Abstract 400: Calcium Responsive Element Binding Protein CREB Molecular Network is Differentially Enriched during Rejection and Quiescence in Heart Transplant Recipients.
Background: Genomics and computational biology provide powerful tools to identify specific regulatory genes and modules that are potential targets for designing interventions for allograft rejection.
Method: Using ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks) we screened the 285 leukocyte microarrays utilized in the Cardiac Allograft Rejection Gene expression Observational (CARGO)-study to reconstruct the peripheral PBMC -network in heart Tx recipients.
Results: We identified several highly connected genes (hubs) implicated in the regulation of the immune response including CREB. We reconstructed the CREB subnetwork during rejection and quiescence, retaining those genes with significant pair-wise mutual information (MI) with the available probe sets for CREB (P <1e-7) conditioned by genes with transcription factor activity. A quiescent network was reconstructed using 139 ISHLT grade 0/0R rejection samples and compared with a rejection network composed by 116 rejections samples (62 grade 1A/1R, 30 grade 1B/1R and 24 samples grade 3A/2R). We found significant differences in the networks for each clinical phenotype. Sixty eight percent of the first neighbors had significant change in MI among enriched gene targets during rejection or quiescence (Figure⇓). (Targets validated in the literature are highlighted).
Conclusion: Computational biological approaches allow the identification of molecular modules from complex cellular networks in transplant rejection and may serve to identify targets for designing immunomodulatory strategies.