Endometriosis, the presence of endometrial glands and stroma outside of the uterine cavity causes chronic pelvic pain and infertility. It affects 10% of women of reproductive age and 35-50% of women who are infertile. The average time for confirmed clinical diagnosis takes between 8-11 years and the molecular mechanisms associated with the pathophysiology of endometriosis still remains poorly understood. Our extensive studies over the past 20 years have characterized the causative factors and molecular changes that are involved in the early onset of disease in a baboon model of experimentally induced endometriosis. MicroRNAs (miR) which are small non-coding RNAs that regulate posttranscriptional gene regulation, have emerged as important regulators that may contribute to pathophysiology of endometriosis. Our preliminary data suggests that induction of endometriosis leads to rapid and significant changes in the expression of several miRs in the baboon. MiR-451 together with miR-144 which is expressed at the same gene locus were significantly down regulated, while miR-21 and miR-29c showed a progressive increase following induction of endometriosis in both ectopic and eutopic tissues. Similar changes have been reported in women with disease. Changes in miR expression which we hypothesize are transcriptionally induced as a consequence of the disease, are associated with the corresponding alterations of their respective target genes, YWHAZ, FKBP4, 15-PGDH and fibrosis. We propose that these changes contribute to the progression of endometriosis and altered endometrial function. To test these hypotheses, in Specific Aim 1 we propose to determine if c-Fos regulation of AP-1 sites on the miR gene promoter, epigenetic changes (methylation) and increased Dicer activity associated with endometriosis is responsible for the aberrant miR expression in the eutopic and ectopic endometrium.
In Specific Aim 2 we will validate the regulation of target genes YWHAZ/??catenin by miR-451 to promote proliferation and invasion by interacting with Yes-associated protein (YAP1).
Aim 3 focuses on the mechanisms by which miR-29c regulates FKBP4 which imparts progesterone resistance and results in a blunted decidualization response. The inhibition of decidualization will be assessed by the validating the expression of decorin and insulin-like growth factor binding protein-1.
Specific Aim 4 will focus on the role of miR-21 in contributing to the development of fibrosis in endometriotic lesions and its potential role in mediating COX-2 mediated inflammation. These innovative studies will contribute to our understanding of the molecular mechanisms underlying the etiology of endometriosis. The proposed aims will functionally link aberrant miR expression, induced in response to the disease, with their respective target genes that induce changes in the eutopic and ectopic endometrium that are pathologically relevant in the etiology of endometriosis.
Endometriosis remains an enigmatic disease whose basic biology still eludes us. The baboon model, in which the induced disease is reflective of the human condition, offers the best hope for understanding the early events associated with the pathophysiology of this disease and more importantly the basic causes that are associated with pain and infertility which are the hallmarks of this disease. Studies proposed in this application focus on how the microRNA's that are induced as a consequence of endometriosis contribute to the pathology of the disease.
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