本文選題：轉(zhuǎn)運(yùn) + 蛋白　； 參考：《中國科學(xué)院研究生院（大連化學(xué)物理研究所）》2007年博士論文

【摘要】： 目前認(rèn)為,致病性(或功能性)SNPs往往因改變蛋白質(zhì)結(jié)構(gòu)、功能或蛋白質(zhì)表達(dá)量而最終導(dǎo)致疾病的發(fā)生。ABC(ATP-Binding Cassette)轉(zhuǎn)運(yùn)蛋白在生物體內(nèi)發(fā)揮著極其重要的生理功能,其基因水平上發(fā)生的SNPs若引起相應(yīng)蛋白結(jié)構(gòu)變化或功能缺陷,將產(chǎn)生一系列嚴(yán)重疾病。本論文基于ABC轉(zhuǎn)運(yùn)蛋白的特點(diǎn),首次從理論和實(shí)驗(yàn)兩方面就ABC轉(zhuǎn)運(yùn)蛋白中SNPs的特征進(jìn)行了研究。 在理論研究方面,主要研究成果有:I、采用嶺偏最小二乘法(rPLS)和線性判別法(LDA)構(gòu)建了以轉(zhuǎn)運(yùn)蛋白中致病性nsSNPs為研究對象的預(yù)測模型,兩種模型的預(yù)測精度均大于84%(訓(xùn)練集762nsSNPs),同時預(yù)測出在ABCB亞家族中有28個nsSNPs可能具有致病性。II、采用rPLS及交叉驗(yàn)證,以ABC家族中的錯義突變?yōu)檠芯繉ο?構(gòu)建了包含5286個錯義突變且蛋白質(zhì)分子量大的理論預(yù)測模型。本模型對致病性錯義突變的預(yù)測精度分別是:訓(xùn)練集82.2%(4098個nsSNPs),測試集81.4%(752個nsSNPs);同時預(yù)測出在ABC家族中有234個錯義突變可能具有致病性。 在實(shí)驗(yàn)研究方面,從2836位大連地區(qū)健康體檢受試者中精選出265個漢族樣本作為研究對象,采用PCR-RFLP方法確定了MDR1/ABCB1基因中功能性SNP位點(diǎn)3435CT的分布特征,其中基因型分別是:CC 32%(n=85),CT 48% (n=127)和TT 20%(n=53),為國內(nèi)首次報道。 綜上,本研究首次將轉(zhuǎn)運(yùn)蛋白的序列保守性特征值與二級結(jié)構(gòu)參數(shù)結(jié)合作為預(yù)測模型的基本參數(shù);此外,因ABC轉(zhuǎn)運(yùn)蛋白為跨膜糖蛋白、分子量大和預(yù)測難度大的特性,本論文不但以轉(zhuǎn)運(yùn)蛋白的nsSNPs構(gòu)建數(shù)據(jù)集,還以非ABC轉(zhuǎn)運(yùn)蛋白中大分子蛋白質(zhì)中nsSNPs構(gòu)建數(shù)據(jù)集,獲得具有高精確度的預(yù)測ABC轉(zhuǎn)運(yùn)蛋白中致病性nsSNPs的理論模型。在實(shí)驗(yàn)方面,獲得中國漢族健康人群中MDR1/ABCB1基因中3435CT位點(diǎn)分布特征的相關(guān)數(shù)據(jù),填補(bǔ)了國內(nèi)相關(guān)研究的空白。以上研究為今后開展理論模型結(jié)果的驗(yàn)證及探究由ABC蛋白引發(fā)疾病的機(jī)制、疾病防治,特別是為提高我國個體化醫(yī)療水平進(jìn)行了探索性的嘗試。
[Abstract]:At present, it is believed that the pathogenicity (or functional SNPs) may result in the development of disease by changing the protein structure, function or protein expression, and that the ATP-Binding Cassette-based transporter plays an extremely important physiological function in organisms. If the SNPs at the gene level causes the corresponding protein structural changes or functional defects, it will lead to a series of serious diseases. Based on the characteristics of ABC transporter, the characteristics of SNPs in ABC transporter were studied theoretically and experimentally for the first time. In the theoretical research, the main research results are: I, using the Ridge partial least Square method (rPLS) and the linear discriminant method (LDA) to construct a prediction model of pathogenicity nsSNPs in the transporter. The prediction accuracy of the two models was greater than 84 (training set 762 ns SNPs). At the same time, it was predicted that 28 nsSNPs in the ABCB subfamily might be pathogenicity. RPLS and cross-validation were used to study the missense mutation in the ABC family. A theoretical prediction model with 5286 missense mutations and high molecular weight of protein was constructed. The prediction accuracy of this model for pathogenicity missense mutations is as follows: training set 82.2and 4098 nsSNPs, test set 81.4 / 752 nsSNPs, and 234 missense mutations may be pathogenicity in ABC family. In the experimental study, 265 Han nationality samples were selected from 2836 healthy volunteers in Dalian as the study subjects. The distribution characteristics of functional SNP site 3435CT in the MDR1/ABCB1 gene were determined by PCR-RFLP method. The genotypes of TT20 and TT20 were reported for the first time in China. In conclusion, the conserved eigenvalues of transporter sequences and secondary structural parameters were used as the basic parameters of the prediction model for the first time, in addition, because ABC transporter was transmembrane glycoprotein, its molecular weight was high and the prediction was difficult. In this paper, the data set was constructed not only by nsSNPs of transporter, but also by nsSNPs of macromolecular protein in non-ABC transporter. The theoretical model of predicting pathogenicity nsSNPs in ABC transporter with high accuracy was obtained. In the aspect of experiment, the data about the distribution of 3435CT loci in the MDR1/ABCB1 gene in healthy Chinese Han population were obtained, which filled the gaps in the relevant research in China. These studies are an exploratory attempt to verify the results of theoretical models and explore the mechanism of disease caused by ABC protein, disease prevention and treatment, especially to improve the level of individualized medical treatment in China.
【學(xué)位授予單位】：中國科學(xué)院研究生院（大連化學(xué)物理研究所）
【學(xué)位級別】：博士
【學(xué)位授予年份】：2007
【分類號】：R341

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