The widespread deposition of fibrin and fibrin degradation products (FDPs) within the nervous system is well documented in demyelinating plaques in Multiple Sclerosis (MS). Given that fibrin, FDPs and their cell surface receptors play a role in both the inflammatory response and tissue remodeling/repair, they are prime candidates to be critical determinants of inflammatory demyelination. Our major hypothesis is that fibrin utilizes receptors of nervous system cells to exert deleterious effects in nervous system pathology. Our preliminary data demonstrate that: 1. Pharmacologic depletion of fibrin reverses relapsing paralysis and ameliorates inflammatory demyelination in autoimmune encephalomyelitis (EAE);2. Fibrin induces microglia activation both in vivo and in vitro;3. Blocking the Mac-1 (CD11b/CD18) fibrin receptor ameliorates fibrin-induced microglia activation in vitro. Our ultimate goal is to design a novel therapeutic approach for fibrin depletion with potential application in MS and other neurologic diseases associated with fibrin deposition. In this grant proposal we will determine the impact of genetic depletion of fibrinogen or genetic elimination of the fibrinogen Mac-1 binding site in animal models for MS (Aim 1). We will examine the involvement of fibrin/Mac-1 interactions in functions of microglia activation, such as proliferation, phagocytosis and cytokine release (Aims 2 and 3). The therapeutic efficacy of 2 known anticoagulants, as well as the efficacy of a specific fibrin/Mac-1 inhibitor will be assessed in 2 animal models of MS (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 anticoagulants in animal models for MS. Identifying the receptors of fibrin actions in the nervous system could ultimately illuminate new therapeutic strategies for the treatment of MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052189-09
Application #
8271390
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Utz, Ursula
Project Start
2005-07-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$410,425
Indirect Cost
$195,543
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J et al. (2016) Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. Front Neurosci 10:46
Zhang, Ming-Dong; Barde, Swapnali; Yang, Ting et al. (2016) Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels. Proc Natl Acad Sci U S A 113:E6686-E6695
Le Moan, Natacha; Baeten, Kim M; Rafalski, Victoria A et al. (2015) Hypoxia Inducible Factor-1α in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease(,.) eNeuro 2:
Lim, Hyung W; Kang, Seung Goo; Ryu, Jae Kyu et al. (2015) SIRT1 deacetylates RORγt and enhances Th17 cell generation. J Exp Med 212:607-17
Ryu, Jae Kyu; Petersen, Mark A; Murray, Sara G et al. (2015) Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 6:8164
Schachtrup, Christian; Ryu, Jae Kyu; Mammadzada, Könül et al. (2015) Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-β signaling and astrocyte functions. Nat Neurosci 18:1077-80
Akassoglou, Katerina (2015) Coagulation takes center stage in inflammation. Blood 125:419-20
Bardehle, Sophia; Rafalski, Victoria A; Akassoglou, Katerina (2015) Breaking boundaries-coagulation and fibrinolysis at the neurovascular interface. Front Cell Neurosci 9:354
Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar et al. (2014) Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62:1345-60
Terrando, Niccolò; Yang, Ting; Ryu, Jae Kyu et al. (2014) Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol Med 20:667-75

Showing the most recent 10 out of 33 publications