Precision medicine for Asian Americans requiring anesthesia

项目总结： 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的代谢物，会导致细胞功能障碍和最终器官。 损坏。对于东亚后裔的亚裔美国人来说，是一种基因变异(存在于近540 世界上有数百万人)严重限制了反应醛的代谢。除了低效的反应醛 新陈代谢，亚洲人在脂质过氧化途径中还会出现其他几个遗传差异；途径 它对器官损伤期间发生的损害进行监管。因为手术后的死亡率是第三大 在美国，器官损伤是导致死亡的主要原因，了解这些 亚洲人的遗传差异可能改变脂质过氧化诱导的器官损伤可能开启新的治疗方法 所有种族减少手术中器官损伤的策略。 在这个MIRA计划中，我们将研究存在于脂质过氧化途径中的遗传差异 亚洲人，包括导致反应醛代谢效率低下的基因变异及其对 器官损伤。为了进行这些研究，我们在基础科学中开发了研究反应性醛的工具 实验室包括一个基因敲入小鼠模型，以反映导致低效的人类遗传变异 反应性醛代谢和检测反应性醛的灵敏分析。我们将使用这些工具来 检查手术中给予的止痛剂是否会加剧低效啮齿动物的细胞损伤 醛代谢。此外，我们还将研究反应性醛如何影响瞬时受体。 潜在的引发器官损伤的渠道。我们还通过开发非侵入性工具扩展了这些乙醛工具 评估人体反应醛水平的方法和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 低效率的反应醛代谢，并在手术中实时监测他们的醛水平。 亚裔美国人是美国增长最快的人口之一，预计将达到 到2050年接近3400万。由于以下原因，亚裔美国人将需要特定的手术麻醉计划 脂质过氧化途径的遗传差异，包括导致低效反应的遗传 醛代谢。为需要这种基因手术的人提供精确的医疗护理 VARIANT最终将降低医疗成本，并提高大部分亚洲人的医疗质量 美国人。正如我们在这里描述的，研究遗传差异也可以提供对生物学的洞察 新的机制和新的战略可以影响所有种族的医疗保健。

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.