PROJECT SUMMARY / ABSTRACT Systemic sclerosis (SSc) is a rare and devastating connective tissue disorder that results in fibrosis and vascular abnormalities that can affect the skin, lungs, gastrointestinal tract, heart, and kidneys. The underlying mechanisms are complex and largely unknown, and no effective treatment exists to stop the progression of fibrosis in SSc or reverse it. Interstitial lung disease ILD) associated with SSc is a leading cause of death inSSc patients. The focus of this proposal is on the epigenetic regulation of KLF4, a transcription factor with anti-fibrotic function in pulmonary fibroblasts (pFBs). KLF4 is downregulated during active fibrosis. The goal is to identify targetable epigenetic factors regulating KLF4 as premises to develop effective therapies for SSc-ILD. To accomplish this, Dr. Renaud will (1) determine the involvement of HDAC(s) in the transcriptional repression of KLF4 in pFBs, (2) build a comprehensive regulatory network based on differentially expressed (DE) genes, microRNAs, and long non-coding RNAs (lncRNAs) to identify and validate the role of miRNAs and lncRNAs in the regulation of KLF4 and (3) track KLF4 regulation within the different cell types and subpopulations of fibroblasts present in lung tissues. Dr. Renaud is a molecular/cellular biologist in the Division of Rheumatology at the Medical University of South Carolina (MUSC). Her long-term career goal is to become an independent translational researcher in fibrosis with a specific interest in epigenetic factors that regulate early phases of fibrosis. To facilitate her transition into an independent investigator, she seeks to further her training in bioinformatics and computational tools for the analysis of single-cell RNAseq data, and in the field of network biology. Dr. Renaud’s successful transition to an independent career will be supported by (1) her primary mentor Dr. Feghali-Bostwick an authority in SSc research with an excellent track record of mentorship, (2) an advisory committee with the relevant expertise, (3) institutional centers and cores, and (4) the Department of Medicine’s support and robust mentorship program. By defining the epigenetic factors responsible for KLF4 downregulation in SSc-ILD, therapeutic strategies aiming to restore antifibrotic levels of KLF4 can be developed to prevent, stop, and possibly reverse the progression of fibrosis. The results of this proposal will provide critical preliminary data supporting extramural applications. The proposed training will enable Dr. Renaud to achieve her long-term objective of becoming an independent investigator.