HUMAN SERUM BIOMARKER FOR NEUROTOXICITY

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The objective of this Phase I application is to develop a sensitive serum- based biomarker for drug-induced neuronal damage in humans. Specifically, we will assess whether elevated serum levels of MAP-tau observed after acetaminophen overdose (OD) reflect neuronal damage. MAP-tau is a cytoskeletal protein primarily localized in neuronal axons; after neuronal damage MAP-tau is proteolytically cleaved. Our previous research demonstrates that cerebrospinal fluid and serum cleaved-tau is a reliable measure of neuronal damage after severe head trauma. Preliminary studies indicate that acetaminophen OD patients demonstrate elevated levels of serum cleaved-tau suggesting that acetaminophen results in neuronal damage. Alternatively, acetaminophen OD patients may develop hepatotoxicity. Low liver MAP-tau levels, 0.3% of brain levels, have been reported. In Preliminary Studies, serum cleaved-tau levels were determined prior to any evidence of hepatotoxicity, therefore, it is unlikely that the serum cleaved-tau observed in OD patients originated from liver. Our Specific Aims will assess serum cleaved-tau levels in an expanded group of acetaminophen OD patients, and three Specific Aims will explore whether serum cleaved-tau may be hepatic origin. Specific Aim 1: Determine if serum cleaved-tau levels are elevated in acetaminophen OD patients with no evidence of hepatotoxicity (N=30). Specific Aim 2: In patients hospitalized with toxic acetaminophen levels determine whether serum cleaved-tau levels are correlated with hepatotoxicity (N=30). Specific Aim 3: Determine serum cleaved-tau levels in patients with acute liver failure (N=30). Specific Aim 4: Characterize MAP-tau and cleaved-tau in post mortem brain, liver and kidney samples. PROPOSED COMMERCIAL APPLICATION: The proposed in vitro serum assay may be utilized to assess brain damage after drug use, drug overdose or environmental neurotoxin exposure