Role of Autophagy in the Pathogenesis of Endometriosis

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DESCRIPTION (provided by applicant): Endometriosis is a benign but very painful gynecological disease which affects reproductive age women leading to infertility. The causes of endometriosis are unclear; thus, and a better understanding of the underlying molecular changes that occur in the endometrium is needed to improve current therapeutic strategies and the reproductive capacity for these patients. The role of autophagy has yet to be investigated in the development of endometriosis. This is an important research direction since activation of this pathway can lead to increased survival (critical initiating event in lesion formation) which hinders anoikis (cell death induced by detachment from a substratum). We propose that activation of autophagy, antagonizing anoikis, leads to endometrial cell survival, implantation at ectopic sites, and generation of endometriotic lesions. The proposed research will contribute to an important missing link (role of autophagy) in our understanding of the genesis of endometriosis. We will address these goals through the following specific aims: (1) we will test the hypothesis that expression of markers of autophagy differs between endometriotic lesions (ectopic endometrium) to eutopic endometrium from women with and without endometriosis; and (2) we will test the hypothesis that autophagic flux modulates formation and/or development of endometriotic lesions using in vivo mouse endometriosis models. Although autophagy has been well studied in a variety of diseases, its role in the development of endometriosis remains an important unanswered question. Our application proposes to use innovative technologies (i.e. RT2-PCR focused signaling pathway autophagy arrays and GFP-LC3 transgenic donor mice in an in vivo endometriosis mouse model) to address our hypothesis. If proven correct, the results generated in this proposal will be critical in (1) improving our understanding of the development of endometriosis, (2) identifying potential new therapeutic targets to reduce the burden of endometriosis and improve the reproductive capacity of women of child-bearing age, and (3) identifying whether treatment with inhibitors of autophagy may be potentially beneficial in endometriosis patients diminishing development of endometriotic lesions.