Role of Autophagy in the Pathogenesis of Endometriosis

描述(申请人提供)：子宫内膜异位症是一种良性但非常痛苦的妇科疾病，影响育龄妇女，导致不孕。子宫内膜异位症的病因尚不清楚，因此，需要更好地了解子宫内膜发生的潜在分子变化，以改进目前的治疗策略，并提高这些患者的生殖能力。自噬在子宫内膜异位症发生发展中的作用还有待研究。这是一个重要的研究方向，因为该通路的激活可以导致存活率增加(病变形成的关键起始事件)，从而阻碍失巢凋亡(从底物脱离导致的细胞死亡)。我们认为，激活自噬，对抗失巢凋亡，导致子宫内膜细胞存活，异位着床，以及子宫内膜异位病变的产生。这项拟议的研究将有助于我们理解子宫内膜异位症的发病机制中缺失的一个重要环节(自噬的作用)。我们将通过以下具体目标来解决这些目标：(1)我们将检验自噬标记物的表达在患有和不患有子宫内膜异位症的子宫内膜异位病变(异位内膜)之间存在差异的假设；以及(2)我们将使用在体小鼠子宫内膜异位症模型来检验自噬通量调节子宫内膜异位病变的形成和/或发展的假说。虽然自噬在多种疾病中已经得到了很好的研究，但它在子宫内膜异位症发生发展中的作用仍然是一个重要的未解答的问题。我们的应用建议使用创新技术(即RT2-PCR聚焦的信号通路自噬阵列和GFP-LC3转基因供体小鼠在体内子宫内膜异位症小鼠模型中)来解决我们的假设。如果被证明是正确的，这项建议产生的结果将在以下方面至关重要：(1)提高我们对子宫内膜异位症发展的理解，(2)确定潜在的新的治疗靶点，以减轻子宫内膜异位症的负担，提高育龄妇女的生殖能力，以及(3)确定自噬抑制剂治疗子宫内膜异位症患者是否可能潜在地有益于减少子宫内膜异位症病变的发展。

DESCRIPTION (provided by applicant): Endometriosis is a benign but very painful gynecological disease which affects reproductive age women leading to infertility. The causes of endometriosis are unclear; thus, and a better understanding of the underlying molecular changes that occur in the endometrium is needed to improve current therapeutic strategies and the reproductive capacity for these patients. The role of autophagy has yet to be investigated in the development of endometriosis. This is an important research direction since activation of this pathway can lead to increased survival (critical initiating event in lesion formation) which hinders anoikis (cell death induced by detachment from a substratum). We propose that activation of autophagy, antagonizing anoikis, leads to endometrial cell survival, implantation at ectopic sites, and generation of endometriotic lesions. The proposed research will contribute to an important missing link (role of autophagy) in our understanding of the genesis of endometriosis. We will address these goals through the following specific aims: (1) we will test the hypothesis that expression of markers of autophagy differs between endometriotic lesions (ectopic endometrium) to eutopic endometrium from women with and without endometriosis; and (2) we will test the hypothesis that autophagic flux modulates formation and/or development of endometriotic lesions using in vivo mouse endometriosis models. Although autophagy has been well studied in a variety of diseases, its role in the development of endometriosis remains an important unanswered question. Our application proposes to use innovative technologies (i.e. RT2-PCR focused signaling pathway autophagy arrays and GFP-LC3 transgenic donor mice in an in vivo endometriosis mouse model) to address our hypothesis. If proven correct, the results generated in this proposal will be critical in (1) improving our understanding of the development of endometriosis, (2) identifying potential new therapeutic targets to reduce the burden of endometriosis and improve the reproductive capacity of women of child-bearing age, and (3) identifying whether treatment with inhibitors of autophagy may be potentially beneficial in endometriosis patients diminishing development of endometriotic lesions.