The overall goal of this Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to build and expand her research and mentoring programs in patient-oriented research in acute lung injury (ALI). This award will allow her to devote more time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees as well as medical students in the Vanderbilt Emphasis Training Program. In addition, the support of this award will allow Dr. Ware to assume an important role as Co-Director of the T32 Clinical and Translational Research Training Program in Pulmonary Medicine training program (NIH 5T32 HL087738). Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will build on studies of organ donors and ALI (primary graft dysfunction, PGD) after lung transplantation, as well as ongoing studies of the mechanistic role of alterations in coagulation and fibrinolysis in ALI. PGD has a major impact on morbidity, mortality and cost of lung transplantation. Studies of PGD are unique in the field of ALI research in their potential to determine the impact of intrinsic donor-derived lung factors on the pathogenesis of ALI. The overall hypothesis of the proposed studies is that alterations in the coagulation and fibrinolytic cascades at both the genetic and protein level in the donor lung are major determinants of PGD in the lung allograft recipient. This hypothesis will be tested in two specific aims: Specific Aim 1: To test the hypothesis that there is a significant association between common polymorphisms in coagulation and fibrinolysis genes in the organ donor and clinical outcomes in the lung transplant recipient, including PGD. These studies will also test the association of donor plasma levels of the protein products of the genes whose polymorphisms are associated with worse or better clinical outcomes. Specific Aim 2: To test the hypothesis that there is a differential contribution of dysregulated coagulation and fibrinolysis in organ donors compared to organ recipients to recipient clinical outcomes including PGD. A better understanding of the influence of the coagulation and fibrinolytic pathways in the donor lung on subsequent development of PGD in the lung recipient will significantly enhance our understanding of the pathogenesis of ALI and may ultimately lead to new therapies for prevention and treatment of PGD in lung transplant recipients as well as potential new therapies for non-transplant associated ALI. These studies may also lead to improved donor selection criteria and donor-recipient matching to reduce the incidence of PGD. The better understanding of disease pathogenesis and improved early diagnosis that will be realized through patient-oriented research and a well trained new generation of clinical researchers in ALI will deepen our knowledge and open up new therapeutic opportunities for this clinical disorder that affects 200,000 Americans annually with a mortality rate of approximately 40%.
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