Blood coagulation pathways culminate in the deposition of fibrin, an extracellular matrix that provides the structural scaffold for the blood clot and orchestrates wound repair. Pathological activation of coagulation (coagulopathy) frequently accompanies infection and contributes to the morbidity of sepsis, a major cause of death in hospitals. Despite extensive research, there has been little progress in our ability to intercede. Recent studies indicate that coagulation pathways also perform critical protective functions during infection and that cytokines previously implicated in coagulopathy also regulate levels of protective fibrin. These observations suggest that septic coagulopathy results from dysregulation of inflammatory pathways that normally aid host defense, but spiral beyond regulatory control during sepsis. This proposal will advance efforts to develop therapeutics for coagulopathy by defining specific mechanisms used by the immune system to control fibrin levels, and by identifying specific pathways that go awry during sepsis.
Aim 1 will use novel in situ assays for key coagulant and fibrinolytic activities in combination with mice depleted of cytokines and/or fibrin-regulating factors to determine how two cytokines (interleukin-6 and interferon-gamma) counter-regulate the deposition of protective fibrin within infected tissues.
Aim 2 will determine what distinguishes protective and pathologic hemostatic perturbations during infection by delineating the importance of specific distinctions between healthy and unhealthy responses;measuring the impact of pathogen class, dose and burden;and defining roles for regulatory cytokines. These studies will be accomplished through the use of well- characterized mouse models of lethal and sublethal infection in combination with newly developed tools for organizing and analyzing complex data. Together, these studies will provide critical experimental data supporting or disputing the concept that all """"""""all bugs bite equally"""""""" with respect to their capacity to activate coagulation during sepsis. By defining the range of unhealthy hemostatic responses that pathogens evoke, these studies aim to identify universal perturbations that can be targeted by treatments for septic coagulopathy. Moreover, by defining the range of healthy hemostatic responses during infection, these studies will foster the development of new treatment strategies that strive to maintain protective levels of hemostatic perturbation during sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071295-08
Application #
8129717
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Ferguson, Stacy E
Project Start
2002-08-21
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2011
Total Cost
$460,647
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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