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首页> 外文学位 >Analysis of Kruppel-like factors 9 and 13 in endometrial function and the pathogenesis of endometriosis.
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Analysis of Kruppel-like factors 9 and 13 in endometrial function and the pathogenesis of endometriosis.

机译：分析子宫内膜功能中Kruppel样因子9和13以及子宫内膜异位症的发病机理。

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摘要

Estrogen and progesterone actions in uterine development and homeostasis are mediated by their cognate receptors Estrogen Receptor alpha and beta 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 Kruppel-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.
机译：雌激素和孕酮在子宫发育和体内平衡中的作用是由它们的同源受体雌激素受体α和β同工型（ESR1，ESR2）以及孕激素受体A和B同工型（PGR-A，PGR-B）介导的，与许多与背景有关的核受体协同调节剂。 ESR和PGR信号传导失调是诸如不育，子宫内膜异位，子宫内膜癌和平滑肌瘤等病理状况发展的根本原因。鉴于共调节蛋白在定义ESR和PGR行动的背景相关结果中的重要作用，因此有必要进一步剖析和了解其与潜在生长，分化和存活的关键信号通路的机械相关性。本研究调查了Kruppel样因子9（KLF9）和13（KLF13）的表达丧失的后果，Kruppel样因子9（KLF9）和13（KLF13）以前被证明可作为PGR辅助激活剂，在建立子宫接受性和发病机理上具有重要意义。子宫内膜异位。我们提出了四个假设：1）子宫内膜KLF13的缺失将导致小鼠的亚生育表型，类似于Klf9 null突变体的表型。 2）子宫内膜KLF9表达的缺失将促进子宫内膜异位症的发展； 3）子宫内膜KLF13表达的丧失将概括KLF9对子宫内膜异位症发展的调控，并类似地增强子宫内膜异位症的建立； 4）高脂肪饮食消耗导致体重增加是子宫内膜异位症建立和发展的危险因素。我们发现，在Klf13基因突变的雌性小鼠中缺乏生育力表型是由于KLF9的代偿功能所致，KLF9在子宫内膜细胞中维持着孕激素对子宫内植入子宫的敏感性。使用具有免疫功能的子宫内膜异位症小鼠模型，我们发现虽然Klf13的丢失对异位病变的发展影响很小，但Klf9的缺失导致通过PGR，ESR和Notch / Hh信号通路的改变而增加了病变的形成。最后，我们确定，从青春期开始就开始摄入高脂饮食会增加免疫功能小鼠模型中的子宫内膜异位病变数目，这与血管生成，氧化应激和炎性途径的活化以及DNA损伤的诱导和总体DNA甲基化的改变有关状态。在一起，我们的研究强调了KLF家族成员KLF9和KLF13在对正确的子宫内膜功能重要的分子事件中的重要性，并为开发新疗法和预防子宫内膜病变的策略提供了“机会之窗”。

著录项

  • 作者

    Heard, Melissa Emma.;

  • 作者单位

    University of Arkansas for Medical Sciences.;

  • 授予单位 University of Arkansas for Medical Sciences.;
  • 学科 Physiology.;Pathology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 189 p.
  • 总页数 189
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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