PROINFLAMMATORY BIOMARKERS FOR MILD BLAST TBI

The coincidence of inflammation and coagulation is a common response of vertebrate tissues to damage, and thus could be a compelling origin for mild blast TBI biomarkers. The diagnosis of mild blast TBI is often missed immediately because, aside from transient confusion and memory deficits, there are little or no objective signs or symptoms of illness. However, multiple experiences with mild blast TBI are cumulative. Our goal is therefore to develop a set of biomarkers in a biological fluid, such as CSF or plasma, which will provide a timely identification of the occurrence, severity, and progression of blast-induced TBI, as well as its response to therapeutic intervention. Preliminary data indicate that non-blast damage to the brain can be accompanied by release of contents from broken cells and by expression of proinflammatory mediators from surviving cells in the vicinity of the damage. Such expressed mediators include TNF , IL-6, and IL-8, as well as leukotrienes and other metabolites. These molecules will flow physiologically into the systemic circulation, and may also be discharged into the general circulation through the compromised blood brain barrier (BBB). In addition, extrinsic and intrinsic coagulation processes are activated by exposure of collagen in the subendothelium and by exposure of phosphatidylserine (PS) on membrane fragments. We therefore hypothesize that mild blast TBI is accompanied by elevated levels of proinflammatory biomarker proteins in the cerebrospinal fluid (CSF) and general circulation. To test this hypothesis, we have proposed the following Specific Tasks:Specific Task 1: To determine changes in TNF¿ and related proinflammatory mediators in CSF and plasma from rats exposed to mild blast TBI.Specific Task 2: To determine the low abundance signaling proteome of CSF and plasma from rats exposed to mild blast TBI.Specific Task 3: To determine the metabolomic biomarkers in CSF and plasma from rats exposed to mild blast TBI.Specific Task 4: To determine candidate biomarkers for mild blast TBI in CSF and plasma from exposed humans.Successful identification of biomarkers for mild blast TBI will be significant as objective diagnostics of exposure; significant as indicators of the biological basis for brain-specific responses to blast exposure; and significant as objective surrogates to follow experimental therapeutics.