The present proposal is a comprehensive five-year training program for the development of an academic career focused on understanding the relationship between T cell immunity and fibrosis in the cornea. I have a strong research background in transplantation immunology and sub-specialty ophthalmology training in cornea, with a clinical interest in corneal fibrosis. As an Advanced Clinical and Research Cornea Fellow at Mass. Eye and Ear and Harvard Medical School, I have continued my work in corneal transplantation immunology, demonstrating the presence of fibrosis in T cell-mediated immune rejection of corneal transplants. Our preliminary data suggest that in corneal transplantation, T cells play a direct role in promoting myofibroblast formation and fibrosis, and that myofibroblasts are in turn capable of regulating alloreactive T cell function. This data has laid the foundation for the current research proposal in which we will investigate the fibrosis-immunity interface in corneal transplantation.
In Specific Aim 1 we will define the critical mechanisms by which effector T cells promote fibrosis and evaluate whether modulation of these mechanisms can prevent fibrosis and transplant failure in vivo.
In Specific Aim 2 we will define the critical mechanisms by which myofibroblasts suppress effector T cells to restore immune homeostasis. The goal of the proposed research is to investigate these fundamental mechanisms and ultimately develop novel therapeutic strategies for the prevention of graft fibrosis and suppression of T cell immunity in organ transplantation. Dr. Reza Dana, a world expert in corneal immunology with a long track-record of fostering the career development of clinician-scientists will serve as my primary mentor, and I will additionally have the support of an advisory team composed of independent NIH-funded scientists, each with extensive experience in mentoring young researchers. The proposed research and career development programming will take place at the Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary and Harvard Medical School, and I will have full access to the significant resources of these institutions. I am committed to a career as a clinician-scientist, with the over-arching goal being to translate my basic science investigations into novel approaches for addressing the unmet needs of patients. The K08 grant proposal detailed here addresses an important and previously unexplored area of corneal pathophysiology while simultaneously providing me the mentorship, resources and academic foundation needed to become an independent clinician-scientist.
Corneal transplantation is the most commonly performed type of solid organ transplantation in the world and T cell-mediated alloimmune rejection is the most common cause of corneal transplant failure. We have recently demonstrated fibrosis in rejected corneal transplants, and in the proposed research we will investigate the interactions between T cell alloimmunity and fibrosis in corneal transplantation. These studies will provide fundamental insights in a previously unexplored area and have the potential to help identify novel therapeutic strategies for i) preventing transplant fibrosis and failure and ii) regulating T cell-mediated immune rejection.
