Precision medicine for Asian Americans requiring anesthesia

项目总结 在美国，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的代谢物，会导致细胞功能障碍和终末器官。 损坏。对于东亚后裔的亚裔美国人来说，一种基因变异(存在于8%的 世界人口)严重限制了反应醛的代谢。我的计划的目标是开发出具体的 无法有效代谢反应性的亚裔美国人的治疗策略(精确麻醉) 以减少手术中的反应性醛毒性。 对于米拉的这一建议，我首先将重点放在确定在基础科学实验室中减少 通过使用心脏缺血模型，反应性醛造成的损伤，特别是这种基因变体， 再灌注损伤。这是我的专业领域，因为我是一名麻醉师，有十多年的基本经验 科学训练研究麻醉剂、镇痛剂和远程条件反射诱导的保护机制 来自心脏缺血-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，包括一个敲入小鼠模型，以反映人类的遗传变异和敏感的分析 检测反应性醛。根据我的初步数据，我们有3种可能的策略可以测试，以减少 该基因变异可导致反应醛引起的器官损伤。我们还将确定如何反应 醛的产生和代谢有助于心脏保护的麻醉机制和交叉反应。 在麻醉剂和远程条件反射之间可能发生的谈话。总的来说，我的计划将提供目标， 治疗和研究活性醛的模型；发现减少醛和细胞的策略 手术中受伤。 亚裔美国人在手术中需要特定的麻醉计划，特别是由于这种基因变异。 降低了它们代谢活性醛的能力。除了反应性醛代谢，这个变种 在药物代谢(尤其是硝酸甘油)和止痛方面也有重要作用。提供 对需要进行这种基因变异手术的人进行精确的医疗护理最终会降低健康 为这一大群亚裔美国人支付护理成本并提高护理质量。

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.