Our research project is designed to test our central hypothesis that activation of the contact factor pathway contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during sepsis induced by specific infectious pathogens. Sepsis is a sequel of molecular and cellular events that perpetually change over the course of this life threatening disease condition. Failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension are hallmarks of severe sepsis, and, by triggering a cardiopulmonary and vascular collapse, leads to death when left untreated. Severe sepsis may be accompanied by disseminated intravascular coagulation (DIC) that aggravates the vasodilation and edema-associated tissue perfusion insufficiency. DIC can lead to the failure of hemostasis, and subsequent bleeding due to the consumption of coagulation factors and platelets. We focus on the contact activation pathway, because 1) there appears to be a causal relationship between pathological activation of the coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation pathway as a therapeutic approach is unlikely to have detrimental consequences for the host. We will define the role of the molecular steps in the contact pathway of coagulation in the development and outcomes of severe sepsis. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and will translate our mechanistic in vitro and ex vivo studies to define th pathological role of activation of the contact pathway in 2 distinct primate models of severe sepsis. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation pathway. Our research may ultimately provide rationale for the development of selective contact activation pathway inhibitors that could benefit sepsis patients infected with pathogens that exploit the contact activation pathway for virulence. Importantly, this approach would not do harm to patients whose infection is controlled by endogenous extrinsic pathway-dependent fibrin formation as part of the innate immune response.

Public Health Relevance

Sepsis is a prevalent, infection-induced acute severe inflammatory response syndrome that typically progresses into hypotension, failure of vasoregulation, insufficient organ perfusion and death within hours to days when left untreated. There is an unmet medical need for the development of safe and effective treatments for sepsis. Our research is designed to identify and characterize novel druggable molecular and cellular mechanisms that arise in sepsis and detrimentally contribute to a pathological state with excess vasodilation, increased blood coagulation, and reduced protective mechanisms that increase pathogen virulence.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM116184-04
Application #
9503744
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2015-09-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Zilberman-Rudenko, Jevgenia; Reitsma, Stéphanie E; Puy, Cristina et al. (2018) Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 38:1748-1760
Ngo, Anh T P; McCarty, Owen J T; Aslan, Joseph E (2018) TRPing out Platelet Calcium: TRPM7 (Transient Receptor Potential Melastatin-Like 7) Modulates Calcium Mobilization and Platelet Function via Phospholipase C Interactions. Arterioscler Thromb Vasc Biol 38:285-286
Rocheleau, Anne D; Khader, Ayesha; Ngo, Anh T P et al. (2018) Pilot study of novel lab methodology and testing of platelet function in adolescent women with heavy menstrual bleeding. Pediatr Res 83:693-701
Zilberman-Rudenko, Jevgenia; Zhao, Frank Z; Reitsma, Stephanie E et al. (2018) Effect of Pneumatic Tubing System Transport on Platelet Apheresis Units. Cardiovasc Eng Technol 9:515-527
Mitrugno, Annachiara; Rigg, Rachel A; Laschober, Nicole B et al. (2018) Potentiation of TRAP-6-induced platelet dense granule release by blockade of P2Y12 signaling with MRS2395. Platelets 29:383-394
Popescu, Narcis I; Silasi, Robert; Keshari, Ravi S et al. (2018) Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. Blood 132:849-860
Healy, Laura D; Rigg, Rachel A; Griffin, John H et al. (2018) Regulation of immune cell signaling by activated protein C. J Leukoc Biol :
Rigg, Rachel A; Healy, Laura D; Chu, Tiffany T et al. (2018) Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. Platelets :1-10
Mitrugno, Annachiara; Sylman, Joanna L; Rigg, Rachel A et al. (2018) Carpe low-dose aspirin: the new anti-cancer face of an old anti-platelet drug. Platelets 29:773-778
Tillman, Benjamin F; Gruber, Andras; McCarty, Owen J T et al. (2018) Plasma contact factors as therapeutic targets. Blood Rev 32:433-448

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