大鼠胰腺促性腺激素释放激素及其受体的研究
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摘要
经典理论认为促性腺激素释放激素(GnRH)是由下丘脑神经元分泌的一种十肽激素，它经下丘脑垂体门脉系统进入垂体前叶，与垂体前叶的促性腺激素分泌细胞上的促性腺激素释放激素受体(GnRHR)结合，刺激卵泡刺激素(FSH)和黄体生成素(LH)的分泌，进而调节性腺的发育与配子的形成。近二十年的大量研究证据表明，GnRH及其受体广泛存在于下丘脑-垂体轴之外，如生殖系统(卵巢、输卵管、前列腺、睾丸以及胎盘等)、免疫系统(T、B淋巴细胞)和许多恶性肿瘤(如乳腺癌、肺癌、胰腺癌及肝癌)，通过自分泌和旁分泌途径对这些组织器官以及恶性肿瘤的生长起调节作用。
我们先前的研究表明，在大鼠的消化系统广泛地存在有GnRH及其受体，并且其受体的基因序列与垂体的基因序列一致，说明大鼠的消化系统能够自身分泌与合成GnRH及其受体，同时这些组织或细胞是GnRH作用的靶细胞，如GnRH类似物可明显促进大鼠
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
颌下腺神经生长因子的分泌，还可明显抑制大鼠胃酸的分泌。但
是大鼠胰腺是否存在GnRH及其受体，它们的基因序列如何，GnRH
对大鼠胰腺的功能有何影响，其受体的信号转导机制怎样，这些
问题均未见报道。
由此我们在以往研究的基础上。进行了以下研究：
应用兔疫组织化学和原位杂交技术在胰腺组织切片上检测
GnRH及其受体的定位及表达；
利用反转录PCR和基因克隆测序的方法对大鼠胰腺GnRH及其
受体的基因序列进行研究；
运用组织块体外孵育法，用不同浓度GnRH类似物进行刺激，
同时借助ELISA、放免法等技术观察在体外条件下GnRH对大鼠胰
腺内、外分泌功能的影响；
借助活体动物实验，由尾静脉注射和十二指肠灌注两种方式给
与GnRH类似物，留取血浆和十H指肠液，分别检测胰腺内、外分
泌功能指标的变化；
原代培养大鼠胰腺腺泡细胞，体外条件下给予GnRH类似物刺
激，应用细胞凋亡检测试剂盒和流式细胞技术，观察GnRH对大鼠
胰腺细胞凋亡的影响：
用ELISA、放免法、激光共聚焦技术和免疫组化染色技术等观
察不同浓度GnRH类似物在不同时间内对大鼠胰腺细胞胞内cAMP、
MAPK、PKC、Ca卜、iNOS含量变化的影响。
通过实验得到主要研究结果如下：
应用免疫组织化学和原位杂交的方法发现，胰腺的外分泌部
部分细胞含有GnRH免疫反应阳性物质，而胰岛细胞未发现GnRH
免疫反应阳性物质。同时胰岛内所有胰高血糖素免疫反应阳性的
4
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
细胞均呈GnRH受体免疫反应阳性，两种阳性细胞的数量及分布特
点完全一致。原位杂交杂交结果显示在胰腺内、外分泌部均发现
GnRHR觎NA杂交信号。结合以往研究发现胰腺外分泌部检测到
GnRH mRNA杂交信号，我们认为胰腺外分泌部细胞能够分泌GnRH，
而其受体分布于胰腺内、外分泌部大部分细胞。
我们从大鼠胰腺提取总RNA，应用反转录PCR的方法分别扩
增GnRH和GnRHR基因，并对产物进行纯化回收，然后进行序列分
析，结果发现大鼠胰腺GnRH基因序列与下丘脑的完全一致：而胰
腺GnRHR基因序列与垂体的完全一致。
应用不同浓度的GnRH类似物进行体外组织块孵育，收集培养
上清液进行检测发现，体外条件下，GnRH能明显增加胰蛋白酶和
胰高血糖素的分泌，降低胰岛素的分泌，并且具有明显的浓度依
赖性。
体内动物实验中我们从尾静脉和十二指肠两种途径给药，结
果发现：尾静脉给药能明显增加胰蛋白酶和胰高血糖素的分泌，
降低胰岛素的分泌；十二指肠给药仅能增加胰蛋白酶的分泌，对
胰岛素和胰高血糖素的分泌均无影响。
最后我们对GnRHR的信号转导分子进行了研究，发现GnRH类
似物刺激胰腺细胞后，PKC活性的变化显示明显的时间和剂量依赖
性，其活性高峰出现在30min；cAMP水平变化里时间和剂量依赖
性，在个2小时含量变化最大，2小时达高峰：瞅瞅在短时间内
即出现活性高峰，且其含量变化里剂量依赖性；i NOS的活性在整
个实验过程中没有出现明显的变化；同时本实验观察＊”变化曲
线时可以看到延迟峰（膜上钙通道开放所致）和瞬时峰（胞内钙
库开放所致）均存在，推测胞内＊“水平的提高有胞内和胞外两
5
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
种来源的＊”的参与，分别应用膜上二型钙通道阻滞剂Lac i di…ne
和胞内钙库阻滞剂Ryanodine的实验进一步证明这一推测，即胞
内C／“水平的提高既有通过膜上乙型钙通道进入胞浆的＊“也有
通过胞内钙库释放进人跑浆的CaZ”的参与。由以上结果我们推测
大鼠胰腺GnRHR的信号转导有叫C－Cd”途径，同时还有cA惭、MAPK
的参与。
综上所述，本研究首次在大鼠胰腺中发
Gonadotropin-releasing hormone (GnRH) is a deca-peptide synthesized by hypothalamus and released from nerve terminals in a pulsatile manner into the hypophysial-portal circulation, stimulating gonadotropin target cells in anterior pituitary. The gonadotropin response to GnRH stimulation is manifested by releasing the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) that play a central role in control of production. Recently, GnRH and its receptor have been found exist in many extra-hypothalamus-pituitary tissues, such as gonad (ovary, oviducU prostate,testis,placenta > et al. ) and immune system ( T and B lymphocytes ). GnRH and its receptor are not only expressed in normal tissues, but also widely exist in various carcinoma that derived from reproductive ( ovary cancer , prostate cancer ) or non-reproductive tissues (breast cancer lung cancers pancreas cancer and hepatocellular carcinoma, et al.). These indicate that they may have certain function in these neoplastic tissues.
Our previous studies found that GnRH and its receptor co-existed in digestive system (such as gastric-intesinal), and
meanwhile, we found their mRNA also present in the same organs mentioned above. We have demonstrated that cDNA sequence of GnRHR in submaxillary was identical to the relative cDNA sequence of GnRHR in pituitary. The suppressive effect of GnRH analogue on the secretion of never growth factor (NGF) in submaxillary showed that these organs are the targets of GnRH. Till now, there still have been no report concerning the expression and function of GnRH and its receptor in pancreas. Based on our previous studies, we conducted the following experiments to further clarify the following uncertainties:
Using immunohistochemistry and in situ hybridization, we detected the expression of GnRH and its receptor in rat pancreas. Meanwhile, we carried out RT-PCR and gene clone, further investigating GnRH and its receptor transcription units and proving their gene sequencing.
In order to study the regulatory role of GnRH in rat pancreas, we established the functional experiments in vitro and in vivo. Further more, we used ELISA and radioimmunoassay to investigate the changes of trypsin, glucagon and insulin in cultural medium, serum and duodenum secretion.
Annexin-V apoptosis kit and flow cytometric analysis were performed to detect the effect of GnRH on pancreatic cell apoptosis.
At last, ELISA, radioimmunoassay , laser confocal scanning microscope and immunohistochemistry were used to study the mechanism of GnRH analogue impact on intracellular PKC activity,
cAMP concerntratiom MAPK level , iNOS concerntration and [Ca2+]j mobilization in rat pancreatic cells in order to reveal the mechanism of GnRHR signal transaction pathways.
The main results were as follows:
Using immunohistochemistry, we detected that GnRH is distribute in the exocrine portion of rat pancreas, while its receptor located in the endocrine portion with the same sites as A cells. We used in situ hybridization to detect GnRHR mRNA and found that it was located in both exocrine and endocrine portion of rat pancreas.
After having detected both GnRH and its receptor molecule and their mRNA in rat pancreas, we carried out RT-PCR, further proving that GnRH and its receptor transcription units do exist in the pancreas and possess the same sequence as the hypothalamus GnRH mRNA and pituitary GnRHR mRNA, respectivly.
By the experiment of pancreatic tissue culture in vitro, we administered different concentration of GnRH analogue into the medium and incubated for Ih. It was found that both trypsin and glucagon concentration in the medium increased in a dose-dependent manner, while insulin decreased in a dose-dependent manner.
By the animal experiment in vivo, we administered GnRH analogue through the caudal vein and duodenum, recpsctively. It was found that administering through caudal vein resulted in the same results as them in vitro, while administering through duodenum resulted that try
我们先前的研究表明，在大鼠的消化系统广泛地存在有GnRH及其受体，并且其受体的基因序列与垂体的基因序列一致，说明大鼠的消化系统能够自身分泌与合成GnRH及其受体，同时这些组织或细胞是GnRH作用的靶细胞，如GnRH类似物可明显促进大鼠
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
颌下腺神经生长因子的分泌，还可明显抑制大鼠胃酸的分泌。但
是大鼠胰腺是否存在GnRH及其受体，它们的基因序列如何，GnRH
对大鼠胰腺的功能有何影响，其受体的信号转导机制怎样，这些
问题均未见报道。
由此我们在以往研究的基础上。进行了以下研究：
应用兔疫组织化学和原位杂交技术在胰腺组织切片上检测
GnRH及其受体的定位及表达；
利用反转录PCR和基因克隆测序的方法对大鼠胰腺GnRH及其
受体的基因序列进行研究；
运用组织块体外孵育法，用不同浓度GnRH类似物进行刺激，
同时借助ELISA、放免法等技术观察在体外条件下GnRH对大鼠胰
腺内、外分泌功能的影响；
借助活体动物实验，由尾静脉注射和十二指肠灌注两种方式给
与GnRH类似物，留取血浆和十H指肠液，分别检测胰腺内、外分
泌功能指标的变化；
原代培养大鼠胰腺腺泡细胞，体外条件下给予GnRH类似物刺
激，应用细胞凋亡检测试剂盒和流式细胞技术，观察GnRH对大鼠
胰腺细胞凋亡的影响：
用ELISA、放免法、激光共聚焦技术和免疫组化染色技术等观
察不同浓度GnRH类似物在不同时间内对大鼠胰腺细胞胞内cAMP、
MAPK、PKC、Ca卜、iNOS含量变化的影响。
通过实验得到主要研究结果如下：
应用免疫组织化学和原位杂交的方法发现，胰腺的外分泌部
部分细胞含有GnRH免疫反应阳性物质，而胰岛细胞未发现GnRH
免疫反应阳性物质。同时胰岛内所有胰高血糖素免疫反应阳性的
4
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
细胞均呈GnRH受体免疫反应阳性，两种阳性细胞的数量及分布特
点完全一致。原位杂交杂交结果显示在胰腺内、外分泌部均发现
GnRHR觎NA杂交信号。结合以往研究发现胰腺外分泌部检测到
GnRH mRNA杂交信号，我们认为胰腺外分泌部细胞能够分泌GnRH，
而其受体分布于胰腺内、外分泌部大部分细胞。
我们从大鼠胰腺提取总RNA，应用反转录PCR的方法分别扩
增GnRH和GnRHR基因，并对产物进行纯化回收，然后进行序列分
析，结果发现大鼠胰腺GnRH基因序列与下丘脑的完全一致：而胰
腺GnRHR基因序列与垂体的完全一致。
应用不同浓度的GnRH类似物进行体外组织块孵育，收集培养
上清液进行检测发现，体外条件下，GnRH能明显增加胰蛋白酶和
胰高血糖素的分泌，降低胰岛素的分泌，并且具有明显的浓度依
赖性。
体内动物实验中我们从尾静脉和十二指肠两种途径给药，结
果发现：尾静脉给药能明显增加胰蛋白酶和胰高血糖素的分泌，
降低胰岛素的分泌；十二指肠给药仅能增加胰蛋白酶的分泌，对
胰岛素和胰高血糖素的分泌均无影响。
最后我们对GnRHR的信号转导分子进行了研究，发现GnRH类
似物刺激胰腺细胞后，PKC活性的变化显示明显的时间和剂量依赖
性，其活性高峰出现在30min；cAMP水平变化里时间和剂量依赖
性，在个2小时含量变化最大，2小时达高峰：瞅瞅在短时间内
即出现活性高峰，且其含量变化里剂量依赖性；i NOS的活性在整
个实验过程中没有出现明显的变化；同时本实验观察＊”变化曲
线时可以看到延迟峰（膜上钙通道开放所致）和瞬时峰（胞内钙
库开放所致）均存在，推测胞内＊“水平的提高有胞内和胞外两
5
第四军医大学博士学位论文：大鼠胰腺促性腺激素释放激素及其受体的研究
种来源的＊”的参与，分别应用膜上二型钙通道阻滞剂Lac i di…ne
和胞内钙库阻滞剂Ryanodine的实验进一步证明这一推测，即胞
内C／“水平的提高既有通过膜上乙型钙通道进入胞浆的＊“也有
通过胞内钙库释放进人跑浆的CaZ”的参与。由以上结果我们推测
大鼠胰腺GnRHR的信号转导有叫C－Cd”途径，同时还有cA惭、MAPK
的参与。
综上所述，本研究首次在大鼠胰腺中发
Gonadotropin-releasing hormone (GnRH) is a deca-peptide synthesized by hypothalamus and released from nerve terminals in a pulsatile manner into the hypophysial-portal circulation, stimulating gonadotropin target cells in anterior pituitary. The gonadotropin response to GnRH stimulation is manifested by releasing the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) that play a central role in control of production. Recently, GnRH and its receptor have been found exist in many extra-hypothalamus-pituitary tissues, such as gonad (ovary, oviducU prostate,testis,placenta > et al. ) and immune system ( T and B lymphocytes ). GnRH and its receptor are not only expressed in normal tissues, but also widely exist in various carcinoma that derived from reproductive ( ovary cancer , prostate cancer ) or non-reproductive tissues (breast cancer lung cancers pancreas cancer and hepatocellular carcinoma, et al.). These indicate that they may have certain function in these neoplastic tissues.
Our previous studies found that GnRH and its receptor co-existed in digestive system (such as gastric-intesinal), and
meanwhile, we found their mRNA also present in the same organs mentioned above. We have demonstrated that cDNA sequence of GnRHR in submaxillary was identical to the relative cDNA sequence of GnRHR in pituitary. The suppressive effect of GnRH analogue on the secretion of never growth factor (NGF) in submaxillary showed that these organs are the targets of GnRH. Till now, there still have been no report concerning the expression and function of GnRH and its receptor in pancreas. Based on our previous studies, we conducted the following experiments to further clarify the following uncertainties:
Using immunohistochemistry and in situ hybridization, we detected the expression of GnRH and its receptor in rat pancreas. Meanwhile, we carried out RT-PCR and gene clone, further investigating GnRH and its receptor transcription units and proving their gene sequencing.
In order to study the regulatory role of GnRH in rat pancreas, we established the functional experiments in vitro and in vivo. Further more, we used ELISA and radioimmunoassay to investigate the changes of trypsin, glucagon and insulin in cultural medium, serum and duodenum secretion.
Annexin-V apoptosis kit and flow cytometric analysis were performed to detect the effect of GnRH on pancreatic cell apoptosis.
At last, ELISA, radioimmunoassay , laser confocal scanning microscope and immunohistochemistry were used to study the mechanism of GnRH analogue impact on intracellular PKC activity,
cAMP concerntratiom MAPK level , iNOS concerntration and [Ca2+]j mobilization in rat pancreatic cells in order to reveal the mechanism of GnRHR signal transaction pathways.
The main results were as follows:
Using immunohistochemistry, we detected that GnRH is distribute in the exocrine portion of rat pancreas, while its receptor located in the endocrine portion with the same sites as A cells. We used in situ hybridization to detect GnRHR mRNA and found that it was located in both exocrine and endocrine portion of rat pancreas.
After having detected both GnRH and its receptor molecule and their mRNA in rat pancreas, we carried out RT-PCR, further proving that GnRH and its receptor transcription units do exist in the pancreas and possess the same sequence as the hypothalamus GnRH mRNA and pituitary GnRHR mRNA, respectivly.
By the experiment of pancreatic tissue culture in vitro, we administered different concentration of GnRH analogue into the medium and incubated for Ih. It was found that both trypsin and glucagon concentration in the medium increased in a dose-dependent manner, while insulin decreased in a dose-dependent manner.
By the animal experiment in vivo, we administered GnRH analogue through the caudal vein and duodenum, recpsctively. It was found that administering through caudal vein resulted in the same results as them in vitro, while administering through duodenum resulted that try
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