瘦素、瘦素受体及其调控因子与子宫内膜异位症相关性的实验研究

发布时间：2018-06-10 21:08

本文选题：瘦素 + 瘦素受体　；参考：《中国人民解放军医学院》2014年硕士论文

【摘要】：子宫内膜异位症（endometriosis, EMT）是一种具有恶性肿瘤生物学行为的妇科良性疾病，定义为细胞水平以上有活性的子宫内膜组织（腺体和间质）在子宫腔被覆内膜及子宫肌层以外的部位出现、生长、浸润、反复出血，可形成结节及包块，引起疼痛、不育等。EMT的发病机制不清，研究表明瘦素及其受体的表达及调控在EMS发生发展过程中起重要作用，它参与了血管新生、细胞增殖与凋亡，免疫调节、炎症反应、新陈代谢。研究EMS病程中瘦素、瘦素受体及其上、下游因子的表达及变化规律，可为EMS发病机制的研究、临床治疗和新药的开发应用提供新的切入点。本研究共分为两部分：一、 SCID小鼠EMT异种移植模型的建立及因子的表达探讨leptin、OB-R及其上下游相关调控因子在SCID小鼠子宫内膜移植病灶及小鼠子宫组织中的表达特点。建立子宫内膜异位症SCID小鼠异种皮下移植模型，，通过免疫组织化学法观察各因子的表达。SCID小鼠异种皮下移植EMT模型成功率高，移植组织存活率高，观察方便，实验周期短，与人EMT的组织学与生化特征一致，可以从时间及空间上全面的反映EMT的病理生理特征。移植组织及小鼠子宫leptin、OB-R、STAT3及p-STAT3的表达强度及定位特征明确，可作为后续实验的参照。二、影响leptin、OB-R及STAT3表达的相关药物对SCID小鼠子宫内膜异位病灶的作用应用子宫内膜异位症的SCID小鼠模型，给予干预leptin代谢的相关药物治疗，观察病灶及小鼠的变化情况，应用实时荧光定量聚合酶链式反应及免疫组织化学法，测定并定位相关因子的表达特征，分析并验证所用药物对子宫内膜异位症的治疗作用及全身影响。结论如下：1.环磷酸腺苷可以抑制leptin的表达，但无法抑制下游OB-R、STAT3的表达及STAT3的活化，因而在EMT治疗中所起的作用有限，具体机制有待进一步研究。2.左卡尼汀在急、慢性炎症过程中，对leptin代谢的影响机制不同，不能降低EMT慢性炎症过程中leptin、OB-R及STAT3的表达，不适用于对EMT的治疗。3.米非司酮可以显著降低leptin、OB-R及STAT3的表达，为治疗EMT的有效药物，但对体重有一定影响。4.孕激素对EMT病灶的抑制可能不通过leptin→OB-R→JAK2/STAT3途径实现。5.S3I-201可以有效抑制EMT病灶中leptin、OB-R、STAT3的表达及STAT3的异常磷酸化，有望成为新的、有效的EMT治疗药物。综上所述，本研究表明： 1、leptin是EMT发生发展过程中的敏感指标，可用于疾病诊断、疗效判断、复发检测等，有望成为EMT参考监测指标。 2、对leptin和OB-R及其上、下游调控因子和相关信号通路的研究，有助于EMT发病机制的深入研究和药物治疗新靶点的开发。
[Abstract]:Endometriosis (EMTs) is a benign gynecological disease with the biological behavior of malignant tumor. Defined as the presence of active endometrial tissue (glands and stroma) above the cellular level in the area outside the endometrium and the myometrium of the uterine cavity, growing, infiltrating, bleeding repeatedly, forming nodules and masses, causing pain, The expression and regulation of leptin and its receptors play an important role in the development of EMS, which is involved in angiogenesis, cell proliferation and apoptosis, immune regulation, inflammatory response, metabolism. To study the expression and variation of leptin, leptin receptor and its upstream and downstream factors in the course of EMS may provide a new entry point for the study of the pathogenesis of EMS, the clinical treatment and the development and application of new drugs. This study was divided into two parts: first, the establishment of EMT xenotransplantation model and the expression of factors in SCID mice; the expression of leptinine OB-R and its upstream and downstream regulatory factors in SCID mouse endometrium transplantation focus and mouse uterus tissue. The xenotransplantation model of SCID mice with endometriosis was established. The expression of various factors in SCID mice was observed by immunohistochemical method. The success rate of xenotransplantation EMT model in SCID mice was high, the survival rate of transplanted tissue was high, the observation was convenient and the experimental period was short. The histopathological and biochemical characteristics of EMT are consistent with those of human EMT, which can reflect the pathophysiological characteristics of EMT in time and space. The expression intensity and localization of leptinine OB-RNT-STAT3 and p-STAT3 in transplanted tissues and mice uterus are clear and can be used as reference for further experiments. Effects of drugs related to the expression of leptinine OB-R and STAT3 on endometrial ectopic lesions in SCID mice models of endometriosis were used to observe the changes of lesions and mice. Real-time fluorescent quantitative polymerase chain reaction and immunohistochemical method were used to detect and locate the expression characteristics of related factors and to analyze and verify the therapeutic effect and systemic effect of the drugs on endometriosis. The conclusion is as follows: 1. Adenosine cyclophosphate can inhibit the expression of leptin, but it can not inhibit the expression and activation of STAT3 downstream. Therefore, the role of adenosine cyclophosphate in the treatment of leptin is limited, and the specific mechanism needs to be further studied. Levocarnitine does not decrease the expression of leptinine OB-R and STAT3 in the process of acute and chronic inflammation, and it is not suitable for the treatment of leptin. Mifepristone can significantly reduce the expression of leptinine OB-R and STAT3, which is an effective drug for the treatment of EMT, but has a certain effect on body weight. The inhibition of progesterone on EMT lesions may not be realized through the leptin OB-R jar 2 / STAT3 pathway. 5. S3I-201 can effectively inhibit the expression of leptinin OB-RtSTAT3 and abnormal phosphorylation of STAT3 in EMT lesions, which may be a new and effective therapeutic drug for EMT. The results show that: 1 leptin is a sensitive index in the course of occurrence and development of EMT, which can be used in disease diagnosis, curative effect judgment, recurrence detection and so on. 2. The study of leptin, OB-R and its upstream and downstream regulatory factors and related signal pathways. It is helpful for the further study of the pathogenesis of EMT and the development of new targets for drug therapy.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R711.71

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