It is becoming increasingly clear that genes traditionally associated with hemostasis function in many other diverse pathophysiologic processes. Examples are the involvement of gene products related to fibrinolysis, e.g., plasminogen, plasminogen activators, and plasminogen activator inhibitors, with their roles in cancer, wound healing, and angiogenesis. These same genes, as well as products of genes of relevance to coagulation, e.g., Tissue Factor, and anticoagulation, e.g., Protein C, also function in embryogenesis, cancer, and acute and chronic inflammatory-based processes, among others. Thus, hemostasis-related genes serve as links between different pathways in health and disease. This Program Project Grant (PPG) builds on existing strengths and integrates the research efforts of experienced investigators who have made major contributions to our understanding of the protein chemistry, molecular and cell biology, gene targeting, and pathophysioiogies of proteins and genes associated with hemostasis. The focus of this PPG is the definition of the in vivo roles of hemostasis-related genes in: the relationships between disseminated intravascular coagulation, systemic inflammation, and organ damage during the progression of sepsis (Project by Castellino); tumorigenesis, metastasis, and angiogenesis (Project by Ploplis); and embryonic and perinatal survival of offspring, as well as in vivo thrombus formation (Project by Rosen). Three core units are proposed as necessary to centrally support this group of projects: (1) an Administrative Core, (2) an Anatomic Pathology Core, and (3) a Mouse Breeding and Husbandry Core. The Project and Core Leaders have a long history of productive interactions with each other and are all based in an infrastructure-rich center devoted to in vivo and in vitro studies of coagulation, anticoagulation, and fibrinolysis. The projects proposed will utilize the same administrative, histopathology, and mouse cores. The PPG will allow increased interactions and collaborations to occur between the laboratories of the Project Leaders in studying the functional roles of hemostasis-related genes, and the overall program that results from these combined efforts will exceed the sum of the individual parts. The research efforts and productivity of students and postdoctorals will benefit greatly from the interactions of the individual laboratories and cores that will result from the PPG, and will serve as a resource for a continual flow of independent investigations in these research areas.
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