Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis

Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis
ABSTRACT
The overarching goal of this Center is to develop advanced tools and insights for improved understanding
of the pathophysiology of endometriosis, a disease in which endometrial tissue grows outside the uterus and
can cause severe dysmenorrhea, pain, infertility and other sequelae. We pursue this goal to enhance the
diagnosis, assessment, and treatment of women suffering from this common and devastating disease. A clear
pathophysiologic understanding of endometriosis has been difficult to achieve due, in part, to the reliance on
surgery for diagnosis and lesion assessment. Reliance on surgery delays diagnosis and prevents frequent or
repeated evaluation. In recent years, however, collaborations between scientists in our team have advanced a
unifying pathophysiological principle--that of progesterone resistance. Most other pathophysiological features of
endometriosis, including persistent epithelial estrogen receptor action, persistent estrogen receptor and
progesterone receptor expression, cellular proliferation, inflammation, pain, and infertility, can be ascribed to
progesterone resistance. Recently, important findings by this consortium show that Sirtuin 1 (SIRT1), an
epigenetic modulator, can cause progesterone resistance, resulting in exacerbation of downstream effects.
SIRT1 is a histone deacetylase that also directly regulates the function of proteins directing inflammatory and
metabolic signaling. We find consistent overexpression of endometrial SIRT1 across all species that we have
tested, including humans, non-human primates, and mice, highlighting a likely central role for SIRT1 in
endometriosis pathophysiology. Furthermore, preliminary studies indicate that SIRT1 overexpression plays a
direct role in lesion survival as well as infertility and has a potential role as a therapeutic target. We present three
key projects based on our burgeoning pathophysiological data to deepen our knowledge, catalyze the
development of novel, non-invasive diagnostic and assessment methods and promote non-hormonal therapeutic
options for affected women. The impact of these three projects on women will be enhanced by patient and
provider educational initiatives from the Endometriosis Outreach and Education (EOE) Core and deep integration
of synergistic data from human, non-human primate, mouse, and in vitro systems, enhanced by the Comparative
Genomics and Bioinformatics (CGB) Core. Collectively, the projects and cores contribute to three synergistic
aims: 1) Enhance early diagnosis and assessment of endometriosis lesions by developing non-invasive
imaging techniques and promoting public awareness; 2) Determine inflammatory and metabolic changes
that underlie the disease process; and 3) Develop new molecular targets for non-hormonal, non-surgical
treatments for endometriosis; The successful completion of these aims will lead to a long-lasting improvement
in the lives of women suffering from endometriosis.