This revised proposal describes a five year training program for the development of an academic career in basic science and medicine. The principal investigator (PI) has completed training in Pediatric hematology-oncology at the University of Michigan and is in the first year of his appointment as Lecturer. The mentor will be David Ginsburg, an internationally recognized leader in the fields of molecular hematology and the genetics of blood clotting diseases. In addition, an advisory committee of successful senior faculty members will provide scientific and career development advice. The experiments presented focus on the roles that von Willebrand Factor (VWF) and the newly described metalloprotease ADAMTS13 play in pathogenesis of the disease thrombotic thrombocytopenic purpura (TTP). ADAMTS13 deficiency in humans causes TTP. In preliminary experiments disruption of the murine ADAMTS13 gene interestingly did not result in TTP, demonstrating additional environmental and/or genetic factors are required to induce TTP in the setting of murine ADAMTS 13 deficiency. In support of this, TTP-like finding were induced with a combination of environmental factors (shigatoxin administration) and genetic crosses (to the CASA/Rk mouse strain).
Specific aim #1 will investigate the hypothesis that ADAMTS 13 regulates VWF-mediated interactions between platelets and endothelial cells;
specific aim #2 investigates the hypothesis that environmental triggers (e.g. infection) or genetic modifiers (e.g. VWF) may trigger TTP or alter the phenotype seen in the ADAMTS13 deficient mice;
specific aim #3 investigates the hypothesis that differences in VWF physiology underlie the variable susceptibility to TTP among different mouse strains;
and specific aim #4 investigates the mechanism of action of shigatoxin in the induction of TTP-like findings. These studies have the potential to further our understanding of TTP, a complex and important disease in humans. This training will build upon the applicant's prior research experience and it is anticipated that it will lead ultimately to his transition to independent investigator. The applicant's goal is to run a successful laboratory in an academic setting and continue to develop his expertise in clinical Pediatric hematology.
