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.