Precision medicine for Asian Americans requiring anesthesia

项目摘要 在美国，每年有超过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伤。 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8%的美国人中）， 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出 治疗策略（精确麻醉）对于亚裔美国人，不能有效地代谢反应 醛，以减少手术期间的反应性醛毒性。 对于这个MIRA的建议，我将首先集中在确定在基础科学实验室的方法，以减少 反应性醛的损伤，特别是这种遗传变异，通过使用心脏缺血模型- 再灌注损伤这是我的专业领域，因为我是一名麻醉师， 研究麻醉、镇痛和远程条件反射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，我们开发了一些工具来研究反应性 包括反映人类遗传变异的基因敲入小鼠模型和 检测活性醛。根据我的初步数据，我们有3种可能的策略来测试，以减少 这种基因变异导致的反应性肾上腺素诱导的器官损伤。我们还将确定 醛的产生和代谢有助于心脏保护的麻醉机制和交叉- 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， 治疗和模型研究反应性醛;发现减少醛和细胞的策略 手术过程中受伤。 亚裔美国人将需要特定的麻醉计划手术，特别是由于这种遗传变异 降低了它们代谢活性醛的能力。除了反应性醛代谢，这种变体 还在药物代谢（特别是硝酸甘油）和疼痛控制中具有重要作用。提供 对需要手术治疗这种基因变异的人进行精确的医疗护理， 护理成本和提高护理质量为这一大子集的亚裔美国人。

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.