91΄σΟγ½Ά

91΄σΟγ½Ά
91΄σΟγ½Ά 91΄σΟγ½Ά
Research Lab Bench
Physiology
Hartmut Weiler, PhD

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 91΄σΟγ½Ά (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

  • (Kespohl M, Goetzke CC, Althof N, Bredow C, Kelm N, Pinkert S, Bukur T, Bukur V, Grunz K, Kaur D, Heuser A, Mülleder M, Sauter M, Klingel K, Weiler H, Berndt N, Gaida MM, Ruf W, Beling A.) Arterioscler Thromb Vasc Biol. 2024 Apr;44(4):843-865 PMID: 38385286 SCOPUS ID: 2-s2.0-85188941808 02/22/2024

  • (Zelaya H, Grunz K, Nguyen TS, Habibi A, Witzler C, Reyda S, Gonzalez-Menendez I, Quintanilla-Martinez L, Bosmann M, Weiler H, Ruf W.) Blood. 2024 Mar 07;143(10):845-857 PMID: 38096370 PMCID: PMC10940062 SCOPUS ID: 2-s2.0-85183567201 12/14/2023

  • (Xue M, Lin H, Liang HPH, Bereza-Malcolm L, Lynch T, Sinnathurai P, Weiler H, Jackson C, March L.) Rheumatology (Oxford). 2024 Feb 01;63(2):571-580 PMID: 37228024 PMCID: PMC10834933 SCOPUS ID: 2-s2.0-85184021231 05/25/2023

  • (Xue M, Jackson CJ, Lin H, Zhao R, Liang HPH, Weiler H, Griffin JH, March L.) Int J Mol Sci. 2024 Jan 19;25(2) PMID: 38279255 PMCID: PMC10816322 SCOPUS ID: 2-s2.0-85183394244 01/27/2024

  • (Zhao R, Xue M, Lin H, Smith M, Liang H, Weiler H, Griffin JH, Jackson CJ.) Wound Repair Regen. 2024;32(1):90-103 PMID: 38155595 SCOPUS ID: 2-s2.0-85181236662 12/29/2023

  • (Maroney SA, Siebert AE, Martinez ND, Rasmussen M, Peterson JA, Weiler H, Lincoln J, Mast AE.) J Thromb Haemost. 2023 Mar;21(3):639-651 PMID: 36696221 PMCID: PMC10200073 SCOPUS ID: 2-s2.0-85149182853 01/26/2023

  • (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

  • (Christopherson PA, Haberichter SL, Flood VH, Sicking UO, Abshire TC, Montgomery RR, Zimmerman Program Investigators.) Res Pract Thromb Haemost. 2022 Oct;6(7):e12807 PMID: 36381287 PMCID: PMC9637542 SCOPUS ID: 2-s2.0-85142096764 11/17/2022

  • (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

  • (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

  • (Shi Q, Weiler H.) Blood. 2022 May 05;139(18):2734-2735 PMID: 35511191 SCOPUS ID: 2-s2.0-85129525401 05/06/2022

  • (Subramaniam S, Liu J, Fletcher C, Ramchandran R, Weiler H.) Front Cell Dev Biol. 2022;10:852989 PMID: 35386206 PMCID: PMC8978257 04/08/2022

Publications of from the