Research Group

  • Dr David M. Briscoe, Principal Investigator
  • Dr Soumitro Pal, Co-Investigator
  • Dr Aninda Basu, Research Associate
  • Dr Alan Contreras, Research Associate
  • Ms Katiana Calzadilla, Technician
  • Ms Evelyn Flynn, Technician

Location

  • Children’s Hospital Boston, Boston, USA

Title

  • The Role of the Vasculature in Transplant Rejection or Long-term Transplant Survival

Transplantation has become widely accepted as the treatment of choice for end-stage organ failure. Unfortunately, transplanted organs eventually fail as a result of immunological attack resulting in two distinct processes called acute and chronic rejection. Acute rejection typically occurs early within the first few months following transplantation. In contrast, chronic rejection is more insidious and takes years to develop. Current treatments for rejection involve immunosuppressive medications that have been most successful at preventing acute rejection. However, these same strategies have failed to interrupt the development of chronic rejection, which is currently the leading cause of graft failure following solid organ transplantation. In this research proposal, we propose that the graft itself can be a dominant force in shaping the chronic rejection process. We focus our studies on vascular endothelial cells, which line all blood vessels within a graft. These cells can regulate the ability of the recipient’s immune system to attack the graft. We have identified genes within endothelial cells that are important in their activation; one called the mammalian target of rapamycin (mTOR), which interacts with another molecule called Akt, may be critical in several responses pertinent to transplant rejection. We have generated mice in which we can regulate the activation of mTOR and Akt within endothelial cells. We will use hearts from these mice as donors in transplantation studies, so that we can we can purposefully activate the donor endothelium and assess its effect on rejection. We will treat animals with the drug rapamycin to inhibit this response and assess its effect. And, lastly using rapamycin-resistant mTOR mice, we can specifically determine if rapamycin targets the endothelium for its effects. Together, these studies will identify if targeting the endothelium should be a component of future therapeutic regimens to promote long-term graft survival.

Progress Report
Final Report