Biomarker of Neurotoxicity in Alcohol Abuse

酒精滥用神经毒性的生物标志物

• 批准号: 6581140
• 负责人: JAMES JEFFREY MULCHAHEY
• 金额: $ 13.47万
• 依托单位: PHASE 2 DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6581140
• 关键词: alcoholism /alcohol abuse; biomarker; chemical cleavage; enzyme linked immunosorbent assay; human tissue; liver failure; nerve injury; nervous system disorder diagnosis; neurotoxicology; proteolysis; statistics /biometry; tau proteins; technology /technique development; western blottings

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.

描述（由申请人提供）：第一阶段申请的目的 是开发一种敏感的生物标志物来量化神经元损伤 来自急性酒精滥用。具体来说，我们将确定是否升高 急性酒精滥用后观察到的 cleaved-tau 血清水平反映了神经元 损害。 MAP-tau 是一种定位于神经元轴突的细胞骨架蛋白；神经元后 损伤 MAP-tau 被蛋白水解裂解。我们之前的研究表明 cleaved-tau 蛋白是严重头部损伤后神经元损伤的可靠生物标志物 外伤和中风。我们的初步研究表明，个人承认 因急性酒精滥用而被送往急诊室 血浆裂解 tau 水平表明急性酒精滥用会导致急性酒精滥用 神经元损伤。另外，急性酒精滥用可能会导致肝毒性。低的 据报道，肝脏 MAP-tau 水平占大脑的 0.3%。初步阶段 研究观察到在没有 肝毒性（AST < 3X ULN），因此不太可能升高 急性酒精滥用后观察到的切割 tau 蛋白源自肝脏。我们的 具体目标将评估术后血清 cleaved-tau 升高的程度 急性酒精滥用，确定血清 cleaved-tau 水平之间的相关性 和血液酒精水平，并探讨 cleaved-tau 是否可能来自肝脏 起源。 具体目标 1：确定急性后血清 cleaved-tau 水平是否升高 与对照组相比，酒精滥用情况。具体目标 2：确定统计数据 术后血清 cleaved-tau 水平与血液酒精水平的关系 急性酒精滥用。具体目标 3：确定血清 cleaved-tau 水平是否 急性肝功能衰竭患者中该值升高。 拟议的商业应用： 所提出的乙醇诱导的神经元损伤的生物标志物最终可以被 以即时检测的形式进行格式化，以帮助医生制定个体化治疗方案 针对酒精滥用和酒精依赖的干预措施。 美国医院出院 超过 180 万患有所有列出的（包括首要列出的）与酒精相关的患者 诊断。 如果这些住院患者有神经毒性，则使用 拟议的生物标志物，那么该检测的潜在市场为每年 5600 万美元。