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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Utz, Ursula
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J. David Gladstone Institutes
San Francisco
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Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar et al. (2014) Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62:1345-60
Davalos, Dimitrios; Baeten, Kim M; Whitney, Michael A et al. (2014) Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol 75:303-8
Chen, Wanqiu; Guo, Yi; Walker, Espen J et al. (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33:305-10
Davalos, Dimitrios; Akassoglou, Katerina (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34:43-62
Davalos, Dimitrios; Akassoglou, Katerina (2012) In vivo imaging of the mouse spinal cord using two-photon microscopy. J Vis Exp :e2760
Schachtrup, Christian; Le Moan, Natacha; Passino, Melissa A et al. (2011) Hepatic stellate cells and astrocytes: Stars of scar formation and tissue repair. Cell Cycle 10:1764-71
Baeten, Kim M; Akassoglou, Katerina (2011) Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke. Dev Neurobiol 71:1018-39
Le Moan, Natacha; Houslay, Daniel M; Christian, Frank et al. (2011) Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1ýý. Mol Cell 44:476-90
Terrando, Niccolò; Eriksson, Lars I; Ryu, Jae Kyu et al. (2011) Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol 70:986-95
Drew, Patrick J; Shih, Andy Y; Driscoll, Jonathan D et al. (2010) Chronic optical access through a polished and reinforced thinned skull. Nat Methods 7:981-4

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