What are your research interests?
My research efforts focus on improving the success of organ transplantation. I am involved in a number of studies. I am a principal investigator and member of the Steering Committee of the National Institutes of Health Adult-to-Adult Living Donor Liver Transplantation (A2ALL) Cohort Study. This is a seven-year study that involves nine of the Unites States’ top liver transplant centers, including Northwestern. This study aims to provide data that will help us inform the process of living donor liver transplantation. The research team is comparing outcomes of living donor transplants with those of patients who received livers from deceased donors as well as assessing all potential complications in the living donors. Also, several ancillary projects within A2ALL include an assessment of the success of living donor liver transplants in patients with hepatocellular carcinoma, hepatitis C and in liver regeneration. I also serve as the principal investigator and member of the Steering Committee for another NIH-funded study called Clinical Trials in Organ Transplantation (CTOT), which investigates the molecular biomarkers in the blood and urine that predict and accurately diagnose rejection and ischemia/reperfusion injury of transplanted organs. Through three national consortia of transplant centers, Northwestern participates in several studies within CTOT that include functional genomics as well as observational and interventional studies in kidney, liver and heart transplant recipients. Finally, I am a principal investigator in another NIH-funded study through the Immune Tolerance Network (ITN). We are investigating the withdrawal of immunosuppressive (anti-rejection) agents in liver transplant recipients in an attempt to elucidate the mechanistic details of immune tolerance in this patient population. This is an exciting area of investigation that has truly been the holy grail of transplantation research – the ability to transplant organs without a need for lifetime immunosuppression.
One of the sequellae of immunosuppression is the development of opportunistic infections such as cytomegalovirus (CMV) infection. CMV is a herpes virus that is present in the majority of adults and can establish a lifelong latent infection. In transplant recipients, reactivation of the virus is frequently observed, and despite effective anti-viral prophylaxis can be associated with serious morbidity and, occasionally, mortality. My laboratory is looking at the molecular mechanisms by which CMV establishes latent infection and reactivates from latency. This research uses a mouse model. Mice are infected with murine CMV and we are using ChIP assays to investigate potential epigenetic mechanisms of transcriptional silencing, including DNA methylation and histone modification. Also, we have postulated that reactivation is triggered by the inflammatory response in the transplanted organ resulting from both ischemia/reperfusion injury and the allo-immune response. The inflammatory cytokine TNF and the transcription factor NFkB are particular targets of this investigation and more recently we have focused our attention on Toll-like receptors (TLRs) and other transcription factors. Kidneys transplanted in mice are analyzed for RNA expression and activation of transcription factors known to be involved in regulating both cellular and viral gene expression. Transgenic and knock-out mice are used to test the requirement of cytokines and TLRs in CMV reactivation focusing primarily on the regulation of the CMV Immediate Early gene promoter/enhancer region.. We are currently creating viral mutants that lack specific binding sites for specific transcription factors in this promoter/enhancer region to test the hypothesis that these transcription factors are required for reactivation. My hope is that this research will lead to strategies for developing molecular approaches that can knock down the triggers viral gene expression and thus prevent reactivation and its associated sequellae.
What is the ultimate goal of your research?
The goal of my research efforts is to increase both access to transplantation as well as success rates. Our program is a national leader in living donor transplantation in an attempt to improve access to transplantation given the shortage of organs from deceased donors. With liver transplantation in particular, we are increasingly focused on establishing its role as a life-saving option for many people with end-sage liver disease who may not have access to livers from deceased donors. At the same time, it is clear that although current results are excellent, we can do better. This involves being able to treat rejection earlier, avoiding the sequellae of immunosuppression such as infections, and ultimately avoiding immunosuppression altogether. I am hopeful that we can achieve these goals in my lifetime.
What brought you to Feinberg?
I came to Northwestern in 1992 because I envisioned a great opportunity to fulfill these goals. It turns out that my instincts were right. The commitment to clinical excellence at Northwestern, combined with an environment of collaboration and a palpable enthusiasm for this type of program have made the Feinberg School of Medicine an exciting place for all of us involved in the challenging field of organ transplantation. I want to highlight the fact that transplantation is a team sport. The advances we have made at Northwestern, both in adult and pediatric transplantation, would not be possible without the commitment, dedication and support of the leadership of this institution and the many individuals involved. I am looking forward to many more achievements in this field that will be made possible only through the unwavering support we have experienced.