Delineating the role of ALDH2 in endometriosis

PROJECT SUMMARY Endometriosis is defined as ectopic endometrial-like tissue (lesions) and affects ~200 million women worldwide. Despite this, little progress has been made over the past 20 years in screening, detection, prognosis, and treatment. The primary symptom of endometriosis is debilitating pain, which profoundly affects quality of life. On average, women experience symptoms for approximately 10 years before being properly diagnosed. Standard treatments, including drugs or surgery, often fail to provide long-term pain relief. Thus, there is an urgent, unmet need to develop improved diagnostic and targeted therapeutic strategies for women suffering from endometriosis. Our central hypothesis is that impaired reactive aldehyde detoxification by ALDH2 underlies endometriosis-associated pain, and that the increased prevalence of the ALDH2*2 mutation among Asian women at least in part explains their increased prevalence of severe symptoms. Supportive of our premise, preliminary data in women with peritoneal endometriosis and pelvic pain show that endometrial ALDH2 activity is decreased, and this is associated with decreased ALDH2 expression and increased 4-HNE adduct formation, indicative of impaired reactive aldehyde detoxification. Further, in these women, endometrial 4-HNE adduct formation correlates with the presence of pelvic pain. Our preliminary data in ALDH2*2 knock-in mice with reduced ALDH2 activity reveal that abdominal pain-associated behaviors are exacerbated in a mouse model of peritoneal endometriosis and increasing ALDH2 activity with an enzyme activator alleviates abdominal pain-associated behaviors. Further, abdominal pain-associated behavior correlates with endometrial 4-HNE adduct formation. Guided by our strong preliminary data, we will further test our hypothesis by: 1) Determining the role of reactive aldehyde detoxification by ALDH2 in endometriosis- associated pain in a mouse model of deep endometriosis; and 2) Determining the role of reactive aldehyde detoxification by ALDH2 in endometriosis-associated pelvic pain in Asian women with wildtype and mutant ALDH2 and peritoneal endometriosis. The contribution of this proposed research is significant because it will address an unmet need for women with endometriosis pain by developing effective treatment and a biomarker to reduce diagnostic delay.