
Hartmut Weiler, PhD
Associate Professor
Locations
- Physiology
Contact Information
Research Interests
Our group investigates the biological functions of the blood coagulation system. This system ensures the physiologic formation of blood clots that stop bleeding from sites of injury, but is also responsible for the pathologic occlusion of blood vessels, which may cause stroke, pulmonary embolism, myocardial infarction, and deep vein thrombosis. On the other hand, failure of the blood clotting system to stop bleeding causes life threatening hemophilia (uncontrolled bleeding).
In addition, the molecules that initiate and regulate the formation of blood clots also engage cellular signaling processes by activating a specific class of so-called protease-activated receptors (PAR's). These receptors regulate the function of vascular wall cells (endothelium and smooth muscle cells), blood platelets, and of innate immune cells, and thereby coordinate the overall host response to injury.
Current projects investigate the cellular and molecular mechanisms by which coagulation pathways modify the host response to bacterial infections, controls the development of the placenta, regulates the activation of the blood coagulation system, and affects recovery of the hematopoietic system from injury and stress. Insights into the physiological functions of the protein C system in these contexts are used to explore the potential for therapeutic interventions targeting this pathway in diseases like severe sepsis, bone marrow failure after exposure to lethal doses of radiation, and in other progenitor cell-driven processes of tissue remodeling after injury.
Bacterial Infections and sepsis
A common polymorphism in coagulation factor V (fV Leiden) is the leading genetic cause of venous thrombosis in Caucasians. In a "Darwinian Approach" we found that heterozygous carriers of this mutation are protected from lethal infection. This could explain why this prothrombotic mutation has not been eliminated during evolution. We are investigating how this naturally occurring mutation prevents death from sepsis, and apply this knowledge towards the design of therapeutic interventions for sepsis.
Placental Development
We found that a natural anticoagulant pathway, the so-called protein C system, is necessary for placental development. Mice lacking the receptors regulating this pathway (the endothelial protein C receptor and Thrombomodulin) fail to establish a functional placenta. Surprisingly, the critical function of these coagulation factor receptors for placentation does not appear to involve the regulation of blood clot formation, but rather seems necessary for the ability of placental stem cells to differentiate into the various cell types comprising the mature placenta. Insights into the underlying mechanisms may provide novel cues about the etiologies of preeclampsia, fetal growth defects, and stem cell biology.
Hematopoiesis
We made the fortuitous observation that the protein C system also regulates how the blood-forming hematopoietic system recovers from injury. Surprisingly, therapeutic supplementation of this pathway by infusion of recombinant thrombomodulin or activated protein C can enhance survival of lethal radiation injury to hematopoietic stem cells in the bone marrow. By understanding the underlying mechanisms, we hope to devise improved approaches for treating bone marrow failure, and aid in the recovery of hematopoietic stem cell function after bone marrow transplantation.
In addition, Dr. Weiler directs the joint Transgenic Core Facility of the Medical College of Wisconsin (MCW) and the Versiti Blood Research Institute. The facility provides a wide range of services facilitating the generation, maintenance, and acquisition of genetically altered mice and rats.
Publications
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Tissue factor pathway inhibitor is required for cerebrovascular development in mice.
(Maroney SA, Westrick RJ, Cleuren AC, Martinez ND, Siebert AE, Zogg M, Ginsburg D, Weiler H, Mast AE.) Blood. 2021 Jan 14;137(2):258-268 PMID: 32735640 PMCID: PMC7820871 08/01/2020
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Macrophage protease-activated receptor 2 regulates fetal liver erythropoiesis in mice.
(Saffarzadeh M, Grunz K, Nguyen TS, Lee YK, Kitano M, Danckwardt S, Rodrigues CDS, Weiler H, Reyda S, Ruf W.) Blood Adv. 2020 Nov 24;4(22):5810-5824 PMID: 33232477 PMCID: PMC7686899 SCOPUS ID: 2-s2.0-85097247813 11/25/2020
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(Majewski MW, Gandhi DM, Holyst T, Wang Z, Hernandez I, Rosas R Jr, Zhu J, Weiler H, Dockendorff C.) RSC Med Chem. 2020 Aug 01;11(8):940-949 PMID: 33479689 PMCID: PMC7496306 01/23/2021
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(Shi Q, Mattson JG, Fahs SA, Geurts AM, Weiler H, Montgomery RR.) Blood Adv. 2020 01 14;4(1):55-65 PMID: 31899798 PMCID: PMC6960468 SCOPUS ID: 2-s2.0-85078174834 01/04/2020
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(Majewski MW, Gandhi DM, Holyst T, Wang Z, Hernandez I, Rosas R, Zhu J, Weiler H, Dockendorff C.) RSC Medicinal Chemistry. August 2020;11(8):940-949 SCOPUS ID: 2-s2.0-85091019890 08/01/2020
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A rat model of severe VWD by elimination of the VWF gene using CRISPR/Cas9.
(Garcia J, Flood VH, Haberichter SL, Fahs SA, Mattson JG, Geurts AM, Zogg M, Weiler H, Shi Q, Montgomery RR.) Res Pract Thromb Haemost. 2020 Jan;4(1):64-71 PMID: 31989086 PMCID: PMC6971331 01/29/2020
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Role of thrombomodulin expression on hematopoietic stem cells.
(Basu S, Liang HPH, Hernandez I, Zogg M, Fields B, May J, Ogoti Y, Wyseure T, Mosnier LO, Burns RT, Carlson K, Weiler H.) J Thromb Haemost. 2020 01;18(1):123-135 PMID: 31628891 PMCID: PMC6940513 SCOPUS ID: 2-s2.0-85074837812 10/20/2019
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The Adult Murine Intestine is Dependent on Constitutive Laminin-γ1 Synthesis.
(Fields B, DeLaForest A, Zogg M, May J, Hagen C, Komnick K, Wieser J, Lundberg A, Weiler H, Battle MA, Carlson KS.) Sci Rep. 2019 12 17;9(1):19303 PMID: 31848396 PMCID: PMC6917708 SCOPUS ID: 2-s2.0-85076615345 12/19/2019
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(Gao C, Schroeder JA, Xue F, Jing W, Cai Y, Scheck A, Subramaniam S, Rao S, Weiler H, Czechowicz A, Shi Q.) Blood Adv. 2019 09 24;3(18):2700-2711 PMID: 31515232 PMCID: PMC6759737 SCOPUS ID: 2-s2.0-85072272107 09/14/2019
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Myeloid cell-synthesized coagulation factor X dampens antitumor immunity.
(Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W.) Sci Immunol. 2019 09 20;4(39) PMID: 31541031 PMCID: PMC6830514 SCOPUS ID: 2-s2.0-85072538893 09/22/2019
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(Gandhi DM, Rosas R Jr, Greve E, Kentala K, D-R Diby N, Snyder VA, Stephans A, Yeung THW, Subramaniam S, DiMilo E, Kurtenbach KE, Arnold LA, Weiler H, Dockendorff C.) Bioorg Med Chem. 2019 09 01;27(17):3788-3796 PMID: 31320211 PMCID: PMC6706283 SCOPUS ID: 2-s2.0-85068855508 07/20/2019
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(Slobodianuk TL, Kochelek C, Foeckler J, Kalloway S, Weiler H, Flood VH.) J Thromb Haemost. 2019 01;17(1):63-71 PMID: 30565388 PMCID: PMC6743498 SCOPUS ID: 2-s2.0-85058806961 12/20/2018