Hartmut Weiler, PhD
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.
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.
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.
Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation.
(Fleischer MI, Röhrig N, Raker VK, Springer J, Becker D, Ritz S, Bros M, Stege H, Haist M, Grabbe S, Haub J, Becker C, Reyda S, Disse J, Schmidt T, Mahnke K, Weiler H, Ruf W, Steinbrink K.) J Thromb Haemost. 2022 Dec;20(12):2823-2836 PMID: 36161697 SCOPUS ID: 2-s2.0-85140121210 09/27/2022
The impact of aberrant von Willebrand factor-GPIbα interaction on megakaryopoiesis and platelets in humanized type 2B von Willebrand disease model mouse.
(Kanaji S, Morodomi Y, Weiler H, Zarpellon A, Montgomery RR, Ruggeri ZM, Kanaji T.) Haematologica. 2022 Sep 01;107(9):2133-2143 PMID: 35142156 PMCID: PMC9425322 SCOPUS ID: 2-s2.0-85131561060 02/11/2022
A novel mouse model of type 2N VWD was developed by CRISPR/Cas9 gene editing and recapitulates human type 2N VWD.
(Shi Q, Fahs SA, Mattson JG, Yu H, Perry CL, Morateck PA, Schroeder JA, Rapten J, Weiler H, Montgomery RR.) Blood Adv. 2022 May 10;6(9):2778-2790 PMID: 35015821 PMCID: PMC9092403 SCOPUS ID: 2-s2.0-85130105632 01/12/2022
Blocking hemophilic arthropathy.
(Shi Q, Weiler H.) Blood. 2022 May 05;139(18):2734-2735 PMID: 35511191 SCOPUS ID: 2-s2.0-85129525401 05/06/2022
Coagulation Factor IIIa (f3a) Knockdown in Zebrafish Leads to Defective Angiogenesis and Mild Bleeding Phenotype.
(Subramaniam S, Liu J, Fletcher C, Ramchandran R, Weiler H.) Front Cell Dev Biol. 2022;10:852989 PMID: 35386206 PMCID: PMC8978257 04/08/2022
Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics.
(Schroeder JA, Kuether EA, Fang J, Jing W, Weiler H, Wilcox DA, Montgomery RR, Shi Q.) J Thromb Haemost. 2021 Oct;19(10):2417-2427 PMID: 34245090 PMCID: PMC8865566 SCOPUS ID: 2-s2.0-85111140299 07/11/2021
Bleeding diathesis in mice lacking JAK2 in platelets.
(Eaton N, Subramaniam S, Schulte ML, Drew C, Jakab D, Haberichter SL, Weiler H, Falet H.) Blood Adv. 2021 Aug 10;5(15):2969-2981 PMID: 34342643 PMCID: PMC8361459 08/04/2021
A thrombin-PAR1/2 feedback loop amplifies thromboinflammatory endothelial responses to the viral RNA analogue poly(I:C).
(Subramaniam S, Ogoti Y, Hernandez I, Zogg M, Botros F, Burns R, DeRousse JT, Dockendorff C, Mackman N, Antoniak S, Fletcher C, Weiler H.) Blood Adv. 2021 Jul 13;5(13):2760-2774 PMID: 34242391 PMCID: PMC8288670 07/10/2021
Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells.
(Giri H, Panicker SR, Cai X, Biswas I, Weiler H, Rezaie AR.) Proc Natl Acad Sci U S A. 2021 Mar 16;118(11) PMID: 33836597 PMCID: PMC7980409 SCOPUS ID: 2-s2.0-85102375682 04/11/2021
Bleeding diathesis in mice lacking JAK2 in platelets
(Eaton N, Subramaniam S, Schulte ML, Drew C, Jakab D, Haberichter SL, Weiler H, Falet H.) Blood Advances. 10 August 2021;5(15):2969-2981 SCOPUS ID: 2-s2.0-85112565305 08/10/2021
Sex-dependent effects of genetic upregulation of activated protein C on delayed effects of acute radiation exposure in the mouse heart, small intestine, and skin.
(Sridharan V, Johnson KA, Landes RD, Cao M, Singh P, Wagoner G, Hayar A, Sprick ED, Eveld KA, Bhattacharyya A, Krager KJ, Aykin-Burns N, Weiler H, Fernández JA, Griffin JH, Boerma M.) PLoS One. 2021;16(5):e0252142 PMID: 34029348 PMCID: PMC8143413 SCOPUS ID: 2-s2.0-85106514258 05/25/2021
Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2.
(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