Fibrinogen, a critical component of blood coagulation, extravasates across a damaged blood-brain barrier (BBB) and accumulates as fibrin deposits at specific sites of injury. The widespread deposition of fibrin within the nervous system is well documented in demyelinating plaques in Multiple Sclerosis (MS). Our published work pioneered studies of fibrinogen in CNS disease. We identified fibrinogen as a novel molecular link between BBB disruption and inflammatory demyelination. We demonstrated novel cellular functions of fibrinogen as an activator of microglia via interaction with the CD11b/CD18 integrin. Given that fibrin and its cell surface receptors play a role in both the inflammatory response in the CNS and tissue remodeling/repair, they are prime candidates to be critical determinants of inflammatory demyelination. Our ultimate goal is to design novel therapeutic approaches to specifically target the proinflammatory functions of fibrin in the CNS with potential application in MS and other neurologic diseases associated with fibrin deposition. In this grant renewal application we employ a multifaceted experimental design to determine the role of fibrinogen in T cell trafficking in the CNS using state-of-the-art in vivo two-photon microscopy (Aim 1), the mechanisms of fibrinogen/CD11b signaling in T cell immune modulation and epitope spreading using genetic models of fibrinogen depletion or specific inhibition of its interactions with its receptors in viv (Aim 2), the pathways downstream of fibrinogen/CD11b/CD18 signaling involved in the activation of the innate and adaptive immune responses in the CNS (Aim 3), and the therapeutic potential in neuroinflammatory disease of two novel inhibitors developed in our laboratory that specifically target the interaction of fibrinogen with CD11b/CD18 without adverse effects in blood coagulation (Aim 4). The proposed studies will provide a cellular and molecular definition of the role of hemostatic factors in the pathogenesis of inflammatory demyelination and will determine the therapeutic efficacy of novel inhibitors of fibrinogen function in neuroinflammation. Identifying the mechanisms of fibrin actions in the nervous system could ultimately illuminate new therapeutic strategies for the treatment of MS.

Public Health Relevance

Fibrinogen is a major plasma component that upon BBB leakage promotes inflammation and degeneration in the CNS. Studying the interplay between fibrinogen and neuroinflammation could provide novel therapies for suppressing innate immune responses and their downstream consequences in a variety of diseases characterized by BBB disruption, such as multiple sclerosis, spinal cord and traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS052189-10
Application #
8506941
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Utz, Ursula
Project Start
2005-07-15
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$609,190
Indirect Cost
$262,052
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
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