THE GENOMICS OF FIBROSIS PROGRESSION
Valeria Mas, Associate Professor, Departments of Surgery and Pathology; Director, Molecular Transplant Research Laboratory, Division of Transplant, Virginia Commonwealth University, Richmond, VA, USA
1. Understand the molecular events involved in fibrogenesis in allograft response to chronic injury.
2. Evaluate the utility of early systematic molecular signatures study of protocol biopsy tissues to identify those patients at high risk of allograft fibrosis progression.
3. Analyze the critical importance of prospective studies with appropriate sample size for power of calculation in biomarker discover of fibrogenesis post-transplantation.
Fibrosis is the replacement of normal tissue by scar tissue as consequence of a reactive or reparative process called fibrogenesis. Stimuli to injury may include cell necrosis, apoptosis, inflammatory cell infiltration, and extra cellular matrix (ECM) alterations. The response to injury triggers the production of cytokines and other extracellular signals, including reactive oxygen species. These stimuli induce a fibrogenic response, resulting in an accumulation of ECM proteins within the organ as consequence of an imbalance between the deposition and degradation of ECM components.
Although self-reliant scar tissue has no effect on long-term outcomes, fibrogenesis will result in organ failure if injury persists or if response to injury is excessive. Protocol biopsies have played an important role demonstrating that fibrosis occurs before graft dysfunction is present.
Transcriptional changes may be detectable prior to histological apparent fibrosis, and discrimination of inflammatory infiltrates according to the group of expressed genes, promises to both improve diagnoses and optimize treatment strategies. Systematic analysis of gene-expression patterns will provide a window into the biology and pathogenesis of allograft fibrosis development. Innovative data of early detection of molecular patterns associated with fibrosis graft development in early protocol biopsies will be presented.
Gene expression analysis results will be presented for two different conditions (Loss of graft function with interstitial fibrosis (IF) and tubular atrophy (TA) in kidney transplant recipients (KTR) and HCV recurrence post-liver transplantation (LT)). For loss of graft function with IF/TA, gene expression (microarrays) in protocol biopsies was performed. Whether the pre-existing histological changes in the time zero biopsies were involved in post-transplant IF/TA progression was considered in the analysis.
For HCV recurrence post-LT, formalin fixed embedded tissues (FFPE) protocol biopsies were evaluated using Whole Genome DASL Assay (Illumina). Prediction modeling systems were established combining molecular and clinical data for predicting risk of allograft fibrosis development.