INTERACTIONS OF FIBRINOGEN WITH p75NTR

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DESCRIPTION (provided by applicant): Fibrin is a blood-derived protein deposited in the nervous system after disease associated with vasculature rupture; such as stroke, multiple sclerosis (MS) and brain glioblastomas. Our previous studies in mice genetically or pharmacologically deficient in fibrinogen demonstrated that fibrin inhibits peripheral nerve regeneration and exacerbates inflammatory demyelination in the central nervous system in an animal model for MS. Our long term goal is to identify the molecular and cellular interface that fibrin utilizes to induce nervous system pathology. The specific hypothesis of this proposal is that fibrin interacts with the p75 neurotrophin receptor (p75NTR) to mediate its effects in the nervous system. Our hypothesis is based on the observations that 1: Fibrinogen and its derivatives directly bind to p75NTR and thus may directly modulate receptor function; 2. p75NTR expression in vivo regulates the bioavailability of fibrin and its derivatives in the nervous system. 3. Fibrinogen and its degradation products mediate diverse survival responses via p75NTR. Based on these observations, the experimental focus of this proposal is on the biochemical, in vivo and in vitro analysis of the p75NTR interactions with fibrinogen. The specific aims are to: 1. Establish the biochemical interactions of p75NTR with fibrinogen and its derivatives, 2: Determine the biological effects induced by fibrin(ogen) in p75NTR - expressing cell types in the PNS and CNS and 3: Establish the contribution of p75NTR / fibrin interactions in nerve regeneration and inflammatory demyelination. Since p75NTR is upregulated in the adult nervous system in response to injury, identifying the molecular interactions of p75NTR with fibrin could potentially provide injury-specific targets for pharmacological intervention in a variety of diseases characterized by vascular damage, endothelial cell activation and decreased capacity for tissue repair.