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: 10206639
• 负责人: Eric Richard Gross
• 金额: $ 43.59万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206639
• 关键词: Aldehydes; Analgesics; Anesthesia procedures; Anesthetics; Asian Americans; Asians; Basic Science; Biological; Biological Assay; Caring; Cause of Death; Ethnic Origin; Far East; Functional disorder; Genetic; Genetic study; Health Care Costs; Human; Human Genetics; Knock-in Mouse; Laboratories; Lipid Peroxidation; Medical; Metabolism; Methods; Monitor; Operative Surgical Procedures; Organ; Other Genetics; Pathway interactions; Phenotype; Population; Quality of Care; Rodent; TRP channel; Time; Translating; United States; cell injury; genetic variant; improved; insight; mortality; mouse model; novel; novel strategies; organ injury; precision medicine; programs; tool; treatment strategy

PROJECT SUMMARY: Nearly 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 descents from East Asia a genetic variant (present in nearly 540 million people in the world) severely limits reactive aldehyde metabolism. Besides inefficient reactive aldehyde metabolism, several other genetic differences occur for Asians within the lipid peroxidation pathway; a pathway which regulates damage that occurs during organ injury. As mortality following surgery is the third leading cause of death in the United States, with organ injury a major cause of this mortality, understanding how these genetic differences in Asians may alter lipid peroxidation-induced organ damage could unlock novel treatment strategies for all ethnicities to reduce organ injury occurring during surgery. For this MIRA program, we will study the genetic differences existing within the lipid peroxidation pathway for Asians, including the genetic variant which causes inefficient reactive aldehyde metabolism and the impact on organ injury. To carry out these studies, we generated tools to study reactive aldehydes in the basic science laboratory including a knock-in mouse model to reflect the human genetic variant that causes inefficient reactive aldehyde metabolism and sensitive assays to detect reactive aldehydes. We will use these tools to examine whether an analgesic given during surgery exacerbates cellular injury for rodents with inefficient aldehyde metabolism. Further, we will also study how reactive aldehydes may impact a transient receptor potential channel to trigger organ injury. We also expanded these aldehyde tools by developing non-invasive methods to assess reactive aldehyde levels in humans and methods to identify phenotypes for inefficient reactive aldehyde metabolism. We plan to use these tools in humans undergoing surgery to identify people with inefficient reactive aldehyde metabolism and monitor their aldehyde levels during surgery in real-time. Asian Americans are one of the fastest growing populations in the United States and are projected to reach nearly 34 million by the year 2050. Asian Americans will require specific anesthetic plans for surgeries due to genetic differences in the lipid peroxidation pathway, including genetics which cause inefficient reactive aldehyde metabolism. 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 a large subset of Asian Americans. As we describe here, studying genetic differences can also provide insight into biological mechanisms and unlock novel strategies that can impact medical care for people of all ethnicities.

项目概要： 美国每年有近 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，有一种基因变异（存在于近 540 世界上有数百万人）严重限制了活性醛的代谢。除了低效的反应醛 新陈代谢方面，亚洲人在脂质过氧化途径中还存在其他一些遗传差异；一条通路 它调节器官损伤期间发生的损伤。由于手术后死亡率位居第三位 美国的死亡原因，器官损伤是造成死亡的主要原因，了解这些死亡原因 亚洲人的遗传差异可能会改变脂质过氧化引起的器官损伤，从而开启新的治疗方法 适用于所有种族的减少手术期间发生器官损伤的策略。 对于这个 MIRA 项目，我们将研究脂质过氧化途径中存在的遗传差异 亚洲人，包括导致反应性醛代谢效率低下的遗传变异及其对 器官损伤。为了进行这些研究，我们开发了在基础科学中研究活性醛的工具 实验室包括敲入小鼠模型，以反映导致效率低下的人类遗传变异 反应性醛代谢和检测反应性醛的灵敏测定法。我们将使用这些工具来 检查手术期间给予的镇痛药是否会加剧效率低下的啮齿动物的细胞损伤 醛代谢。此外，我们还将研究活性醛如何影响瞬时受体 引发器官损伤的潜在通道。我们还通过开发非侵入性来扩展这些醛工具 评估人体活性醛水平的方法以及识别低效表型的方法 反应性醛代谢。我们计划在接受手术的人类身上使用这些工具来识别人员 反应性醛代谢效率低下，并在手术过程中实时监测其醛水平。 亚裔美国人是美国增长最快的人口之一，预计将达到 到 2050 年，亚裔美国人将需要特定的手术麻醉计划，因为 脂质过氧化途径的遗传差异，包括导致反应效率低下的遗传因素 醛代谢。为携带该基因需要手术的人提供精准医疗服务 变体最终将降低大部分亚洲人的医疗保健成本并提高医疗质量 美国人。正如我们在这里所描述的，研究遗传差异还可以深入了解生物学 机制并解锁可以影响各族裔人民医疗保健的新战略。