【摘要】：目的:利用糖尿病腎病(diabetic nephropathy,DN)患者微分離的腎小球全基因組表達數(shù)據(jù),借助CMAP(Connectivity Map)數(shù)據(jù)庫和生物信息學(xué)方法,探尋具有DN治療作用的潛在藥物。方法:選取中國漢族DN患者29例和正常對照6例,獲取腎組織后,激光微分離腎小球,提取RNA后,利用Affymetrix U133 Plus 2.0全基因組表達譜芯片檢測獲得基因表達數(shù)據(jù),獲得不同分期DN患者之間的差異表達基因后,進一步通過2種不同的生物信息學(xué)方法尋找DN的潛在治療藥物;并闡明DN治療藥物可能的分子作用機制。結(jié)果:1.與正常對照相比,早期和晚期DN患者腎小球的差異表達基因分別為100和1602個(FDR0.05,變化倍數(shù)1.5);DN晚期和早期相比,腎小球有1194個基因出現(xiàn)差異表達(FDR0.05,變化倍數(shù)1.5)。對DN晚期和早期相比的差異表達基因進行功能分析,基因本體論(Gene ontology,GO)分析顯示,差異表達基因主要涉及細胞外刺激、組織生長發(fā)育、免疫和細胞信號傳導(dǎo)等,進一步的通路分析顯示細胞外基質(zhì)受體相互作用、細胞與細胞外基質(zhì)的連接、補體系統(tǒng)、細胞因子受體相互作用和PI3K-Akt信號通路等出現(xiàn)明顯變化;2.利用DN晚期和早期相比的差異表達基因和CMAP數(shù)據(jù)庫,篩選出小白菊內(nèi)酯(parthenolide)、蓽茇酰胺(piperlongumine)、15d-PGJ2(15-脫氧前列腺素 J2)和 LY-294002(PIBK抑制劑)等候選藥物具有逆轉(zhuǎn)晚期DN患者基因變化的作用,提示上述藥物可能具有DN治療的潛能,進一步的文獻分析表明這些藥物對DN均有一定的治療作用,可能作為NF-kB抑制劑、組蛋白去乙�；敢种苿I3K信號通路抑制劑或者PPARγ激動劑等發(fā)揮腎臟保護作用。結(jié)論:利用DN患者腎小球全基因組表達譜和CMAP數(shù)據(jù)庫能夠快速篩選出具有DN治療潛能的藥物;文獻分析也驗證了該方法的可靠性;相關(guān)藥物可以進行下一步的動物和臨床試驗以證實其治療的安全性和有效性。
[Abstract]:Aim: to explore the potential drugs for the treatment of diabetic nephropathy (diabetic nephropathy,DN) by using microisolated glomerular genomic expression data, CMAP (Connectivity Map) database and bioinformatics. Methods: 29 patients with DN in Chinese Han nationality and 6 normal controls were selected. After renal tissue was obtained, glomeruli were isolated by laser microseparation, RNA was extracted, and gene expression data were obtained by Affymetrix U133 Plus 2.0 whole genome expression microarray. After obtaining the differentially expressed genes among DN patients at different stages, we further explored the potential therapeutic drugs for DN by two different bioinformatics methods, and elucidated the possible molecular mechanism of DN treatment drugs. The result is 1: 1. Compared with normal controls, the differential expression genes in glomeruli of early and late DN patients were 100,1602 (FDR0.05, variation multiple 1.5); DN late and early stage respectively), and there were 1194 differentially expressed genes (FDR0.05, change multiple 1.5) in glomeruli of early and late DN patients. Functional analysis of differentially expressed genes in late and early stages of DN showed that differentially expressed genes were mainly involved in extracellular stimulation, tissue growth and development, immunity and cell signal transduction. Further pathway analysis showed that there were significant changes in extracellular matrix receptor interaction, cell / extracellular matrix connection, complement system, cytokine receptor interaction and PI3K-Akt signaling pathway. 2. By using the differentially expressed genes and CMAP database of late and early stage of DN, the candidate drugs such as (parthenolide), lonymine (piperlongumine), 15d-PGJ2 (15-deoxyprostaglandin J _ 2) and LY-294002 (PIBK inhibitor) could reverse the gene changes in patients with advanced DN. It is suggested that these drugs may have the potential of DN therapy. Further literature analysis shows that these drugs have some therapeutic effects on DN and may be used as NF-kB inhibitors. Histone deacetylase inhibitors, PI3K signaling pathway inhibitors or PPAR 緯 agonists play a role in renal protection. Conclusion: the genome-wide expression profile and CMAP database of DN patients can be used to quickly screen the drugs with DN therapeutic potential, and the reliability of the method is verified by literature analysis. Related drugs can be tested in future animal and clinical trials to demonstrate the safety and efficacy of the treatment.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R587.2;R692.9

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