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The overall objective of this proposal is to establish genetically-based animal models for investigating the in vivo role of thrombomodulin (TM) in suppressing thrombosis. Homologous recombination has been employed to generate mice with heterozygous TM gene deletions but the production of homozygous TM deletions leads to embryonic lethality. The basis for fetal death will be ascertained and mice with the most profopund abnormality of TM compatible with embryonic viability will be produced. These investigations will include the generation of mice with transient fetal TM expression/heterozygous TM deletions, and specific TM mutations of increasing functional severity. The intercrossing of the above mice should produce animals with the maximum possible functional defect of this natural anticoagulant mechanism. In vivo techniques will then be developed to establish the extent of the hypercoagulable state induced by the TM deletions/TM mutations and ascertaining the effects of these abnormalities in producing thrombotic events. These studies will include quantitation of the generation of activated PC and thrombin by immunoassay techniques, and the determination of thrombotic events in genetic backgrounds with increased susceptibility to thrombosis due to defects of the fibrinolytic mechanism. This animal model may provide a general approach for testing the effects of other gene products on the development of thrombotic events. Finally, the effect of the hypercoagulable state on the development of atherosclerosis and the effect of atherosclerosis on the hypercoagulable state will be ascertained. These investigations will employ genetic and nutritional manipulations in mouse models to vary the intensity of the hypercoagulable state and the severity/nature of the atherosclerotic state. The animals will then be examined for thrombotic phenomena and characterized with regard to atherosclerotic lesions.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.