TIMP-4基因多态性与子宫内膜异位症发病关系的研究
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摘要
子宫内膜异位症（EM）是一种良性的妇科疾病，累及10%的生育期妇女，25%-35%不孕患者与此病相关。目前其病因仍不清楚,大量研究发现EM是一种多因素疾病,系统研究发现EM在位内膜在粘附、侵袭和血管形成等诸多方面有别于正常的子宫内膜，遗传因素在其发病中有重要作用，而高水平雌激素的存在是疾病存在、发展的必要因素。基质金属蛋白酶抑制剂（Tissue inhibitor ofmatrix metalloproteinases，TIMPs）是体内细胞分泌的一类蛋白酶抑制剂，它们可以与基质金属蛋白酶原（matrix metalloproteinases，MMPs）或活性酶以1:1比例结合形成复合物，从而抑制MMPs酶原激活及活性。TIMPs与MMPs协同调节局部的蛋白水解，与组织重建、胚胎植入、肿瘤的侵袭和转移密切相关。TIMP-4是基质金属蛋白酶抑制剂家族中的一员，有研究表明TIMP-4基因-930位点到-916位点这段序列与雌激素反应元件的公认序列具有很高的同源性。
【目的】检测TIMP-4在子宫内膜异位症患者子宫在位及异位内膜中的表达情况，并进一步对TIMP-4的rs202071287、rs113215452基因片段的多态性进行初步研究，探讨这两个位点的SNP与子宫内膜异位症的相关性。
【方法】（1）采集35名在长春市妇产医院手术治疗的子宫内膜异位症患者在位及异位内膜组织，同期住院的对照组患者30例，利用免疫组化方法检测TIMP-4蛋白在子宫内膜组织的表达情况;（2）利用微波法合成稀土上转换荧光纳米离子（UCNPs），表面修饰SiO2层，完成表面功能化并与免疫球蛋白连接，制备UCNPs标记的免疫球蛋白，通过免疫组化（SP）方法检测TIMP-4在EM患者在位内膜组织的表达;（3）对在该院手术治疗的171例子宫内膜异位症患者及对照组各抽取静脉血2毫升，提取DNA，利用限制性内切酶法检测TIMP-4的rs202071287、rs113215452基因片段的多态性。
【结果】（1）TIMP-4蛋白在子宫在位及异位内膜组织中均有表达，该蛋白主要定位于子宫内膜腺上皮细胞，小血管壁也有轻度染色，基质无普遍着色。该蛋白在正常子宫内膜组织及EM患者在位内膜组织中表达强度从月经早期开始上升，月经中期达到高峰，月经晚期回落，逐渐降至最低点，表达具有时空差异。TIMP-4在EM患者在位及异位内膜表达增强，与对照组比较具有统计学意义。（2）利用稀土制备了上转换发光的荧光纳米离子NaGdF_4：Yb~(3+), Er~(3+)，粒子形貌规则且粒径均一，大小约为65nm左右，在980nm激发光下，可发出肉眼可见的绿色光（550nm）.包覆了二氧化硅外壳，在硅球表面修饰氨基合成了UCNP@SiO_2-NH_2粒子，粒径增大到70nm且仍具有良好的分散性。实现氨基功能化后，将该粒子通过共价键与免疫球蛋白联接，并将修饰后的免疫球蛋白成功应用于传统的免疫组化试验中，通过抗原抗体的特异性结合，成功地检测了TIMP-4蛋白在子宫内膜腺细胞中的表达，并实现了子宫内膜细胞的靶向定位。（3）EM组与对照组TIMP-4的rs202071287和rs113215452位点的基因型频率及等位基因频率分布均未见统计学差异（P>0.05）。
【结论】
（1）TIMP-4主要定位于子宫内膜腺上皮细胞，小血管壁也有轻度染色，在正常子宫内膜组织和EM患者在位内膜组织中表达强度具有时空差异，在EM患者在位及异位内膜组织中表达较对照组增强，TIMP-4可能与子宫内膜异位症的发生相关。
（2）制备了上转换荧光纳米粒子，通过抗原抗体的特异性结合，检测了TIMP-4蛋白在子宫内膜腺细胞中的表达，研发了一种新的荧光免疫组化方法，同时实现了子宫内膜的靶细胞定位，为EM的荧光诊断、靶向治疗奠定了前期实验基础。
（3）TIMP-4基因rs202071287和rs113215452酶切位点多态性可能与EM发生无关。
【创新性】
（1）首次检测TIMP-4蛋白在EM患者在位及异位内膜组织中的异常表达;明确该蛋白集中在子宫内膜细胞的局限性表达。
（2）制备稀土上转换纳米离子（UCNPs）并与免疫球蛋白成功连接，于传统的免疫组化技术相结合，利用抗原抗体特异性反应，检测到TIMP-4在EM患者在位内膜组织中的表达。研发了一种新的荧光免疫组化方法，同时实现子宫内膜细胞的靶向定位检测，开辟了EM的荧光诊断及靶向治疗的新领域。实现稀土纳米粒子的生物利用，为进一步的活体细胞标记及肿瘤标示动物实验奠定了前期的基础。
Endometriosis (EM) is a kind of benign gynecological diseases, involving10%of women of reproductive age.25%-35%infertility patients were associated with thedisease. At present, the etiology is still not clear and many studies have found thatEM is a multifactorial disease. System research had found that eutopic endometriumof EM in adhesion, invasion, and angiogenesis was different from normalendometrium, and genetic factors had an important role in its pathogenesis.Otherwise, the high levels of female hormones are necessary factors in diseaseexistence and development. Inhibitors of matrix metalloproteinases (Tissue inhibitorof matrix metalloproteinases, TIMP) is a kind of protease inhibitors in vivo secretedby the cell, they can inhibit MMPs activation and activity by combining withmatrix metalloproteinase (matrix metalloproteinases, MMPs) or active enzymecombined with a ratio of1:1complex formation. TIMPs and MMPs coordinatelyregulated proteolysis localized, and closely related with tissue remodeling, embryoimplantation, tumor invasion and metastasis. TIMP-4is a member of matrixmetalloproteinase inhibitor family. The studies have shown that the sequence from-930to-916sites has high homology to estrogen response element.
Objective: Study the expression of TIMP-4by immunohistochemical method inthe uterus and ectopic endometrium in patients with endometriosis. Furthermore, wewill study the polymorphism of rs202071287and rs113215452gene fragments ofTIMP-4in EM patients, in order to explore the correlation between the two SNPsand endometriosis.
Method:(1)The endometrium of35endometriosis and30uterine fibroids patientswho in Changchun Obstetrics and Gynecology Hospital were collected to detectprotein expression of TIMP-4in the endometrium by immunohistochemical method;(2) The up-conversion luminescent material for optically written display, NaGdF4：Yb~(3+), Er~(3+) up-conversion nanoparticies(UCNPs) were prepared by microwaveirradiation,which were completed the surface functionlization and connected withimmune-globulin for preparating Fluorescent Nanoparticles Probe to detect protein expression of TIMP-4in the endometrium and achieve the locatization of targetcells；(3)171patients with surgically-confirmed severe ovarian endometriosis(rAFS StagesIV) and174patients without endometriosis were conducted inObstetrics and Gynecology Hospital.2mL venous blood samples were taken toextract DNA, which was detecting the SNPs of rs202071287and rs113215452byrestriction enzyme.
Result:(1) TIMP-4protein was expressed in the uterus and ectopic endometrialtissues, which was mainly located in endometrial glandular epithelial cells, vascularwall also has mild staining, and matrix has no general coloring. The proteinexpressed in normal and EM uterus endometrial tissue began to rise from the earlymenstruation, peaking in the middle period of the menstrual and menstrual late falldown in the late period; gradually fell to the lowest level. TIMP-4was positiveexpressed in uterus and ectopic endometrial tissues, and was stronger compared withcontrols in Statistical significance.(2) The up-conversion luminescent material foroptically written display, NaGdF_4：Yb~(3+), Er~(3+) up-conversion nanoparticies(UCNPs)were prepared by microwave irradiation. The particle size was about65nm and thesamples exhibit green (550nm) fluorescence excited by a980nm diode laser. TheUCNP@SiO_2-NH_2nanocomposites， the size of which was70nm were preparedand conjugated with polyclonal antibody. Then，the ability of polyclonal antibodyfluorescent probes was detected to recognize the expression of Tissue inhibitor ofmetalloproteinase-4(TIMP-4) in the endometrial gland cells byImmunohistochemistry.(3) The genotype frequency of rs202071287andrs113215452were no significant difference (P>0.05) between EM group and thecontrol group, and the allele frequency of rs202071287and rs113215452were nosignificant difference (P>0.05) too.
Conclusions:(1) TIMP-4was mainly located in endometrial glandular epithelialcells, vascular wall also has mild staining, and the expression in normal endometrialtissue and EM positive tissue intensity has spatial and temporal difference.Compared with the control group, expression in patients with EM positive andectopic endometrial tissue were stronger than control group, TIMP-4may be correlated with the occurrence of endometriosis.(2) The results showed that theas-prepared UCNPs have uniform shape and size distribution. TheUCNP@SiO_2-NH_2nanocomposites offered some distinct advantages, such as gooddistribution and water-solubility, strong and stable upcoversion fluorescence as wellas significant auto-fluorescence from biological tissues resting in low signal tobackground ratio, and were potentially to apply to detect the expression of protein intissues at980nm excitation.(3) The polymorphism of rs202071287andrs113215452in TIMP-4gene may not be associated with EM patients.
Innovitor: combining rare earth conversion luminous nano materials andimmunohistochemical method, a new fluorescence immunoassay technology, whichwill be used to check the expression of TIMP-4in endumetrium. A new technologyof fluorescence immunoassay was researched and developed, which will lay thefoundation for the development of technology in the field of biological probes.
【目的】检测TIMP-4在子宫内膜异位症患者子宫在位及异位内膜中的表达情况，并进一步对TIMP-4的rs202071287、rs113215452基因片段的多态性进行初步研究，探讨这两个位点的SNP与子宫内膜异位症的相关性。
【方法】（1）采集35名在长春市妇产医院手术治疗的子宫内膜异位症患者在位及异位内膜组织，同期住院的对照组患者30例，利用免疫组化方法检测TIMP-4蛋白在子宫内膜组织的表达情况;（2）利用微波法合成稀土上转换荧光纳米离子（UCNPs），表面修饰SiO2层，完成表面功能化并与免疫球蛋白连接，制备UCNPs标记的免疫球蛋白，通过免疫组化（SP）方法检测TIMP-4在EM患者在位内膜组织的表达;（3）对在该院手术治疗的171例子宫内膜异位症患者及对照组各抽取静脉血2毫升，提取DNA，利用限制性内切酶法检测TIMP-4的rs202071287、rs113215452基因片段的多态性。
【结果】（1）TIMP-4蛋白在子宫在位及异位内膜组织中均有表达，该蛋白主要定位于子宫内膜腺上皮细胞，小血管壁也有轻度染色，基质无普遍着色。该蛋白在正常子宫内膜组织及EM患者在位内膜组织中表达强度从月经早期开始上升，月经中期达到高峰，月经晚期回落，逐渐降至最低点，表达具有时空差异。TIMP-4在EM患者在位及异位内膜表达增强，与对照组比较具有统计学意义。（2）利用稀土制备了上转换发光的荧光纳米离子NaGdF_4：Yb~(3+), Er~(3+)，粒子形貌规则且粒径均一，大小约为65nm左右，在980nm激发光下，可发出肉眼可见的绿色光（550nm）.包覆了二氧化硅外壳，在硅球表面修饰氨基合成了UCNP@SiO_2-NH_2粒子，粒径增大到70nm且仍具有良好的分散性。实现氨基功能化后，将该粒子通过共价键与免疫球蛋白联接，并将修饰后的免疫球蛋白成功应用于传统的免疫组化试验中，通过抗原抗体的特异性结合，成功地检测了TIMP-4蛋白在子宫内膜腺细胞中的表达，并实现了子宫内膜细胞的靶向定位。（3）EM组与对照组TIMP-4的rs202071287和rs113215452位点的基因型频率及等位基因频率分布均未见统计学差异（P>0.05）。
【结论】
（1）TIMP-4主要定位于子宫内膜腺上皮细胞，小血管壁也有轻度染色，在正常子宫内膜组织和EM患者在位内膜组织中表达强度具有时空差异，在EM患者在位及异位内膜组织中表达较对照组增强，TIMP-4可能与子宫内膜异位症的发生相关。
（2）制备了上转换荧光纳米粒子，通过抗原抗体的特异性结合，检测了TIMP-4蛋白在子宫内膜腺细胞中的表达，研发了一种新的荧光免疫组化方法，同时实现了子宫内膜的靶细胞定位，为EM的荧光诊断、靶向治疗奠定了前期实验基础。
（3）TIMP-4基因rs202071287和rs113215452酶切位点多态性可能与EM发生无关。
【创新性】
（1）首次检测TIMP-4蛋白在EM患者在位及异位内膜组织中的异常表达;明确该蛋白集中在子宫内膜细胞的局限性表达。
（2）制备稀土上转换纳米离子（UCNPs）并与免疫球蛋白成功连接，于传统的免疫组化技术相结合，利用抗原抗体特异性反应，检测到TIMP-4在EM患者在位内膜组织中的表达。研发了一种新的荧光免疫组化方法，同时实现子宫内膜细胞的靶向定位检测，开辟了EM的荧光诊断及靶向治疗的新领域。实现稀土纳米粒子的生物利用，为进一步的活体细胞标记及肿瘤标示动物实验奠定了前期的基础。
Endometriosis (EM) is a kind of benign gynecological diseases, involving10%of women of reproductive age.25%-35%infertility patients were associated with thedisease. At present, the etiology is still not clear and many studies have found thatEM is a multifactorial disease. System research had found that eutopic endometriumof EM in adhesion, invasion, and angiogenesis was different from normalendometrium, and genetic factors had an important role in its pathogenesis.Otherwise, the high levels of female hormones are necessary factors in diseaseexistence and development. Inhibitors of matrix metalloproteinases (Tissue inhibitorof matrix metalloproteinases, TIMP) is a kind of protease inhibitors in vivo secretedby the cell, they can inhibit MMPs activation and activity by combining withmatrix metalloproteinase (matrix metalloproteinases, MMPs) or active enzymecombined with a ratio of1:1complex formation. TIMPs and MMPs coordinatelyregulated proteolysis localized, and closely related with tissue remodeling, embryoimplantation, tumor invasion and metastasis. TIMP-4is a member of matrixmetalloproteinase inhibitor family. The studies have shown that the sequence from-930to-916sites has high homology to estrogen response element.
Objective: Study the expression of TIMP-4by immunohistochemical method inthe uterus and ectopic endometrium in patients with endometriosis. Furthermore, wewill study the polymorphism of rs202071287and rs113215452gene fragments ofTIMP-4in EM patients, in order to explore the correlation between the two SNPsand endometriosis.
Method:(1)The endometrium of35endometriosis and30uterine fibroids patientswho in Changchun Obstetrics and Gynecology Hospital were collected to detectprotein expression of TIMP-4in the endometrium by immunohistochemical method;(2) The up-conversion luminescent material for optically written display, NaGdF4：Yb~(3+), Er~(3+) up-conversion nanoparticies(UCNPs) were prepared by microwaveirradiation,which were completed the surface functionlization and connected withimmune-globulin for preparating Fluorescent Nanoparticles Probe to detect protein expression of TIMP-4in the endometrium and achieve the locatization of targetcells；(3)171patients with surgically-confirmed severe ovarian endometriosis(rAFS StagesIV) and174patients without endometriosis were conducted inObstetrics and Gynecology Hospital.2mL venous blood samples were taken toextract DNA, which was detecting the SNPs of rs202071287and rs113215452byrestriction enzyme.
Result:(1) TIMP-4protein was expressed in the uterus and ectopic endometrialtissues, which was mainly located in endometrial glandular epithelial cells, vascularwall also has mild staining, and matrix has no general coloring. The proteinexpressed in normal and EM uterus endometrial tissue began to rise from the earlymenstruation, peaking in the middle period of the menstrual and menstrual late falldown in the late period; gradually fell to the lowest level. TIMP-4was positiveexpressed in uterus and ectopic endometrial tissues, and was stronger compared withcontrols in Statistical significance.(2) The up-conversion luminescent material foroptically written display, NaGdF_4：Yb~(3+), Er~(3+) up-conversion nanoparticies(UCNPs)were prepared by microwave irradiation. The particle size was about65nm and thesamples exhibit green (550nm) fluorescence excited by a980nm diode laser. TheUCNP@SiO_2-NH_2nanocomposites， the size of which was70nm were preparedand conjugated with polyclonal antibody. Then，the ability of polyclonal antibodyfluorescent probes was detected to recognize the expression of Tissue inhibitor ofmetalloproteinase-4(TIMP-4) in the endometrial gland cells byImmunohistochemistry.(3) The genotype frequency of rs202071287andrs113215452were no significant difference (P>0.05) between EM group and thecontrol group, and the allele frequency of rs202071287and rs113215452were nosignificant difference (P>0.05) too.
Conclusions:(1) TIMP-4was mainly located in endometrial glandular epithelialcells, vascular wall also has mild staining, and the expression in normal endometrialtissue and EM positive tissue intensity has spatial and temporal difference.Compared with the control group, expression in patients with EM positive andectopic endometrial tissue were stronger than control group, TIMP-4may be correlated with the occurrence of endometriosis.(2) The results showed that theas-prepared UCNPs have uniform shape and size distribution. TheUCNP@SiO_2-NH_2nanocomposites offered some distinct advantages, such as gooddistribution and water-solubility, strong and stable upcoversion fluorescence as wellas significant auto-fluorescence from biological tissues resting in low signal tobackground ratio, and were potentially to apply to detect the expression of protein intissues at980nm excitation.(3) The polymorphism of rs202071287andrs113215452in TIMP-4gene may not be associated with EM patients.
Innovitor: combining rare earth conversion luminous nano materials andimmunohistochemical method, a new fluorescence immunoassay technology, whichwill be used to check the expression of TIMP-4in endumetrium. A new technologyof fluorescence immunoassay was researched and developed, which will lay thefoundation for the development of technology in the field of biological probes.
引文
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