Molecular Markers for Progression of Pulmonary Fibrosis in Systemic Sclerosis

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DESCRIPTION (provided by applicant): Title: Molecular Markers for Progression of Pulmonary Fibrosis in Systemic Sclerosis Candidate: Dr. Assassi is an Assistant Professor in the Division of Rheumatology and in the Center for Clinical Research and Evidence Based Medicine. He has recently completed a Master's Degree Program in Clinical Research. He was selected as one of just two CCTS-KL2 (K12) Scholars in 2009 at the University of Texas-Health Science Center at Houston (UTHSC-H). Dr. Maureen D. Mayes (primary mentor) and Dr. Filemon K. Tan (co-mentor) are his mentors in the ongoing KL2 Award. Under their guidance, the candidate has published the largest gene expression profiling study in systemic sclerosis (SSc) to date. Dr. Jon E. Tyson (co-mentor) mentored his Master's Thesis project, investigating the clinical predictors for progression of interstitial lung disease (ILD) in SSc. The results of this large prospective study have been recently published. These productive mentor-mentee relationships will build the basis for the success of this K23 proposal. Environment: UTHSC-H is one of the largest systemic sclerosis centers in the nation. This proposal takes advantage of the infrastructure provided by the ongoing NIH-funded prospective cohort of early SSc patients, the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS-PI: Dr. Mayes) and the active Scleroderma Clinic at our institution. The candidate's adjunct appointment in the Center for Clinical Research and Evidence Based Medicine provides access to a diverse group of investigators with expertise in biostatistics, bioinformatics and epidemiology. The candidate and his mentors also have ongoing collaborations with the CCTS Core Laboratories and Clinical Research Units at the UTHSC-H. The candidate has been able to co-author 21 peer-reviewed publications (17 in the last two years) in this supportive environment. Training Plan and Career Goals: The proposed four-year program provides intensive mentoring, didactic course work and independent scientific review. The didactic curriculum complements the candidate's prior training in the Master's program with courses in genomics and proteomics, longitudinal and Bayesian data analysis, bioethics and advanced grant writing. Candidate's research efforts are focused on combining high- throughput molecular data with sophisticated epidemiology and biostatistical approaches for development of predictive biomarkers in SSc. This proposal will establish candidate's independent area of expertise with a goal of applying for NIH R01 Award, focusing on identification of predictive biomarkers in rheumatic diseases and examination of their clinical usefulness in prospective studies. Proposed Research: SSc is associated with substantial morbidity and mortality. Pulmonary involvement is the primary cause of SSc-related death. Sequential measurements of pulmonary function in patients with SSc have shown remarkable variability in the progression of ILD, ranging from an indolent course to a rapidly progressive disease leading to respiratory failure and eventually death. Although ILD is one of the most important determinants of disease in SSc, the routinely obtained demographic and clinical data are inadequate to predict the course of this devastating disease complication. Gene expression profiling with microarrays allows the simultaneous assessment of thousands of transcripts in a given tissue. Our previous studies indicate that SSc patients can be subclassified at the molecular level based on presence of an Interferon (IFN) gene expression pattern. The objective of the current proposal is to build multivariate models with gene expression profiling and serum chemokine data that will have greater predictive value for the course of ILD over the currently known parameters. We hypothesize that microarray gene expression profiling and multiplex chemokine assays will improve our currently inadequate ability to predict the course of ILD. We will identify peripheral blood cell and skin gene expression patterns that can predict the course of ILD. Then we will examine the independent predictive significance of these classifier transcripts in a multivariate model after inclusion of other known predictors. We also will investigate the interplay between immune dysregulations and fibrosis in SSc by comparison of gene expression profiles present in the concomitantly collected peripheral blood and skin samples. Several serum chemokines correlating with the IFN gene expression signature have been identified. These chemokines correlate with disease activity in other connective tissue disease. In this proposal, we will examine whether these IFN inducible chemokines also correlate with progression of SSc-ILD in the GENISOS cohort. The proposed novel translational and analytic approaches can lead to methodological advances in the field of autoimmunity and can address a significant knowledge gap in SSc clinical care and clinical trial design. Furthermore, the accompanying mentoring and course work will prepare Dr. Assassi to become an independent and productive clinician scientist and a leader in rigorously designed and conducted translational research in rheumatic diseases.