甲酰肽受體1（Formyl peptide receptor 1, FPR1）屬于A族G蛋白偶聯(lián)受體，可被菌源性甲?；募安糠植《緛碓吹牡鞍姿せ?，引起嗜中性粒細(xì)胞趨化、脫顆粒和超氧離子釋放,?；罨疐PR1有助于清除病原菌和損傷組織，在先天性免疫反應(yīng)中發(fā)揮重要的作用,。
中國科學(xué)院上海藥物研究所/國家新藥篩選中心,、復(fù)旦大學(xué)和上海交通大學(xué)的科研人員對(duì)該受體開展了藥物基因組學(xué)研究，通過檢測(cè)209名漢族人群FPR1基因的單核苷酸多態(tài)性（Single nucleotide polymorphisms, SNP）構(gòu)建了相應(yīng)的單倍型,，發(fā)現(xiàn)有5個(gè)SNP位點(diǎn)的等位基因頻率與其他人種存在顯著差異,。據(jù)此，他們把呈現(xiàn)漢族人群中主要單倍型的FPR1基因在CHO-Gα16細(xì)胞中表達(dá),，應(yīng)用該受體的選擇性激動(dòng)劑（fNle-Leu-Phe-Nle-Tyr-Lys-fluorescein）評(píng)估各單倍型與環(huán)孢菌素的親和力,。研究表明，環(huán)孢菌素對(duì)帶有V101L多態(tài)性位點(diǎn)的FPR1之親和力及其功能的抑制效應(yīng)明顯高于表型為V101的受體,。這一結(jié)果提示帶有FPR1基因V101L多態(tài)性位點(diǎn)的病人在長期接受環(huán)孢菌素A治療時(shí),，有可能會(huì)因FPR1受體功能被過度抑制而產(chǎn)生未曾關(guān)注過的毒副作用。
由王明偉教授領(lǐng)銜實(shí)施的這項(xiàng)研究歷時(shí)4年,，得到國家重大科技專項(xiàng)的資助,，相關(guān)成果2月4日在著名學(xué)刊Biochemical Journal上在線發(fā)表（http://www.biochemj.org/bj/imps/abs/BJ20121839.htm）。該雜志的編輯認(rèn)為“該論文從藥物基因組學(xué)的探索中產(chǎn)生假說,，并隨之在具體的實(shí)驗(yàn)中進(jìn)行驗(yàn)證,，是開展轉(zhuǎn)化醫(yī)學(xué)研究的一個(gè)很好范例”。（生物谷Bioon.com）
doi:10.1042/BJ20121839
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V101L of human formyl peptide receptor 1 (FPR1) increases the receptor affinity and augments the antagonism mediated by cyclosporins
Caihong Zhou, Yan Zhou, Jia Wang, Yang Feng, Haonan Wang, Jinglun Xue, Yani Chen, Richard D. Ye and Ming-Wei Wang
Genetic variation plays a major role in drug response variability. Cyclosporin A (CsA), a widely used immunosuppressive agent, is a specific antagonist for formyl peptide receptor 1 (FPR1), which is an important G protein-coupled chemoattractant receptor in the innate immune system. In order to study the variable responses of cyclosporins to different FPR1 mutants, we investigated the distribution of human FPR1 haplotypes among 209 healthy Han Chinese subjects. The haplotype pattern in Han Chinese were characterized based on five single nucleotide polymorphisms (SNPs), including rs5030878 (p.T11I), rs2070745 (p.V101L), rs5030880 (p.R190W), rs1042229 (p.N192K) and rs867228 (p.A346E). Receptor binding affinity of cyclosporins to FPR1 haplotypes was assessed using fNle-Leu-Phe-Nle-Tyr-Lys-fluorescein in CHO-Gα16 cells stably transfected with cDNAs encoding the top 12 FPR1 haplotypes in Han Chinese. Variants of FPR1 carrying a single amino acid substitution of leucine for valine at position 101 (p.L101) displayed significantly higher pKi values for CsA and CsH, indicative of an improved receptor affinity. The polymorphism of FPR1 p.L101 also enhanced the inhibitory effects of cyclosporins on fMLF-induced activities including calcium mobilization, cell chemotaxis and MAPK phosphorylation. These results point to a possible complication for clinical use of CsA in patients carrying the p.L101 allele of FPR1.
