Role of ALDH1A in endometrial homeostasis and endometriosis inflammation

Project Summary Endometriosis is a debilitating disease characterized by abnormal growth of endometrial tissue outside of the uterus and afflicts 11% of women of reproductive age. Endometriosis has heterogenous symptoms including chronic pain, heavy periods, and an overall decrease in quality of life. Several proposed theories for endometriosis pathogenesis implicate endometrial stem cells. However, endometrial stem cells and their role in endometriosis and normal endometrial homeostasis are not well understood. Previous work from our lab has identified high enzymatic activity of aldehyde dehydrogenase 1A (ALDH1A) as a putative endometrial stem cell marker. ALDH1A isozymes ALDH1A1, ALDH1A2, and ALDH1A3 are responsible for the conversion of retinaldehyde into retinoic acid (RA) which, in a normal physiological context, controls endometrial cell differentiation and homeostasis within the endometrium. Interestingly, in patients with endometriosis, ectopic endometriotic lesions overexpress ALDH1A compared to eutopic endometrial tissue. Our lab has found that ectopic endometriotic lesion organoids (ELOs) with high activity of ALDH1A (ALDHHI) display increased transcriptomic signatures of inflammation, cytokine release, and calcium signaling compared to eutopic ALDHHI endometrial organoids (EOs) from the endometrium. Additionally, previous literature in other models and diseases shows that the inhibition of ALDH1A results in anti-inflammatory effects. To further investigate these preliminary findings, I will use conditional knockout of ALDH1A in the mouse uterus to investigate in vivo how ALDH1A contributes to endometrial homeostasis, including endometrial cell differentiation and endometrial regeneration. Additionally, I will use 3D patient-derived organoids from eutopic endometrial tissue and ectopic endometriotic lesions as an in vitro model system to prioritize the translational aspect of my findings. Our lab is uniquely poised to use ELOs as an exciting and invaluable disease model system for analysis and therapeutic target screening. I will use these ELOs to study the effects of pharmacologically inhibiting ALDH1A on cytokine release, calcium signaling, and macrophage recruitment and activation. This proposal will be the first of its kind to investigate the ALDH1A in endometrial homeostasis in vivo, as well as investigate the therapeutic potential of pharmacological inhibition of ALDH1A on the inflammatory response of endometriotic lesions in vitro. Ultimately, this study will define the role of ALDH1A in endometrial differentiation and regeneration, as well as identify a pathogenic role of ALDH1A in inflammation in endometriotic lesions. This F31 fellowship will not only provide financial support to conduct my research, but also allow me to further develop technical, communication, and professional skills. My trainee development will set me up for long-term career success to discover and create novel therapeutics for endometriosis.