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Weiler Project
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Hartmut Weiler, Ph.D. |
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Associate Investigator
Blood Research Institute
The Blood Center of Southeastern Wisconsin |
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Department of Physiology Director
Transgenic Core
Medical College of Wisconsin |
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Current Research
Interests: |
| · Developmental function of Thrombomodulin |
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| 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.
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| 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. |
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genetically engineered designer-mouse to detect and analyze Thrombosis
risk factors |
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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. |
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these mice exhibit a prethrombotic or hypercoaculable 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. |
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Research Team |
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Linda Cioffi |
Research
Scientist |
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Berend Isermann |
Postdoctoral Fellow |
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Sara Hendrickson |
Research
Technologist |
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Mark Zogg |
Animal
Care Specialist |
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Manimala Mahesh |
Embryonic
Stem Cell Specialist |
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Marjorie Cummiskey |
Transgenic Core Specialist |
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GRANT
SUPPORT
MCW intramural,
Endothelial Gene array. (06/1999 through 06/2000)
RO-1 HL60655-01A1,
Thrombomodulin Function, (04/1999 through 03/2004)
RECENT INVITED
LECTURES
- ISTH 1999,
Washingtin D.C. Oral communication of abstracts as above
- "Placental Defects
in Thrombomodulin deficient mice" Tox Talks, Magee-Womens Research
Institute, San Francisco, June 1999. Invited Lecture.
- "Developmental
Function of the Coagulation System: Why Embryos need to Clot" Roswell
Park Cancer Institute, Buffalo NY, Jan 1999 Invited Seminar
Speaker
- "Modeling
Thrombosis in Mice" Pediatric Grand Rounds, Childrens Hospital of
Wisconsin, April 30, 1999 Joint Lecture with Dr. R. Montgomery
RECENT
PUBLICATIONS
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- 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)
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RECENT
ABSTRACTS
- ISTH 17th Annual
Meeting, Washington, D.C, 1999
- Lindner V,
Hendrickson SB, Miano JM, Cooley BC, and Weiler H: Thrombomodulin
Function and Expressiopn in a Murine Model of Arterial Injury.
- Isermann BI and
Weiler H: The letahl Consequences of Thrombomodulin-deficiency persist
in the complete absence of Fibronogen, and are corrected by TM
expression in the placenta
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| Contact Information |
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Phone: (414) 937-3813
Fax: (414)
937-6284
E-mail: hweiler@bcsew.edu |
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