Precision medicine for Asian Americans requiring anesthesia

项目概要： 美国每年有近4000万人接受手术麻醉。反应性 醛类，在手术过程中产生的，是有毒的代谢产物，其驱动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，一种遗传变异（存在于近540 世界上有100万人）严重限制了反应性醛代谢。除了低效的反应性醛 亚洲人在脂质过氧化途径中存在其他几种遗传差异; 调节器官损伤时的损伤因为手术后的死亡率是 死亡原因在美国，与器官损伤的主要原因，这种死亡率，了解如何这些 亚洲人的遗传差异可能会改变脂质过氧化诱导的器官损伤，这可能会揭示新的治疗方法 所有种族的战略，以减少手术期间发生的器官损伤。 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和对 器官损伤为了进行这些研究，我们生成了在基础科学中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。我们将使用这些工具， 检查手术期间给予的止痛剂是否会加重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 可能导致器官损伤。我们还通过开发非侵入性的 评估人体中反应性醛水平的方法和鉴定低效醛的表型的方法 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 并在手术过程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年将达到3400万人亚裔美国人将需要特定的麻醉计划， 脂质过氧化途径中的遗传差异，包括导致低效反应性的遗传差异， 醛代谢为需要手术的人提供精准的医疗护理， 变异将最终降低医疗保健成本，并提高护理质量的一个大的子集，亚洲 美国人正如我们在这里所描述的，研究遗传差异也可以提供对生物学的深入了解。 机制和解锁新的策略，可以影响所有种族的人的医疗保健。

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.