Precision medicine for Asian Americans requiring anesthesia

为需要麻醉的亚裔美国人提供精准医疗

• 批准号: 9319777
• 负责人: Eric Richard Gross
• 金额: $ 37.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319777
• 关键词: Aldehydes; Analgesics; Anesthesia procedures; Anesthetics; Area; Asian Americans; Basic Science; Biological Assay; Cardiac; Caring; Data; Far East; Functional disorder; Generations; Goals; Health Care Costs; Human Genetics; Injury; Knock-in Mouse; Laboratories; Medical; Metabolism; Methods; Modeling; Myocardial Ischemia; Nitroglycerin; Operative Surgical Procedures; Organ; Pain management; Population; Quality of Care; Reperfusion Injury; Role; Testing; Toxic effect; Training; United States; Variant; cell injury; conditioning; drug metabolism; genetic variant; improved; mouse model; precision medicine; programs; tool; treatment strategy

PROJECT SUMMARY Greater than 40 million people in the United States annually are provided anesthesia for surgery. Reactive aldehydes, produced during surgery, are toxic metabolites which drive cellular dysfunction and end-organ damage. For Asian Americans that are descendants from East Asia, a genetic variant (present in 8% of the world population) severely limits reactive aldehyde metabolism. The goal for my program is to develop specific treatment strategies (precision anesthesia) for Asian Americans that cannot efficiently metabolize reactive aldehydes in order to reduce reactive aldehyde toxicity during surgery. For this MIRA proposal, I will initially focus on determining in the basic science laboratory methods to reduce injury from reactive aldehydes, particularly for this genetic variant, by using models of cardiac ischemia- reperfusion injury. This is my area of expertise, as I am an anesthesiologist with over a decade of basic science training studying mechanisms of anesthetic-, analgesic- and remote conditioning-induced protection from cardiac ischemia-reperfusion injury. To carry out these studies, we generated tools to study reactive aldehydes including a knock-in mouse model to reflect the human genetic variant and sensitive assays to detect reactive aldehydes. From my preliminary data, we have 3 possible strategies to test in order to reduce reactive aldehyde-induced organ damage for this genetic variant. We will also determine how reactive aldehyde generation and metabolism contribute to anesthetic mechanisms of cardiac protection and the cross- talk that may occur between anesthetics and remote conditioning. Broadly, my program will provide targets, treatments, and models to study reactive aldehydes; discovering strategies to reduce aldehydes and cellular injury during surgery. Asian Americans will require specific anesthetic plans for surgeries particularly due to this genetic variant decreasing their ability to metabolize reactive aldehydes. Besides reactive aldehyde metabolism, this variant also has an important role in drug metabolism (in particular for nitroglycerin) and pain control. Providing precision medical care for people who require surgery with this genetic variant will ultimately reduce health care costs and improve quality of care for this large subset of Asian Americans.

项目概要 美国每年有超过 4000 万人接受手术麻醉。反应性 手术过程中产生的醛是有毒代谢物，会导致细胞功能障碍和终末器官 损害。对于来自东亚的亚裔美国人来说，一种基因变异（存在于 8% 的人中） 世界人口）严重限制了反应性醛代谢。我的计划的目标是开发具体的 针对无法有效代谢反应性亚裔美国人的治疗策略（精准麻醉） 醛类以减少手术期间的反应性醛毒性。 对于这个 MIRA 提案，我首先将重点放在确定基础科学实验室的方法上，以减少 通过使用心脏缺血模型，特别是对于这种遗传变异，活性醛造成的损伤 再灌注损伤。这是我的专业领域，因为我是一名麻醉师，拥有十多年的基础知识 研究麻醉、镇痛和远程调理诱导保护机制的科学培训 心脏缺血再灌注损伤。为了进行这些研究，我们生成了研究反应性的工具 醛类，包括反映人类遗传变异的敲入小鼠模型和敏感测定 检测活性醛。根据我的初步数据，我们有 3 种可能的策略可供测试，以减少 这种遗传变异引起的反应性醛诱导的器官损伤。我们还将确定如何反应 醛的产生和代谢有助于心脏保护和交叉麻醉的麻醉机制 麻醉师和远程调节之间可能发生的谈话。总的来说，我的计划将提供目标， 研究活性醛的治疗方法和模型；发现减少醛和细胞的策略 手术期间受伤。 亚裔美国人将需要特定的手术麻醉计划，特别是由于这种基因变异 降低它们代谢活性醛的能力。除了反应性醛代谢外，这种变体 在药物代谢（特别是硝酸甘油）和疼痛控制中也具有重要作用。提供 对需要接受这种基因变异手术的人进行精准医疗服务最终将损害健康 护理成本并提高这一大批亚裔美国人的护理质量。