations and fibrotic outcomes and (b) correlate patient SSc mRSS scores with chemokine signaling pathways using three large SSc studies gene expression data available from the publicly available database Gene Expression Omnibus (GEO).
Fibrotic diseases are a major public health problem that result in significant morbidity and mortality worldwide. Fibrosis is one of the largest groups of disorders for which there are no effective therapies; thus, there is an urgent need to (1) improve patient outcomes and (2) alleviate patient symptoms and suffering related to fibrosis. Our proposed project will address this need by (1) elucidating key molecular pathways driving the progression of fibrosis and (2) identifying therapeutic targets to improve outcomes and fibrosis related symptoms.
