The long term objective of this training program is the development of the candidate's academic career in laboratory research into the mechanisms of thrombosis. This program will provide the candidate with the opportunity to build on his existing expertise and develop a unique set of new skills that will help him to successfully transition into an independent investigator. Training will be provided in basic science concepts and the use of mouse models for thrombosis research. Towards this goal, a comprehensive, multi-faceted career development plan is proposed. This encompasses instruction in laboratory techniques, and participation in relevant workshops and research seminars that are incorporated into an intense, well-mentored research experience under the combined mentorship of Drs. Nigel Mackman and Nigel Key, both of whom are Distinguished Professors of Medicine and internationally renowned for their expertise in coagulation research. To further enhance this training, the program has enlisted the expertise of a multidisciplinary advisory committee that consists of senior investigators with expertise in clinical and laboratory based coagulation research and career development. The proposed research will focus on understanding the mechanism by which activation of coagulation and thrombosis occurs in heparin induced thrombocytopenia (HIT). This is a major and potentially devastating cause of drug induced thrombocytopenia that occurs in some patients receiving heparin. Paradoxically, despite a decrease in platelet count, the most feared complication of HIT is the development of arterial and venous thrombosis, the pathophysiological mechanism of which is poorly understood. The candidate's preliminary results demonstrate that HIT antibody complexes can activate monocytes in vitro leading to the release of procoagulant tissue factor (TF) bearing microparticles (MPs). The central hypothesis of this application is that HIT antibody complexes induce monocyte TF expression in a toll- like receptor 4 (TLR-4) dependent manner leading to the release of TF-bearing MPs that lead to activation of coagulation and thrombosis. This hypothesis will be tested in a series of innovative, complementary studies involving in vivo experiments in transgenic mouse models and in vitro human experiments. The expected outcome of this proposal is evidence supporting a role for both monocyte derived, TF-bearing MPs in the activation of coagulation in HIT, and TLR-4 in the mechanism of activation of monocytes by HIT antibody complexes. These experiments will lay the foundation for future studies using animal models of arterial and venous thrombosis to determine the role of TF-bearing MPs in the development of thrombosis in HIT. In addition, future clinical studies could prospectively evaluate levels of monocyte derived TF-bearing MPs as a biomarker of susceptibility to thrombosis in HIT in humans. The career development plan, proposed research project and the institutional environment at the University of North Carolina at Chapel Hill provide the ideal environment for the candidate to acquire the technical and academic skills necessary to develop into a successful, NIH funded independent investigator.
Millions of Americans receive heparin every year and a life threatening complication of heparin treatment is the development of blood clots because of the body's reaction to receiving heparin. The goal of this application is to understand the reason for this complication so that it can be prevented. This could result in significant benefit to both patients and the healthcare system.
|Kasthuri, Raj S; Glover, Sam L; Jonas, William et al. (2012) PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of Fc?RI. Blood 119:5285-93|