Goal: Unravel mechanisms by which endometriosis decreases fertility and causes pregnancy loss to develop alternative therapeutic approaches to resolve multigenerational, heritable reproductive anomalies and thereby improving the health of women, their daughters and their granddaughters. Project 1 Efforts: Mechanisms of Reduced Fecundity in Endometriosis: a role for matrix metalloproteinase enzymes (MMPs) and their inhibitors (TIMPs). This project is funded by the NIH, an MU PRIME Award and RIF. Drs. Susan Nagel, Peter Sutovsky (Animal Science), John Critser (Veterinary Pathobiology) and J. Wade Davis (Biostatistics) are co-investigators.
Project 1 Accomplishments: Using an animal model for endometriosis, we have discovered that: 1) TIMP-1, synthesized and secreted by endometriotic lesions, localizes in the thecal layer of the ovarian follicle wall diminishing follicular development and impeding ovulation thereby reducing fecundity. Structural and functional anomalies in follicular development and ovulation have been characterized. And in vivo, administrationofTIMP-1 blocking antibodies restores follicular development and ovulation, foretelling of a potential novel therapeutic approach. These experiments have also led to novel discoveries regarding how TIMP-1 blocks ovulation by not only MMP-dependent pathways but also by MMP-independent mechanisms. 2) Structural and functional anomalies in metaphase II oocytes, zygotes, 8-cell embryos and blastocysts, including alterations in morphology and quality biomarker localization, also contribute to the reduced fecundity. The data from these experiments will facilitate mechanistic studies as to how endometriosis reduces fecundity, provide an avenue to test safety and efficacy of new therapeutic approaches, and assist rapid of translation of data into knowledge of human endometriosis. Two publications have resulted:
Stilley JAW, Woods-Marshall R, Sutovsky M, Sutovsky P, Sharpe-Timms KL. Reduced fecundity in female rats with surgically-induced endometriosis and in their daughters: A potential role for Tissue Inhibitors of Metalloproteinase1. Biol Reprod 2009; 80:649-656. Epub 2008 Nov 19. PMID: 19020297
Stilley JAW, Birt JA, Nagel SC, Sutovsky M, Sutovsky P, Sharpe-Timms KL. Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development. Biol Reprod 2010; Epub 2010, April 21. PMID: 20410455 Project 1 Honors: Dr. Lou DePaolo, Head of the National Institute of Child Health and Human Development Reproductive Sciences Branch, presents our research as part of his Annual Report to the NIH Institute Director and Deputy Director as exemplary of the high caliber, high impact work from scientists in the NICHD. Project 2: Endometriosis triggers short term epigenetic changes and long term, multigenerational epigenetic reprogramming leading to subfertility and pregnancy loss. In 2009 this project was funded by the MU Research Board to collect preliminary data. Drs. Susan Nagel, Kristen Taylor (Pathology and Anatomical Sciences) and J. Wade Davis (Biostatistics) are co-investigators on this project.
Project 2 Accomplishments: Using an animal model for endometriosis, we have discovered: 1) An anomalous in vivo morphological phenotype of oocytes and 8 cell preimplantation embryos in both rats with surgically-induced endometriosis (Endo, F0) compared to surgical sham (Sham, F0) as well as their daughters (without any experimental intervention, eF1, sF1) using biomarkers of oocyte and embryo quality including ubiquitin, nucleoporin and others. 2) Differences expression of in ~12 genes in the apoptosis pathway were detected in 8 cell embryos from Endo F0 rats and their F1 daughters using genome-scale microarrays and further validated by real time quantitative PCR. Ongoing studies are determining whether apoptosis is induced in Endo rat embryos by caspase-dependent or independent pathways. 3) Post-natal development and subsequent reproductive competence of F1 rats born from F0 rats was examined to determine if endometriosis in the founder generation caused effects in the daughters. 4) To determine how developmental exposure to endometriosis alters DNA methylation of programmed genes, state-of-the-art methods were used to quantify the degree of altered methylation in CpG islands of genes which are differentially expressed in F0 and F1 Endo and Sham rats and which meet strict inclusion criteria.
Project 3: Anti-inflammatory and fertility-preserving curcumin analogs in endometriosis. I serve as one of the Multiple PIs on this collaborative project with Drs. Robert Taylor and Friedrich Alfred Wieser at Emory University in Georgia. An application for NIH funding was submitted July 2010. One presentation was accepted for presentation and the Annual Meeting of The Society for the Study of Reproduction in 2009.
Wieser W, Yu J, Sharpe-Timms KL, Sidell N, Taylor RN. Effects of a curcumin analog, EF24, on reproductive function in rats. Soc Study Reprod August 2009 Pittsburg, PA