臺灣博碩士論文加值系統

生長激素（growth hormone, GH）是促進人體生長最重要的激素，尤其是對青春期前的兒童更為重要。造成生長遲緩的因素可分為環境和遺傳因素，而生長激素是治療不同原因所造成生長遲緩的最佳藥物。在臨床治療發現，生長激素缺乏症（growth hormone deficiency, GHD）的病人在接受生長激素治療後的第一年效果顯著，但生長高度卻因人而異，故認為與個人的遺傳基因特異性有關。我們以單核苷酸多型性（single nucleotide polymorphism, SNP）的方法篩選出適合而且與生長調節有關的遺傳標記。分析的結果顯示GHR codon440（G/T）在統計上有顯著的差異（p＜0.05）。此多型性是核苷酸從guanine（G）變成thymine（T），導致在GHR基因上的第440個氨基酸從cysteine變成了phenylananine。經身高的統計發現帶有GHR codon440 T/T genotype的GHD病人在接受生長激素治療的第一年，其平均生長高度較其他兩種genotype還來的高。為了瞭解這單核苷酸多型性所產生的機轉，我們將GHR codon440 G/G和T/T genotype的cDNA送入CHO-K1細胞做表現，再利用報導基因分析比較兩者之間活性的差異。結果顯示GHR-T/T genotype經由GH刺激後所產生的訊號傳遞較GHR-G/G genotype強（p=0.017）。另外，在生長激素誘導下，帶有GHR-T/T genotype的CHO-K1細胞，其p-STAT5（Tyr694）與p-PKCβII（Ser660）的量高於帶有GHR-G/G genotype的CHO-K1細胞。因此，我們認為GHR codon440（G/T）基因的多型性與GHD病人身高的調節有很大的相關性。

Growth hormone (GH) is the most important one to stimulate human body growth and it is especially significant for children before puberty. Although the factors resulting in slow growth can be divided into the environment factor and the heredity factor, administering growth hormone is the best treatment for different slow growth. In clinical study, the therapy efficacy is significant for the patients with growth hormone deficiency (GHD), one year after treatment with growth hormone. However, their growth altitudes are different. Hence, it is thought to relate to individual hereditary characteristics. Here, we found out the suitable genetic marker related growth adjustment by assaying single nucleotide polymorphism (SNP). The results for GHR condon440 (G/T) revealed a statistically significant difference between GHD patients and normal controls (p<0.05). When the nucleotide change in this site is from G to T, it would lead to a non-synonymous amino acid change from cysteine to phenylalanine. One year after growth hormone treatment, GHD patients with GHR-T/T genotype gained higher average height than G/G and G/T genotypes. In order to realize the mechanism of this polymorphism, growth hormone receptors with G/G or T/T genotype in their condon440 were transfected into CHO-K1 cells. Reporter assays for TK promoter were conducted to compare bioactivity bioactivity of two genotypes. Our data revealed that Cells with T/T genotoype of GHR had higher alkaline phosphatase activity than G/G genotype after luciferase activity was normalized. Futhermore, GH-induced phosphorylation of STAT5 (Tyr694) and p-PKCβII（Ser660）in CHO-K1 cells expressing T/T genotype of GHR was higher than those of G/G genotype. Therefore, it could be concluded that GHR condon440 (G/T) polymorphism is obviously associated to GHD patient’s tall regulation.

致謝………………………………………………………………1
中文摘要…………………………………………………………2
Abstract…………………………………………………………4

第一章 前言…………………………………………………6
第一節 導論………………………………………………7
第二節 研究目的………………………………………10

第二章 文獻回顧……………………………………………11
第一節 人體的生長……………………………………12
第二節 生長激素的調節與生理功能…………………14
第三節 生長激素缺乏的臨床症狀……………………16
第四節 生長激素的臨床治療…………………………18
第五節 生長激素在細胞內訊息傳導機制……………19
一、生長激素的結構………………………………19
二、生長激素受體…………………………………20
三、GHR的訊息傳導路徑…………………………23
四、GHR訊息傳導的調控…………………………26

第三章 材料與方法…………………………………………29
第一節 病人及檢體的收集…………………………………30
第二節 DNA萃取……………………………………………31
第三節 SNP分析……………………………………………32
第四節 RNA萃取……………………………………………33
第五節 GHR-G/G表現質體的製作…………………………34
第六節 GHR-T/T表現質體的製作…………………………36
第七節 轉染（Transfection）…………………………37
第八節 細胞培養……………………………………………38
第九節 免疫螢光染色（Immunofluoresence）………39
第十節 報導基因分析（Reporter assay）……………40
第十一節 西方墨點分析（Western blotting）………42
第十二節 統計方法…………………………………………44

第四章 結果…………………………………………………45
一、病人的基本資料……………………………………46
二、SNP的分析…………………………………………46
三、多變項回歸分析……………………………………47
四、病患接受治療後的第一年身高統計………………48
五、免疫螢光染色………………………………………48
六、報導基因分析………………………………………49
七、西方墨點分析………………………………………50

第五章 討論…………………………………………………51

圖與表………………………………………………………57

參考文獻……………………………………………………73

附錄…………………………………………………………83

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