Endometriosis is one of the most common benign gynecologic conditions affecting women of reproductive age. Formation of endometriotic implants requires ectopic attachment and proliferation of endometrial stroma and glands. Prominent features of endometriosis include inflammatory reaction and increased oxidative stress. We propose a novel hypothesis that inhibition of the mevalonate pathway by statins will inhibit growth of endometrial stroma and endometriotic implants as well as decrease oxidative stress. Specifically, we postulate that statins affect endometrial stromal cells by: (i) inhibiting isoprenylation of proteins, especially small GTPases such as Ras and Rho leading to modulation of signal transduction pathways regulating growth, and (ii) decreasing generation of reactive oxigen species, which also affect growth. This underlying hypothesis is based on evidence that in several tissues, such as vascular smooth muscle, products of the mevalonate pathway facilitate isoprenylation of small GPTases and thus activate signal transduction pathways promoting growth. In vascular smooth muscle and in several other tissues, inhibition of the mevalonate pathway by statins inhibits growth and exerts antioxidant effects. Our preliminary studies have shown that moderate oxidative stress stimulates endometrial stromal proliferation. Furthermore, our preliminary data indicate that statins inhibit endometrial stromal proliferation, while blocking ERK1/2 phosphorylation.
The specific aims of this proposal are to study in depth the effects of statins on growth and oxidative stress: (i) in endometrial stromal cells and (ii) in endometriotic implants in a nude mouse model. These studies will provide new insight into the mechanisms regulating growth and function of endometrial tissues. Ultimately, the proposed research may lead to the development of new treatements of endometriosis, such as clinical use of statins.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Yale University
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Liu, Ying; Tal, Reshef; Pluchino, Nicola et al. (2018) Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 22:67-76
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Sahin, Cagdas; Mamillapalli, Ramanaiah; Taylor, Hugh S (2018) Bone Marrow-Derived Cells Trafficking to the Oviduct: Effect of Ischemia-Reperfusion Injury. Reprod Sci 25:1037-1044
Moridi, Irene; Mamillapalli, Ramanaiah; Cosar, Emine et al. (2017) Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis. Reprod Sci 24:526-533
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Flannery, Clare A; Saleh, Farrah L; Choe, Gina H et al. (2016) Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab 101:2883-91
Flannery, Clare A; Fleming, Andrew G; Choe, Gina H et al. (2016) Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium. Endocrinology 157:3699-3708
Kulp, Jennifer L; Mamillapalli, Ramanaiah; Taylor, Hugh S (2016) Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes. Reprod Sci 23:455-63

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