Biomarker of Neurotoxicity in Alcohol Abuse

描述(由申请人提供)：本第一阶段申请的目的 是开发一种灵敏的生物标记物来量化由此导致的神经元损伤 死于急性酒精滥用。具体来说，我们将确定是否提升了 急性酒精滥用后血清裂解tau水平反映神经元 损坏。 MAP-tau是一种定位于神经元轴突的细胞骨架蛋白； 损伤MAP-tau被蛋白水解性切割。我们之前的研究表明 裂解tau蛋白是重型颅脑损伤后神经元损伤的可靠生物标志物 创伤和中风。我们的初步研究表明，个人被允许 因急性酒精滥用而被紧急送往急诊部的人数上升 血浆裂解tau水平表明急性酒精滥用会导致急性 神经元损伤。或者，急性酒精滥用可能会导致肝脏毒性。低 肝脏MAP-tau水平，占大脑的0.3%，已有报道。在预赛中 研究发现，在不存在裂解-tau蛋白的情况下， 肝毒性(AST&lt；3X ULN)，因此不太可能升高 肝源性急性酒精滥用后观察到的裂解tau现象。我们的 特定的目标将评估血清裂解tau升高的幅度 急性酒精滥用，确定血清裂解tau水平之间的相关性 和血液酒精水平，并探索是否裂解tau可能是肝脏 起源。 具体目标1：确定急性发作后血清裂解tau水平是否升高 酒精滥用与对照组相比。具体目标2：确定统计数字 酒精性脂肪肝患者血清裂解tau蛋白水平与血酒精水平的关系 急性酒精滥用。具体目标3：确定血清裂解tau水平 在急性肝功能衰竭患者中升高。 建议的商业应用： 被提议的酒精诱导的神经元损伤的生物标记物最终可能是 以护理点分析的形式，帮助医生制定个性化的 对酗酒和依赖的干预。美国医院出院 超过180万名ALL患者，包括第一批与酒精有关的患者 诊断。如果这些住院患者有神经毒性，使用 建议的生物标记物，那么该检测的潜在市场为每年5600万美元。

DESCRIPTION (provided by applicant): The objective of this Phase I application is to develop a sensitive biomarker for quantifying neuronal damage resulting from acute alcohol abuse. Specifically, we will determine whether elevated serum levels of cleaved-tau observed after acute alcohol abuse reflect neuronal damage. MAP-tau is a cytoskeletal protein localized in neuronal axons; after neuronal damage MAP-tau is proteolytically cleaved. Our previous research demonstrates that cleaved-tau is a reliable biomarker of neuronal damage after severe head trauma and stroke. Our Preliminary Studies indicate that individuals admitted to the Emergency Department for acute alcohol abuse demonstrated elevated plasma cleaved-tau levels suggesting that acute alcohol abuse results in acute neuronal damage. Alternately, acute alcohol abuse may cause hepatotoxicity. Low liver MAP-tau levels, 0.3 percent of brain, have been reported. In Preliminary Studies elevated cleaved-tau levels were observed in the absence of hepatotoxicity (AST < 3X ULN), therefore it its unlikely that the elevated cleaved-tau observed after acute alcohol abuse originated from liver. Our Specific Aims will assess the magnitude of serum cleaved-tau elevation after acute alcohol abuse, determine the correlation between serum cleaved-tau levels and blood alcohol levels, and explore whether cleaved-tau may be of hepatic origin. Specific Aim 1: Determine if serum cleaved-tau levels are elevated after acute alcohol abuse compared to controls. Specific Aim 2: Determine the statistical relationship between serum cleaved-tau levels and blood alcohol levels after acute alcohol abuse. Specific Aim 3: Determine whether serum cleaved-tau levels are elevated in patients with acute liver failure. PROPOSED COMMERCIAL APPLICATION: The proposed biomarker for ethanol-induced neuronal damage can ultimately be formatted in a point-of-care assay to assist physicians in developing individualized interventions for alcohol abuse and dependence. United States hospital discharged more than 1.8 million patients with all-listed, including first-listed, alcohol-related diagnoses. If these hospitalized patients had neurotoxicity measured using the proposed biomarker, then the potential market for the assay is $56 million per year.