Staff Collaborate Conference Room

Hartmut Weiler, PhD

Hartmut-Weiler

Hartmut Weiler, PhD

Associate Professor

Locations

  • Physiology

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 Blood Research Institute / Blood Center of Wisconsin. The facility provides a wide range of services facilitating the generation, maintenance, and acquisition of genetically altered mice and rats.

Publications