三叶因子3诊断学应用价值的临床实验研究
文献类型：学位论文
| 作者 | 杜廷义 |
| 学位类别 | 博士 |
| 答辩日期 | 2013-11 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 张云 |
| 关键词 | 三叶因子3 慢性肾脏疾病 肿瘤转移 疾病标志物 ELISA |
| 其他题名 | The Clinical Experimental Research for Trefoil Factor 3 as a Novel Disease Biomarker |
| 学位专业 | 动物学 |
| 中文摘要 | 三叶因子（trefoil factor, TFF）家族是具有一个或多个三叶因子结构域的蛋白质多肽，在进化上具有高度的保守性，具有耐热、耐酶消化的理化特性。哺乳动物的TFF有三个成员(TFF1、TFF2和TFF3)。粘膜组织，如胃肠道和呼吸道粘膜等是TFF的主要合成场所。生理条件下，TFF的分布具有组织专一性，具有粘膜保护和创伤修复作用。TFF在肿瘤组织中广泛表达，在肿瘤的发生、发展、侵袭、转移过程中发挥着重要作用，可能是癌基因在对不同刺激做出反应时的共有递质。TFF生物学功能存在一个复杂的调控过程，单链TFF可通过膜受体而激活相关信号通路，TFF也可以通过与其它蛋白质的结合而协同发挥作用。TFF在临床医学领域主要应用在粘膜保护、粘膜损伤相关疾病的预防和治疗及肿瘤病理的诊断与干预等方面。TFF的作用机制和功能行使相关信号通路仍然是目前研究的重点，TFF与??-晶状体蛋白天然复合物的发现有助于对TFF的进一步认识和深入研究。TFF是一个具有重要功能的多肽家族，生理状态下表达于胃肠道黏膜组织及其他黏膜组织的分泌细胞。当机体发生消化系统炎症、肿瘤等病理改变时，TFF会伴随病理过程而发生异常表达和/或持续分泌。肿瘤病理学研究资料表明TFF的异常表达与疾病预后相关，而从基因表达谱、肿瘤分泌蛋白谱、生物信息学等多种分析角度出发的研究结果，进一步肯定了TFF多肽检测和TFF-mRNA检测在相关疾病的临床实验诊断，特别是在肿瘤复发、肿瘤转移的监测及疗效观察、预后判断等方面，具有良好的实验诊断效能。因此，对于相关疾病的实验诊断，TFF可能是一个潜在的生物学标志物；但其实际应用前景还需要更加充分的、前瞻性的临床研究资料来加以判断。三叶因子3（TFF3）在机体的粘膜保护和细胞迁移中发挥着重要作用。临床研究资料表明：TFF3的异常表达与胃肠道炎性疾病，实体瘤等疾病相关。本实验研究的目的首先在于明确TFF3在不同的临床常见疾病中的分布特征。为此，研究进行了大规范样本为基础的前瞻性随机实验设计，以ELISA为主要技术手段，检测分析了在不同常见疾病分组中的血清TFF3浓度分布。并根据分析结果，随之进行了对5组（共计150例）不同阶段慢性肾脏疾病（CKD）患者样本的血清、尿液TFF3浓度检测及部分肾活检组织的TFF3免疫组织化学染色分析（IHC）。实验研究结果显示：包括正常对照组在内，30个临床常见疾病分组中，以CKD，转移/继发性肿瘤以及急性胃肠道炎症三个疾病中的血清TFF3水平为最高，依次为200.9ng/ml，95.7ng/ml和71.7ng/ml。并且，患者血清及尿液中的TFF3的浓度水平与CKD的严重程度具有较为明显的相关趋势： CKD分期为1-5阶段患者的血清TFF3浓度依次为23.6ng/ml，29.9ng/ml，54.9ng/ml，85.0ng/ml 和176.6ng/ml，而肌酐（Cr）校正后的尿液中TFF3浓度依次为367.1ng/mg?Cr，910.6ng/mg?Cr，1,149.0ng/mg?Cr，1,610.0ng/mg?Cr 和 3,475.0ng/mg?Cr。IHC结果表明：在病变的肾脏组织中，TFF3的表达集中于肾小管上皮细胞内。本项实验研究结果表明：在TFF3的临床应用研究，特别是疾病标志物应用的相关研究中，机体的肾脏损伤情况不容忽视。研究结果同时提示：对于TFF3与CKD发生发展之间相互关系的进一步研究，将有助于加强对TFF3在临床疾病中的病理生理作用及其机制的理解和认识。而TFF3能否成为CKD的候选疾病标志物，这还需要更加深入的基础研究和临床研究资料加以判断。 |
| 英文摘要 | Trefoil factor (TFF) family is a group of peptides with one or several trefoil factor domains in their structure, which are highly conserved in evolution, and characterized with heat and enzymatic digestion resistance. The mammalian TFFs have three members（TFF1-3）, and the gastrointestinal tract and the airway system are major organs of their expression and secretion. At physiological conditions, with a tissue-specific distribution，TFF plays an important role in mucosal protection and wound healing. But in the malignant tissues, TFF is widely expressed，correlated strongly with the genesis, metastasis and invasion of tumor cells. These phenomena indicated that TFF may be a possible common mediator of oncogenic responses to different stimuli. The biologic functions of TFF involve complex regulatory processes. Single chain TFF may activate cell membrane receptors and induce specific signaling transduction. On the other hand, TFF can form a complex with other proteins to exert its biological effects. In clinical medicine, TFF is primarily applied as drugs in the mucosal protection, in the prevention and the treatment of mucosal damage-related diseases and as pathological biomarkers of tumors. At present the first hand actions and the molecular mechanisms related to TFFs are still the major challenges in TFF research. And the discovery of the naturally occurring complex of TFF and crystallins is highly valuable to the understanding of the biological functions and action mechanisms of TFF.The TFF, expressed physiologically in the secretory cells of gastrointestinal mucosa and other mucosal tissues, is a unique peptide family with important biologic functions. Aberrant expression and/or continued secretion of TFF might be existed concurrently with the disorder processes of digestive system inflammation, tumor or other related pathological changes. The pathological research data of tumor tissues has showed that the abnormal expression of TFF was associated with the prognosis of these disease. Based on the results collected from the studies by the means of the gene expression profiling, the tumor secretome and the bioinformatic analysis, it was positively confirmed that the clinical detection of TFF peptides or TFF-mRNA possessed an excellent diagnostic performance dealing with the related diseases, especially for the monitor of the recurrence or the metastasis of tumors and for the estimation of the therapeutic efficacy and the prognosis. Therefore, TFF might be a potential biomarker for the related diseases; but its practical value still requested further prospective clinical studies of multi-centers to estimate.TFF3 is a small peptide that plays an important role in mucosal protection, cell proliferation and cell migration. The aberrant expression of TFF3 is correlated with gastrointestinal inflammation, solid tumors and other clinical diseases. The objective of this study was to identify the distribution characteristics of serum TFF3 in common clinical diseases. For this purpose, a large prospective randomized study of 1,072 Chinese patients was performed using an enzyme-linked immunosorbent assay (ELISA) to examine the serum TFF3 concentrations in patients with different disease. A matched case-control study was conducted on patients with chronic kidney disease (CKD) stages 1-5 Immunohistochemistry (IHC) was performed using renal tissues to determine the relationship between the severity of CKD and the serum and urine concentrations of TFF3 peptides. In the results of this experimental study, the mean serum concentrations of TFF3 in patients with CKD, metastatic and secondary carcinoma (MC) and acute gastroenteritis (AG) (200.9 ng/ml, 95.7 ng/ml and 71.7 ng/ml, respectively) were significantly higher than those in patients with other common clinical diseases. A positive correlation tendency was observed between the serum TFF3 concentrations and the severity of CKD. The mean serum TFF3 values for CKD stages 1-5 were 23.6 ng/ml, 29 |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10174]  |
| 专题 | 昆明动物研究所_动物活性蛋白多肽组学 |
| 推荐引用方式 GB/T 7714 | 杜廷义. 三叶因子3诊断学应用价值的临床实验研究[D]. 北京. 中国科学院研究生院. 2013. |
入库方式： OAI收割
来源：昆明动物研究所
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