Biology and Biomarkers in Organ Failure - Paul Keown
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Vital organ dysfunction is associated with profound changes in gene and protein expression that provide important insights into the cellular biology of these states, highlight potential targets for ...
Vital organ dysfunction is associated with profound changes in gene and protein expression that provide important insights into the cellular biology of these states, highlight potential targets for therapeutic intervention, and offer the opportunity for development of clinical biomarkers for diagnosis and therapy. Over 9000 genes are differentially expressed in kidney failure, of which the majority are down-regulated. Gene set enrichment analysis shows the mRNA processing and transport, protein transport, chaperone functions, the unfolded protein response and other key cellular functions are prominently inhibited while the complement system, liproprotein metabolism and other functions are up-regulated. Organ transplantation causes a rapid and highly dynamic perturbation of gene networks including chemotaxis and cell migration, inflammation and innate immunity and wound and tissue healing. Transcripts for many key cytokines and chemokines, which are respectively enhanced and reduced during renal failure and dialysis consistent with the complex inflammatory nature of this state, gradually normalize during the first months after organ transplantation. Even in healthy and well-functioning graft recipients, however, gene expression differs markedly from normal reflecting residual alterations in cell biology. The occurrence of acute graft rejection engenders a distinct alteration in gene and protein expression that reflects changes in the genes encoding cytoskeletal organization and biogenesis, signal transduction, immune system processes, cell motility and leukocyte activation. Alterations in the plasma proteome include increases in proteins that encompass processes related to inflammation, complement activation, blood coagulation and wound repair. These may be integrated to create sensitive and specific biomarkers of rejection or quiescence.
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