Estrogen and progesterone actions in uterine development and homeostasis are mediated by their cognate receptors Estrogen Receptor α and β isoforms (ESR1, ESR2) and Progesterone Receptor A and B isoforms (PGR-A, PGR-B) in concert with numerous context-dependent nuclear receptor co-regulators. Dysregulation of ESR and PGR signaling is an underlying cause of the development of pathological conditions such as infertility, endometriosis, endometrial cancer and leiomyoma. Given the important roles of co-regulatory proteins in defining the context-dependent outcomes of ESR and PGR actions, the further dissection and understanding of their mechanistic relevance to key signaling pathways underlying growth, differentiation and survival are warranted. The present studies investigated the consequences of the loss of expression of Krüppel-like factors 9 (KLF9) and 13 (KLF13), highly related proteins previously demonstrated to function as PGR co-activators, in the establishment of uterine receptivity and in the pathogenesis of endometriosis. We addressed four hypotheses: 1) Loss of endometrial KLF13 will result in a subfertility phenotype in mice, similar to that for Klf9 null mutants; 2) Loss of endometrial KLF9 expression will promote endometriosis development; 3) Loss of endometrial KLF13 expression will recapitulate KLF9's regulation of endometriosis development and similarly, enhance endometriosis establishment; and 4) High fat diet consumption leading to weight gain is a risk factor for endometriosis establishment and progression. We found that the lack of a fertility phenotype in Klf13 null mutant female mice is due to compensatory functions by KLF9, which maintained progesterone sensitivity in uterine endometrial cells for peri-implantation uterine receptivity. Using an immunocompetent mouse model of endometriosis, we found that while loss of Klf13 had minimal impact on ectopic lesion development, absence of Klf9 resulted in increased lesion establishment through alterations in PGR, ESR and Notch/Hh signaling pathways. Finally, we determined that high fat diet intake beginning at pre-puberty increased endometriotic lesion numbers in the immunocompetent mouse model which was associated with activation of angiogenic, oxidative-stress, and inflammatory pathways and with induction of DNA damage and alterations in global DNA methylation status. Together, our studies highlighted the importance of KLF family members KLF9 and KLF13 in the molecular events important for proper endometrial function and provide 'windows of opportunity' for the development of novel therapies and preventive strategies against endometrial pathologies.
|Advisor:||Simmen, Rosalia C.M.|
|Commitee:||Gaddy, Danna, MacLeod, Stewart, Simmen, Frank, Wight, Patricia|
|School:||University of Arkansas for Medical Sciences|
|Department:||Physiology and Biophysics|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 75/09(E), Dissertation Abstracts International|
|Keywords:||Endometriosis, Endometrium, Progesterone receptor, Uterus|
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