Studying the Rejection Mechanisms in Composite Tissue Allotransplantation Using Genomic Microarray

Studying the rejection mechanisms in composite tissue allotransplantation using genomic microarray Composite tissue allotransplantation (CTA) refers to transplantation of a functional allograft containing heterogeneous tissues, such as a hand or a larynx. It holds great clinical potential since it can be applied to treat defects that can not be mended using autologous tissues. However, the immunological barrier between donor and recipient leads to rejection and is difficult to overcome. Although immunosuppresants such as cyclosporine A has been widely used to treat rejection clinically, various potentially serious side effects do not justify their use for non-life-saving CTAs. In view of understanding rejection process in more details at the molecular level would be helpful for our ultimate goal to defeat rejection after CTA, we propose the following specific aims: 1. To map gene expression profiles in allograft and in PBMCs during progression of rejection: Genomic microarray will be applied to gain insights into the gene expression profile during the progression of rejection. Both local (graft) and systematic (peripheral blood mononuclear cell) information about rejection process will be collected and compared. 2. To map gene expression profiles in allograft transplantation after cyclosporine A treatment Although cyclosporine A has many side effects, it is effective to suppress CTA rejection. In this aim, we will study the gene expression profile in the animal undergone CTA and cyclosporine A treatment. Molecular targets potentially involved in suppressing CTA rejection are expected to be found. 3. To search for gene(s) whose expression may serve as early biomarkers for rejection By looking into the gene expression pattern at the early time point before graft appearance changes after CTA, we expect to find genes whose alteration in expression may indicate the occurrence of rejection. Different allotransplantation systems will be applied for validation. 4. To prolong allograft survival by manipulating expression profiles of specific genes discovered from aim 1 and 2 For the genes identified from aim 1 and 2 and have the characteristics of upstream signaling regulators, we will specifically target them with siRNA or drug treatment to test if survival of the allograft could be prolonged, or furthermore, rejection can be prevented. After finishing these aims, we expect to gain insights into the phenomena of allograft rejection. In addition, we will discover genes that could serve as biomarkers for early diagnosing rejection. Furthermore, it is expected to find genes as regulators of rejection and could potentially be manipulated to prevent rejection to occur. In the long term, we hope the knowledge gained from this proposal could be applied clinically as diagnostic or therapeutic tools for managing rejection following composite tissue allotransplantation.

Project ID:PC9709-0451
External Project ID:NSC97-2314-B182-022-MY3