Role of Autophagy in the Pathogenesis of Endometriosis

自噬在子宫内膜异位症发病机制中的作用

• 批准号: 8737035
• 负责人: MEERA NANJUNDAN
• 金额: $ 18.67万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737035
• 关键词: Address; Affect; Age; Anoikis; Area; Autophagocytosis; Autophagosome; Benign; Cell Death; Cell Line; Cell Survival; Cells; Development; Disease; Eating; Endometrial; Endometrium; Epithelial Cells; Event; Extracellular Matrix; Female of child bearing age; Fertility; Generations; Genetic Transcription; Goals; Growth; Histologic; Hydroxychloroquine; Immunohistochemistry; Implant; Infertility; Integrin-mediated Cell Adhesion Pathway; Lead; Lesion; Link; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Mission; Modeling; Molecular; Mus; National Institute of Child Health and Human Development; Organelles; PARK7 gene; Pain; Pathogenesis; Pathway interactions; Patients; Process; RNA; Recurrence; Regulation; Relative (related person); Reproductive Health; Research; Resistance; Risk; Role; Signal Pathway; Site; Staining method; Stains; Testing; Therapeutic; Tissue Microarray; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Woman; base; disorder later incidence prevention; endometriosis; human FRAP1 protein; implantation; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; innovative technologies; mouse model; new therapeutic target; novel; prevent; protein expression; public health relevance; reproductive; response; treatment strategy

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.

描述（由申请人提供）：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。子宫内膜异位症的原因尚不清楚;因此，需要更好地了解子宫内膜中发生的潜在分子变化，以改善这些患者的当前治疗策略和生殖能力。自噬在子宫内膜异位症发展中的作用还有待研究。这是一个重要的研究方向，因为该途径的激活可导致存活率增加（损伤形成中的关键起始事件），从而阻碍失巢凋亡（由从基质脱离诱导的细胞死亡）。我们认为，自噬的激活，拮抗失巢凋亡，导致子宫内膜细胞存活，异位部位种植，并产生子宫内膜异位病变。拟议的研究将有助于我们理解子宫内膜异位症的起源中一个重要的缺失环节（自噬的作用）。我们将通过以下具体目标来实现这些目标：（1）我们将检验自噬标志物的表达在患有和不患有子宫内膜异位症的妇女的异位病变（异位子宫内膜）与在位子宫内膜之间不同的假设;和（2）我们将检验自噬通量使用体内小鼠子宫内膜异位症模型调节异位病变的形成和/或发展的假设。虽然自噬在各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展中的作用仍然是一个重要的未回答的问题。我们的申请提出使用创新技术（即RT 2-PCR聚焦信号通路自噬阵列和体内子宫内膜异位症小鼠模型中的GFP-LC 3转基因供体小鼠）来解决我们的假设。如果被证明是正确的，本提案中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）确定用自噬抑制剂治疗是否可能对子宫内膜异位症患者有益，病变