DESCRIPTION (provided by applicant): Candidate: The candidate, Todd Grazia, M.D. is an Instructor in the division of Pulmonary and Critical Care Medicine at the University of Colorado Health Sciences Center. He has currently just completed an NRSA F-32 titled "Antigen Presentation in CD4-mediated Cardiac Rejection." Dr. Grazia has previously worked with vascular endothelial cells and their response to oxygen radicals and inflammation. During his Fellowship, he became interested in clinical heart/lung transplantation. Consequently, he has developed a particular interest in T-cell destructive responses and the role of the allograft endothelial cell as an immune target in cardiothoracic solid organ transplantation. Dr. Grazia's short-term goal is continue to develop both the professional and research skills to become an independent investigator. Long term, Dr. Grazia hopes to develop a successful independently funded laboratory focused on allograft destructive cellular immunity and vascular biology of cardiothoracic solid organ transplantation. This proposed Mentored Clinical Scientist Award would provide him with the support to develop these skills. Career Development: Dr. Grazia's career development will include: 1) development of new research skills, such as the development of well-defined effector cell isolated animal models of cardiac rejection 2) formal educational activities including courses in advanced immunology, molecular biology techniques, responsible research conduct, and grant writing 3) involvement in administrative activities essential to developing professional skills such as serving on the lung Transplant Protocol Development Committee. Environment: Dr. Grazia is currently in an environment that is conducive to excellent research. His sponsor, Dr. Ronald Gill and Collaborator, Dr. Mark Geraci are outstanding extramurally funded independent investigators with established records in research. Research: Current therapy to prevent allograft loss focuses on the inhibition of antigen recognition and costimulatory signaling. However, investigators have not been able to significantly improve graft survival. Consequently, elucidation of T-cell effector mechanisms may allow for a new-targeted approach to abrogate rejection and lengthen significantly the time to chronic rejection. Dr. Grazia's goal will therefore be to elucidate the mechanisms by which effector CD4 and CD8 T-cells kill a cardiac allograft. The hypotheses will be that 1) in vivo CD4 T-cell mediated rejection and in vitro CD4 T-cell mediated endothelial cell injury are dependent on TNF superfamily death receptors, such as TNFR1/2 and/or Fas. 2) in vivo CD8 T-cell mediated rejection is dependent on the cytotoxic molecules, such as perforin and/or Fas. 3) critical genes specific to CD4 versus CD8-mediated rejection can be identified by microarray analysis. Results have the potential to identify critical effector pathways, whose targeted inhibition could lead to attenuation of graft injury and markedly increased patient survival.