Hartmut Weiler, Ph.D.

Senior Investigator
Blood Research Institute
BloodCenter of Wisconsin

Assistant Professor
Department of Physiology
Medical College of Wisconsin

Director, Transgenic Core
Medical College of Wisconsin

Selected Publications
Grant Support
Laboratory Staff
Contact Information

Research Interests
Developmental Function of Thrombomodulin

Thrombomodulin (TM) is an endothelial surface thrombin receptor that suppresses the activation of the blood clotting mechanism. Formation of a thrombin-TM complex alters the substrate specificity of thrombin to generate the natural anticoagulant, activated protein C.

In humans, genetic deficiencies leading to the reduced function of the TM-protein C pathway are commonly inherited risk factors for thrombotic disease. The complete ablation of TM function in mice by gene targeting results in post-implantation embryonic lethality 9 days after fertilization, before the establishment of a functional cardiovascular system.

TM deficient embryos exhibit an overall growth retardation that is followed by a rapid and complete resorption of the mutant embryos.

Biochemical and genetic evidence indicates that the receptor's survival function in development does not involve the known anticoagulant mechanisms of protein C activation or thrombin binding, but a yet unknown activity that is absolutely required for a normal interaction between the embryonic trophoblast and the maternal environment.

We are employing gene replacement- and cell-type restricted knock-out technology, embryo transfer, tetraploid embryo aggregation, and in vitro analysis of trophoblast cell lines to describe in precise molecular terms the mechanism underlying TM function in development and to delineate the physiological consequences of complete receptor deficiency in different stages of embryogenesis and in adult mice.

A Genetically Engineered Designer-mouse to Detect and Analyze Thrombosis Risk Factors

In contrast to TM knock-out animals, mice (TMPro-mice) expressing a mutated receptor molecule with minimal ability to accelerate the thrombin-dependent protein C activation survive to birth and are viable.

However, these mice exhibit a prethrombotic or hypercoagulable state associated with microvascular thrombosis and an increased susceptibility to thrombosis risk factors. We utilize this mouse line as an in vivo model system to investigate the interaction of a hypercoagulable state with additional suspected genetic cardiovascular risk factors, or epigenetic risk factors such as inflammation and vascular injury.

Secondly, we are employing the TMPro mouse to search for novel interactions and gene defects that may cause thrombotic cardiovascular disease in humans.

Selected Publications

• Weiler-Guettler H, Yu K, Soff G, Gudas L, Rosenberg RD: Thrombomodulin gene regulation by cAMP and retinoic acid in F9 embryonal carcinoma cells. Proc Natl Acad Sci USA 89:2155-2159 (1992).
• Healy A, Rayburn H, Rosenberg RD, Weiler-Guettler H: The absence of the blood clotting regulator thrombomodulin causes embryonic lethality in mice before develop-ment of a functional cardiovascular system. Proc Natl Acad Sci USA 92:850-854 (1994).
• Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD: Human von Willebrand factor gene sequences target expression to a subpopulation of endothelial cells in transgenic mice. Proc Natl Acad Sci USA 92:4567-4571 (1995).
• Weiler-Guettler H, Aird WC, Husain M, Rayburn H, Rosenberg RD: Targeting of trans-gene expression to the vascular endothelium of mice through homologous recombination at the TM locus. Circ Res 78:180-187 (1996).
• Weiler-Guettler H, Aird WC, Rayburn H, Husain M, Rosenberg RD: Developmentally regulated expression of the blood clotting modulator thrombomodulin during mouse post-implantation development. Development 122:2271-2281 (1996).
• Aird WC, Edelberg JM, Weiler-Guettler H, Simmons WW, Smith TW, Rosenberg RD: Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment. J Cell Biol. 138:1117-1124 (1997).
• Zhang Y, Weiler-Guettler H, Wilhelm O, Deng Y, Qiu F, Nakagawa K, Klevesath M, Wilhelm S, Graeff H, Bohrer H, Nakagawa M, Martin E, Stern DM, Rosenberg RD, Ziegler R, Nawroth PP: Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity. J. Clin. Invest. 101, 1301-1309 (1998).
• Weiler-Guettler H, Christie PD, Beeler DL, Healy AM, Hancock WW, Rayburn H, Edelberg JM, Rosenberg RD: A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J. Clin. Invest. 101, 1983-1991 (1998 ).
• Conway EM, Pollefeyt S, Cornellisen J, DeBaere I, Steiner-Mosonyi M, Weitz JI, Weiler-Guettler H, Carmeliet P, and Collen D: Structure-function analyses of thrombomodulin by gene-targeting in mice: The cytoplasmic domain is not required for normal fetal development. Blood (1999) 93: 3442-3450.
• Christie PD, JM Edelberg, MH Picard, AS Foulkes, W Mamuya, H Weiler-Guettler, RH Rubin, P Gilbert, and RD Rosenberg: A Murine Model of Myocardial Microvascular Thrombosis. J.Clin.Invest. (1999) 104: 533-539.
• Weiler-Guettler H and Rosenberg RD: Hemostatic regulation by the vascular wall. in: Vascular Medicine, Nawroth,P. et al. (eds.) Schattauer Verlagsgesellschaft, Heidelberg, 1999 (Book Chapter, published in German language). 

Grant Support

• RO1 HL60655, Thrombomodulin Function in Development and Cellular Physiology (04/1999 through 03/2009).
• R21/R33 AI080557, Activated Protein C for Treatment of Radiation Combined Injury (07/2008 through 06/2013).
• R01 HL93388, Mechanism of Activated Protein C Action in Sepsis Therapy (09/2008-06/2012

Laboratory Staff

Employment Opportunities
If opportunities are available, they will be listed on the Employment page.
 

Contact Information
Phone: (414) 937-3813
Fax: (414) 937-6284
E-mail: hartmut.weiler@bcw.edu