Principal Investigator(s):
Hugh Taylor, MD
Co-Investigator(s):
Valerie Flores, MD / Ramanaiah Mamillapalli, PhD
Institution:
Yale School of Medicine
Abstract:
Endometriosis is a debilitating gynecologic disease affecting 1 in 10 reproductive-aged women. It is characterized by pelvic pain, reduced quality of life, and high economic burden—the yearly cost exceeds $22 billion annually. Endometriosis is a systemic disorder, with inflammation playing a significant role in disease pathophysiology. Estrogens stimulate endometriosis growth, while progesterone normally inhibits of estrogendependent proliferation. The ability of endometriosis to respond to normal circulating levels of progesterone is compromised. Preliminary data show that progesterone receptor levels are altered in women with endometriosis. While the mechanism of decreased PR expression in endometriotic lesions is not known, epigenetic changes mediated by the inflammatory environment of endometriosis is a plausible explanation. In endometriosis, nuclear factor kappa-light-chain-enhancer of activated B cells (NF B) is chronically activated, resulting in a chronic inflammatory state. Inflammation is commonly encountered in cancer, where it is induces methylation of tumor suppressor genes. In endometriosis, chronically activated NF B and the resultant proinflammatory state may similarly result in altered methylation. Specifically, it may cause aberrant methylation of the progesterone receptor gene blocking transcription. We have also found altered abundance of microRNAs 125b and let7b in endometriosis. The altered miRNA levels in endometriosis directly regulates inflammatory cytokine production, exacerbating the inflammatory response through lack of suppression of NF B activity. Thus, miRNAs can mediate progesterone resistance by allowing NF B to remain constitutively active. In women with endometriosis, we hypothesize that progesterone resistance is due to microRNA mediated inflammation; in turn, inflammation drives loss of progesterone responsiveness by altering Pgr methylation, leading to decreased expression and therefore function of PR. Our first grant proposal aims to determine the correlation between NF B, Pgr methylation, and PR levels in lesions of women with endometriosis. Our second grant proposal aims to identify the correlation between NF B expression, miRNA 125b and let7b expression, Pgr methylation, and PR levels in human endometriotic lesions. Lastly, utilizing a murine model of endometriosis in CD1 mice, we will determine the effect of NF B inhibitors and miRNA modulators on the methylation status of Pgr, and expression of PR. Through this work, we will gain further insight into the molecular mechanisms leading to progesterone resistance— identifying the role of inflammation in endometriosis. Such insight will allow us to develop novel, non-hormonal therapeutic targets for treating endometriosis (inflammatory modulating agents, miRNA modulators, or NF B inhibitors) that can block inflammation and potentially restore progesterone response. In doing so, endometriosis may be effectively treated without hormonal manipulation, restoring quality of life in women suffering from this disease while also maintaining fertility.
