Uncovering the genomic regulatory network of myofibroblast differentiation in systemic sclerosis-associated interstitial lung disease

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ABSTRACT This application is for a Mentored Clinical Scientist Research Career Development Award entitled “Uncovering the genomic regulatory network of myofibroblast differentiation in systemic sclerosis-associated interstitial lung disease”, submitted by Dr. Eleanor Valenzi, an Assistant Professor of Medicine within the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh. The short-term goals detailed in this submission are designed to help the applicant achieve her long-term objective of becoming an independent physician- scientist and leader in the field of autoimmune interstitial lung disease (ILD) research. These short-term goals include (1) advancing knowledge of computational and molecular biology (2) expansion of technical and analytic tools to effectively perform translational ILD research, and (3) development of leadership skills to obtain academic independence. This work will be completed in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh, a rich research environment with a strong commitment to and proven track record of fostering the development of physician-scientists. The central objective of this research proposal is to investigate the gene regulatory networks driving myofibroblast differentiation in systemic sclerosis- associated interstitial lung disease (SSc-ILD), as myofibroblasts are the key effector cell in fibrosis and no treatments currently exist to target these cells. Interstitial lung disease is the leading cause of death in systemic sclerosis, the rheumatic disease with the highest case mortality. The applicant’s prior published work identified the transcriptome of the SSc-ILD pathogenic myofibroblasts in explanted lung tissues, however the specific gene regulatory networks driving differentiation of resident fibroblasts to pathogenic myofibroblasts remain unknown. Additional preliminary data implicates resident pulmonary fibroblasts as the primary source of myofibroblasts, and the RUNX2/3 transcription factors (TFs) as putative positive regulators of myofibroblast differentiation. The primary hypothesis is that RUNX2 and RUNX3, in association with specific composite motif TF partners, promote myofibroblast differentiation and the aberrant myofibroblast phenotype in SSc-ILD. With this proposal, the applicant will expand on her prior work with the following specific aims: (1) define the epigenetic and transcriptional programs essential to myofibroblast differentiation, (2) reconstruct the regulatory network of RUNX2/3 in myofibroblasts, and (3) determine the mechanism by which RUNX2/3 regulate the critical myofibroblast effector functions of extracellular matrix expression and contractility. This proposal will determine the SSc-ILD myofibroblast RUNX2/3 gene regulatory program and establish a pipeline for downstream investigation of the critical implicated transcription factors and the mechanisms by which they regulate the myofibroblast phenotype.