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.

PROJECT NARRATIVE Approximately 40% of Asian Americans that are descendants from East Asia possess a genetic variant severely limiting their ability to metabolize reactive aldehydes. This project will develop strategies specifically for those with this genetic variant to reduce organ damage caused by reactive aldehydes during surgery.