In applying for the mentored clinician scientist development award, the principal investigator is requesting support for an intensive program of laboratory training under the supervision of Dr. Walter Kisiel, Professor of Pathology at the University of New Mexico Health Sciences Center. The objectives of this proposal are designed to strengthen the applicant's scientific background in the biochemical basis of coagulation and endothelial cell biology, areas essential for an understanding of human thrombotic disorders. The award, if funded, will facilitate the long-term goals of the applicant in developing an independent scientific career in the field of hemostasis and thrombosis medicine. The Candidate and her mentor have developed a career development plan which includes a) assurance of protected research time of 80-90 percent b) a training program exposing the Candidate to new areas of scientific investigation in biochemistry, vascular biology, adhesion receptors, and vertebrate biology c) graduate level studies to reinforce the laboratory experience and d) an advisory panel of established investigators with expertise in disciplines related to the proposal. The studies proposed in this application will extend the applicant's previous work on Heparin-induced Thrombocytopenia (HIT) and Thrombosis (HITT). Life-threatening thromboses occurs in 10-20 percent of patients who develop HIT. The pathogenesis of thrombosis in HIT remains uncertain. Unlike most other immune mediated thrombocytopenic disorders, antibodies to endothelial cells can be demonstrated in HIT/HITT. It is hypothesized that concurrent platelet and endothelial cell activation is critical for the development of thromboses in susceptible individuals. To study the biological basis by which thrombosis develops in HIT, the following specific aims will be studied: 1) Characterizing the interactions of HITT antibodies with endothelial cells. 2) Defining the biological basis of thrombosis in HITT using murine models. 3) Generation of monoclonal antibodies (MoAbs) to PF4/heparin and functional characterization of PF4/heparin MoAbs with respect to thrombosis. It is expected that these proposed studies will contribute to a fundamental understanding of pathogenetic mechanisms for thrombosis in HITT, and lead to future investigations addressing therapeutic interventions in HITT.
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