Modifications of glycated Hb:Novel biomarkers of alcohol

糖化血红蛋白的修饰：酒精的新型生物标志物

• 批准号: 7083271
• 负责人: YOUSEF AL-ABED
• 金额: $ 19.59万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7083271
• 关键词: acetaldehyde; adduct; alcoholic beverage consumption; alcoholism /alcohol abuse; antigens; behavioral /social science research tag; biomarker; chemical synthesis; disease /disorder model; drug addiction; endoribonucleases; enzyme activity; enzyme linked immunosorbent assay; erythrocytes; glycation; hemoglobin As; immunoconjugates; immunologic assay /test; laboratory mouse; laboratory rabbit; laboratory rat; mass spectrometry; method development; nuclear magnetic resonance spectroscopy; plasma; substance abuse related behavior

DESCRIPTION (provided by applicant): Chronic and binge drinking affect millions of Americans each year. A recent study revealed that alcohol contributes to 4% of the global burden of disease which is equivalent to the world-wide impact of tobacco use and hypertension (Reviewed in Room et al, Lancer 2005). In addition, alcohol abuse is associated with heavy social and economic burdens (approximately $185B annually). Based on sensitivity and specificity, the most reliable screening techniques for alcohol abuse are self-reporting methods. Clearly, the major shortcoming of self-reporting alcohol use by abusers is under-reporting. Interestingly, no biomarkers of binge drinking are available. Our long-term goal is to develop reliable methods to detect acute and chronic alcohol abuse. Our central hypothesis is that two stable acetaldehyde-modified glycosylated hemoglobin (Hb) adducts are produced following (A) binge and (B) chronic drinking and these represent specific and abundant markers of (A) acute and (B) chronic alcohol abuse, respectively. Our preliminary data show that (a) acetaldehyde modifies glycosylated Hb to form stable adducts; (b) glycosylated HbAo represents approximately 20% of the total Hb in healthy persons (while glycosylated HbA1c represents 3-5%); and (c) two types of Hb-acetaldehyde adducts form depending on the length and concentration of alcohol metabolite exposure. Specific aims: We propose to (1) conjugate acetaldehyde adducts onto protein carriers (that represent adducts formed following binge and chronic drinking, respectively) for the development of specific antibodies and (2) develop specific and sensitive immunoassay methods for detecting these biomarkers in the red blood cells and serum/plasma using rat experimental models of acute/binge drinking or chronic alcohol administration, respectively. Relevance to public health: Alcohol abuse, including chronic alcohol abuse (or alcoholism) and binge drinking (defined as having equal to or >5 drinks on one occasion within the past month) is the third leading cause of preventable death in the US. Binge drinking has significantly increased in the past few years, affecting up to 39 out of 100 teens and young adults interviewed. Although alcohol treatment programs are successful for helping alcohol abusers, many alcohol abusers are not treated because we lack good methods for identifying alcohol abusers. Currently, self-reporting methods (questionnaires) are used to detect alcohol abuse because we do not have better procedures that reliably determine alcohol abuse using blood, saliva, or urine. Our early studies show that acetaldehyde (alcohol's breakdown product in the blood) binds to modified hemoglobin (the major protein found in red blood cells) following binge and chronic drinking to form two different 'markers.' We will develop specific methods for identifying binge and chronic alcohol-specific markers in the blood/red blood cells of rats administered acute or chronic alcohol. Future studies will be designed to measure these alcohol-specific-markers in humans following binge and chronic alcohol intake.

描述（由申请人提供）：慢性饮酒和酗酒每年影响数百万美国人。最近的一项研究表明，酒精占全球疾病负担的 4%，相当于烟草使用和高血压对全球的影响（Room 等人综述，Lancer 2005）。此外，酗酒还会带来沉重的社会和经济负担（每年约$185B）。基于敏感性和特异性，最可靠的酒精滥用筛查技术是自我报告方法。显然，滥用者自我报告饮酒情况的主要缺点是报告不足。有趣的是，目前还没有酗酒的生物标志物。我们的长期目标是开发可靠的方法来检测急性和慢性酒精滥用。 我们的中心假设是，在（A）暴饮暴食和（B）长期饮酒后会产生两种稳定的乙醛修饰的糖基化血红蛋白（Hb）加合物，它们分别代表（A）急性和（B）慢性酒精滥用的特异性和丰富的标记物。我们的初步数据表明，(a) 乙醛修饰糖基化 Hb 形成稳定的加合物； (b) 糖基化 HbAo 约占健康人总 Hb 的 20%（而糖基化 HbA1c 占 3-5%）； (c) 根据酒精代谢物暴露的时间和浓度，形成两种类型的 Hb-乙醛加合物。具体目标：我们建议（1）将乙醛加合物缀合到蛋白质载体（分别代表暴饮暴食和长期饮酒后形成的加合物）以开发特异性抗体，以及（2）开发特异性和灵敏的免疫测定方法来检测这些生物标志物红细胞和血清/血浆分别使用急性/酗酒或慢性饮酒的大鼠实验模型。 与公共卫生的相关性：酗酒，包括慢性酗酒（或酗酒）和酗酒（定义为过去一个月内一次饮酒量等于或超过 5 杯）是美国可预防死亡的第三大原因。过去几年，酗酒现象显着增加，受访的 100 名青少年和年轻人中多达 39 人受到影响。尽管酒精治疗计划成功地帮助了酗酒者，但许多酗酒者没有得到治疗，因为我们缺乏识别酗酒者的良好方法。目前，自我报告方法（问卷）用于检测酒精滥用，因为我们没有更好的程序可以使用血液、唾液或尿液可靠地确定酒精滥用。我们的早期研究表明，在暴饮暴食和长期饮酒后，乙醛（血液中酒精的分解产物）会与修饰的血红蛋白（红细胞中发现的主要蛋白质）结合，形成两种不同的“标记物”。我们将开发特定方法来识别急性或慢性饮酒大鼠的血液/红细胞中的暴食和慢性酒精特异性标记物。未来的研究将旨在测量人类在暴饮暴食和长期饮酒后的这些酒精特异性标记物。