Translational Animal Models in Drug Discovery and Development

by

Xinkang Wang

DOI: 10.2174/97816080546951120101
eISBN: 978-1-60805-469-5, 2012
ISBN: 978-1-60805-591-3



Indexed in: Scopus, EBSCO.

Animal models of diseases play a pivotal role in drug discovery and development, not only for proof of the concept studies of efficacy...[view complete introduction]
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Mouse Models of Coagulation Factor Deficiencies for Translational Research

- Pp. 67-121 (55)

Meghann P. McManus and David Gailani

Abstract

In vertebrates, formation of a clot at a site of blood vessel injury requires a group of plasma proteins (coagulation factors) that regulate generation of the protease α- thrombin. α-Thrombin mediates a number of key activities during clot formation, including conversion of soluble plasma fibrinogen into an insoluble fibrin mesh, activation of platelets, and stimulation of vascular endothelial cells. While α-thrombin is required for life, dysregulated generation of this protease can contribute to life-threatening thrombotic disorders and consumptive coagulopathies. The coagulation factors were originally identified and characterized using plasma clotting assays. While deficiency of any single coagulation factor results in an abnormal result in one or more of these in vitro assays, the severity of the associated bleeding disorder can range from fatal hemorrhage to complete absence of symptoms. Genes for coagulation factors have been manipulated by a variety of “knockout”, “knock-in”, and transgenic strategies in mice. In this chapter, we review insights gained into hemostasis, thrombosis and wound healing through studies involving mouse models of coagulation deficiencies. The chapter is divided into sections focusing on deficiencies associated with lethal phenotypes (prothrombin, tissue factor, tissue factor pathway inhibitor, factor V, factor VII, factor X and γ-glutamyl carboxylase), deficiencies associated with severe bleeding disorders that do not compromise viability (fibrinogen, factor VIII, factor IX and factor XIII), and those not associated with abnormal hemostasis (factor XI, factor XII and high molecular weight kininogen) and the translational value of each model in drug discovery and development is discussed.

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