气道Orai1通道干预对小鼠实验性变应性鼻炎的影响
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摘要
目的：构建针对小鼠ORAI1基因进行RNA干扰从而下调细胞内Orai1蛋白表达的重组慢病毒Lenti-ORAI1-shRNA,并测定重组慢病毒的感染效率与干扰效率。建立Lenti-ORAI1-shRNA感染小鼠鼻腔的体内模型,并测定其对小鼠鼻黏膜中ORAI1基因的转录抑制效率的动态变化；建立Lenti-ORAI1-shRNA气道内干预变应性鼻炎小鼠模型并观察其对鼻炎症状、小鼠鼻腔局部与全身炎症相关免疫细胞功能的影响并初步探寻其机制。
材料与方法：针对小鼠ORAI1基因序列设计RNA干扰靶序列,合成靶序列的寡聚DNA,与经ClaI及MluI双酶切的pLVTHM慢病毒载体连接,转化大肠杆菌感受态细胞,产生重组RNA干扰慢病毒表达载体,将pRSV-REV质粒、pMDlg-pRRE粒、pMD2.G与pLVTHM/ORAI1-shDNA重组质粒混合感染293T细胞包装慢病毒并测定病毒滴度。用包装好的Lenti-ORAI1-shRNA感染PANC-1细胞,流式细胞分析测定其感染效率,荧光定量PCR检测其对ORAI1基因的转录抑制效率。将BALB/c小鼠随机分为7组,一组为正常对照组,另外六组为Lenti-ORAI1-shRNA干预组。将干预组小鼠麻醉后,鼻腔滴入8μl0.3%溶血卵磷脂,1小时后鼻腔滴入20μl滴度为1×109tu/ml的Lenti-ORAI1-shRNA进行感染。分别于感染1,3,7,14,21,28天后处死小鼠,测定其鼻黏膜ORAI1mRNA水平。将小鼠随机分为5组：正常对照组(normal),正常小鼠Lenti-ORAI1-shRNA干预组(NLI),变应性鼻炎组(AR),变应性鼻炎小鼠Lenti-GFP干预组(AR-GFP),变应性鼻炎小鼠Lenti-ORAI1-shRNA干预组(AR-LI)。后三组小鼠以).5mg/ml OVA/20mg/ml Al(OH)3溶液腹腔注射3次致敏,40mg/ml OVA鼻腔滴入8次激发建立变应性鼻炎小鼠模型,对NLI组与AR-LI组小鼠于首次鼻腔激发前3天鼻腔滴入20gl滴度为1×109tu／ml的Lenti-ORAI1-shRNA进行干预,对AR-GFP小鼠滴入相同剂量及滴度的Lenti-GFP进行干预。计数各组小鼠末次鼻腔激发后10分钟内喷嚏数及挠鼻数,Real-time RT PCR法测定各组小鼠鼻黏膜及脾脏ORAI1、LTC4S、EAR3、 germline Cε与IL-4mRNA水平,Western Blotting法测定各组小鼠鼻黏膜Orai1、IL-33、IL-17E与TSLP及脾脏Orai1蛋白表达水平,免疫组化法观察各组小鼠鼻黏膜、鼻黏膜相关淋巴与脾脏中Orai1表达分布情况。ELISA法测定各组小鼠鼻腔灌洗液与血清中LTC4、ECP、OVA-IgE与IL-4的浓度。
结果：PANC-1细胞经Lenti-ORAI1-shRNA感染后可表达慢病毒所携带的GFP基因而发出绿色荧光,当感染复数为10时,Lenti-ORAI1-shRNA感染PANC-1细胞48小时后感染效率为98.28%,对细胞ORAI1基因的转录抑制效率为90.5%；而用于对照的空载慢病毒在相同条件下感染效率为98.75%,对ORAI1基因的转录抑制效率为-3%。小鼠鼻腔感染Lenti-ORAI1-shRNA后,鼻黏膜ORAI1mRNA水平随感染时间逐渐降低,至第3天时达最低,随后逐渐升高,感染后一月左右Orai1mRNA水平仍低于正常对照组水平。AR-LI组小鼠鼻黏膜与脾脏ORAI1mRNA水平均较AR组下降,其鼻黏膜Orai1蛋白表达水平也低于AR组小鼠,末次鼻腔激发后挠鼻数与喷嚏数较AR组小鼠也都明显减少；AR-GFP组小鼠鼻黏膜与脾脏ORAI1mRNA水平,Orai1表达水平及末次激发后喷嚏数与挠鼻数与AR组小鼠相比均无明显差异。免疫组化结果提示AR-LI组小鼠鼻黏膜上皮层与固有层、鼻黏膜相关淋巴组织、脾脏生发中心等部位Orai1表达均较AR组小鼠减少。AR-LI组小鼠鼻黏膜与脾脏中LTC4S、 EAR3、germline Cε与IL-4的mRNA水平均明显低于AR组小鼠,其鼻腔灌洗液中LTC4、OVA-IgE与IL-4的浓度以及血清中LTC4、ECP、OVA-IgE与IL-4的浓度也均低于AR组小鼠,AR-GFP组小鼠鼻黏膜与脾脏中LTC4S、 EAR3、germline Cε与IL-4的mRNA水平与AR组小鼠无明显差异,其鼻腔灌洗液与血清中LTC4、ECP、OVA-IgE与IL-4的浓度与AR组小鼠也无明显差异。AR组小鼠鼻黏膜中IL-33、IL-17E与TSLP的表达水平均明显高于正常对照组小鼠,AR-LI组小鼠鼻黏膜中IL-33与TSLP的表达水平较AR组有所下降,但IL-17E的表达水平与AR组相比无明显差异。AR-GFP组小鼠鼻黏膜中IL-33、IL-17E与TSLP的表达水平与AR组小鼠相比均无明显差异。
结论：成功构建针对ORAI1基因进行RNA干扰的重组慢病毒Lenti-ORAI1-shRNA; Lenti-ORAI1-shRNA能够成功感染PANC-1细胞并有效抑制ORAI1基因的转录水平。Lenti-ORAI1-shRNA鼻腔滴入可成功感染小鼠鼻黏膜细胞,感染后第3天对ORAI1基因的转录抑制效率达到最高。变应性鼻炎小鼠Lenti-ORAI1-shRNA鼻腔干预后可有效下调其鼻黏膜与脾脏中Orai1表达水平,并减轻其鼻炎症状。下调鼻黏膜中Orai1表达不仅可降低变应性鼻炎小鼠鼻黏膜中肥大细胞、嗜酸性粒细胞、B细胞与Th2细胞中相关炎性介质的转录与释放,也可降低全身如脾脏与血清中上述免疫细胞炎性介质的转录与释放。Lenti-ORAI1-shRNA鼻腔干预对小鼠变应性鼻炎炎症的抑制作用可能与其阻碍了鼻黏膜上皮细胞中IL-33与TSLP蛋白的合成和表达有关
Objective:To construct and produce the recombinant lentivirus Lenti-Orai1-shRNA which can inhibit the transcription of murine ORAI1gene through RNA interference, and to detect its infection efficacy and inhibition efficacy of ORAI1transcription of the recombinant lentivirus. To establish the murine model of Lenti-ORAI1-shRNA infection in the nasal cavity in vivo, and to determine the kinetics of the inhibition efficacy of Orail transcription in the nasal mucosas by this method. To set up the establishment of the model of Lenti-ORAI1-shRNA infection in the nasal cavity of AR mice and assess its impact on AR symptoms, functions in the immune cells in the nasal mucosa and the spleen and to study its mechanisms primarily.
Methods:The interfering sequence that corresponded to the ORAI1gene was designed, chemically synthesized and then inserted into the lentiviral vector pLVTHM which had been restriction digested by the restriction enzymes MluI and Clal. The resultant clones were verified by sequencing. The recombinant lentiviruses were produced by co transfection of293T cells with the interferential plasmid, the pRsv-REV plasmid, the pMDLg-pRRE plasmid, and the pMD2.G plasmid according to standard protocols. the PANC cells were infected with lenti-ORAI1-shRNA and the viral infection efficacy was determined by fluorescence-activated cell sorting for GFP expressed in the transfected cells. The viral inhibition efficacy of ORAI1transcription was analyzed by Real-time RT PCR. Twenty-one BALB/c mice were randomly devided into seven groups, one of which was normal control group and the other6groups were Lenti-ORAI1-shRNA intervention groups. On day0, after the mice in the intervention groups were anesthetized,8μl lysophosphatidylcholine (in PBS,0.3%w/v) was delivered into the nasal airway via inhalation-driven instillation. The lentivirus (1×109tu/ml) were delivered into the nostrils of the mice1h after LPC delivery. The transfected mice were sacrificed on day1, day3, day7, day14, day21, day28, the mRNA levels of ORAI1in their nasal mucosas were measured using real-time RT-PCR. The mice were ramdomly devided into five groups:normal group (normal), normal mice with Lenti-ORAI1-shRNA intervention (NLI), AR mice (AR), AR mice with Lenti-GFP intervention (AR-GFP), AR mice with Lenti-ORAI1- shRNA intervention (AR-LI). The mice in the last three groups were sensitized by intraperitoneal injection with0.2ml of0.5mg/ml OVA/20mg/ml Al(OH)3solution for3times, and then were challenged by inhalation-driven instillation with20μl of40mg/ml OVA solution for8times. NLI and AR-LI mice accepted nasal instillation with20μl of Lenti-ORAI1-shRNA (1×109tu/ml)3days before the first challenge. AR-GFP mice received nasal instillation with the same dose of Lenti-GFP. The nasal symptoms of each mouse were evaluated by counting the number of sneezes and episodes of nasal rubbing during the10min immediately after the last intranasal challenge. The level of ORAI1, LTC4S, EAR3, germline Cε and IL-4mRNA in the nasal mucosa and spleen in each mice were measured using real-time RT-PCR. The level of Orai1, IL-33, IL-17E and TSLP expressions in the nasal mucosas and Orail expression in spleen in each mice were detected using Western Blotting. The distribution and intensity of Orai1expression in the nasal mucosa, NALT, and spleen in each mice were determined using immunohistochemical staining. Total and differential cell (epithelial cell, lympocyte, eosinophil and neutrophil) numbers were counted in nasal lavage fluid (NLF) obtained from each mice. The concentration of LTC4, ECP, OVA-IgE and IL-4in the NLF and serum in each mice were detected using ELISA.
Resutls:The expression of GFP could be detected in PANC cells48hours after infected with Lenti-ORAI1-shRNA. When the multiplicity of infection is10, the transfection efficacy of Lenti-ORAI1is98.28%, and the transfection efficacy of Lenti-GFP is98.75%; and the inhibition efficacy of Lenti-ORAI1is90.5%, and that of lenti-GFP is-1.4%. After nasal infection with Lenti-ORAI1-shRNA, the ORAI1mRNA in the nasal mucosas of the mice reached the lowest level3days after the infection, and was still lower than the normal control group1month after the infection. The levels of ORAI1mRNA in the nasal mucosas and spleens of AR-LI mice were lower compared with the AR mice, and the Orail expression level in the nasal mucosas was also lower than AR mice, and their counts of sneezes and nasal rubbing were also fewer compared to AR mice. The expressions of Orai1in the cells in the epithelial layer and lamina propria of nasal mucosa, NALT and the germinal center of spleen of the AR-LI mice were decreased compared to the AR mice. The levels of LTC4S, EAR3, germline Cε and IL-4mRNA in the nasal mucosas and spleens of AR-LI mice were reduced compared with the AR mice, and the concentrations of LTC4, OVA-IgE and IL-4in NLF, the concentrations of LTC4, ECP, OVA-IgE and IL-4in serum were also decrease compared to AR mice. The expression levels of IL-33, IL-17E and TSLP were all higer in AR mice compared with normal controls, and the expressions of IL-33and TSLP were reduced in AR-LI mice.
Conclusion:The recombinant lentivirus Lenti-Orail-shRNA was successfully produced, and it could effectively infect PANC cells and inhibit the transcription of murine ORAI1gene through RNA interference. Innasal instillation with Lenti-ORAI1-shRNA could effectively infect the cells in the epithelial layer of nasal mucosa. The inhibition efficacy of ORAI1transcription in nasal mucosa reached the highest level3days after the infection. Lenti-ORAI1-shRNA intervention in the nasal cavities of AR mice could downregulate the Orai1expressions in their nasal mucosas and spleens, and alleviated their AR symptoms. Downregulation of Orai1expression in the nasal mucosa of AR mice not only could reduce the inflammatory cells in NLF, but also could reduce the inflammatory mediators synthesis and release in mast cells, eosinophils, B cells and Th2cells. The inhibition of IL-33and TSLP synthesis in the nasal epithelial cells by Lenti-ORAI1-shRNA might be the reasons for its effect of reducing the immune cells responses in AR mice.
材料与方法：针对小鼠ORAI1基因序列设计RNA干扰靶序列,合成靶序列的寡聚DNA,与经ClaI及MluI双酶切的pLVTHM慢病毒载体连接,转化大肠杆菌感受态细胞,产生重组RNA干扰慢病毒表达载体,将pRSV-REV质粒、pMDlg-pRRE粒、pMD2.G与pLVTHM/ORAI1-shDNA重组质粒混合感染293T细胞包装慢病毒并测定病毒滴度。用包装好的Lenti-ORAI1-shRNA感染PANC-1细胞,流式细胞分析测定其感染效率,荧光定量PCR检测其对ORAI1基因的转录抑制效率。将BALB/c小鼠随机分为7组,一组为正常对照组,另外六组为Lenti-ORAI1-shRNA干预组。将干预组小鼠麻醉后,鼻腔滴入8μl0.3%溶血卵磷脂,1小时后鼻腔滴入20μl滴度为1×109tu/ml的Lenti-ORAI1-shRNA进行感染。分别于感染1,3,7,14,21,28天后处死小鼠,测定其鼻黏膜ORAI1mRNA水平。将小鼠随机分为5组：正常对照组(normal),正常小鼠Lenti-ORAI1-shRNA干预组(NLI),变应性鼻炎组(AR),变应性鼻炎小鼠Lenti-GFP干预组(AR-GFP),变应性鼻炎小鼠Lenti-ORAI1-shRNA干预组(AR-LI)。后三组小鼠以).5mg/ml OVA/20mg/ml Al(OH)3溶液腹腔注射3次致敏,40mg/ml OVA鼻腔滴入8次激发建立变应性鼻炎小鼠模型,对NLI组与AR-LI组小鼠于首次鼻腔激发前3天鼻腔滴入20gl滴度为1×109tu／ml的Lenti-ORAI1-shRNA进行干预,对AR-GFP小鼠滴入相同剂量及滴度的Lenti-GFP进行干预。计数各组小鼠末次鼻腔激发后10分钟内喷嚏数及挠鼻数,Real-time RT PCR法测定各组小鼠鼻黏膜及脾脏ORAI1、LTC4S、EAR3、 germline Cε与IL-4mRNA水平,Western Blotting法测定各组小鼠鼻黏膜Orai1、IL-33、IL-17E与TSLP及脾脏Orai1蛋白表达水平,免疫组化法观察各组小鼠鼻黏膜、鼻黏膜相关淋巴与脾脏中Orai1表达分布情况。ELISA法测定各组小鼠鼻腔灌洗液与血清中LTC4、ECP、OVA-IgE与IL-4的浓度。
结果：PANC-1细胞经Lenti-ORAI1-shRNA感染后可表达慢病毒所携带的GFP基因而发出绿色荧光,当感染复数为10时,Lenti-ORAI1-shRNA感染PANC-1细胞48小时后感染效率为98.28%,对细胞ORAI1基因的转录抑制效率为90.5%；而用于对照的空载慢病毒在相同条件下感染效率为98.75%,对ORAI1基因的转录抑制效率为-3%。小鼠鼻腔感染Lenti-ORAI1-shRNA后,鼻黏膜ORAI1mRNA水平随感染时间逐渐降低,至第3天时达最低,随后逐渐升高,感染后一月左右Orai1mRNA水平仍低于正常对照组水平。AR-LI组小鼠鼻黏膜与脾脏ORAI1mRNA水平均较AR组下降,其鼻黏膜Orai1蛋白表达水平也低于AR组小鼠,末次鼻腔激发后挠鼻数与喷嚏数较AR组小鼠也都明显减少；AR-GFP组小鼠鼻黏膜与脾脏ORAI1mRNA水平,Orai1表达水平及末次激发后喷嚏数与挠鼻数与AR组小鼠相比均无明显差异。免疫组化结果提示AR-LI组小鼠鼻黏膜上皮层与固有层、鼻黏膜相关淋巴组织、脾脏生发中心等部位Orai1表达均较AR组小鼠减少。AR-LI组小鼠鼻黏膜与脾脏中LTC4S、 EAR3、germline Cε与IL-4的mRNA水平均明显低于AR组小鼠,其鼻腔灌洗液中LTC4、OVA-IgE与IL-4的浓度以及血清中LTC4、ECP、OVA-IgE与IL-4的浓度也均低于AR组小鼠,AR-GFP组小鼠鼻黏膜与脾脏中LTC4S、 EAR3、germline Cε与IL-4的mRNA水平与AR组小鼠无明显差异,其鼻腔灌洗液与血清中LTC4、ECP、OVA-IgE与IL-4的浓度与AR组小鼠也无明显差异。AR组小鼠鼻黏膜中IL-33、IL-17E与TSLP的表达水平均明显高于正常对照组小鼠,AR-LI组小鼠鼻黏膜中IL-33与TSLP的表达水平较AR组有所下降,但IL-17E的表达水平与AR组相比无明显差异。AR-GFP组小鼠鼻黏膜中IL-33、IL-17E与TSLP的表达水平与AR组小鼠相比均无明显差异。
结论：成功构建针对ORAI1基因进行RNA干扰的重组慢病毒Lenti-ORAI1-shRNA; Lenti-ORAI1-shRNA能够成功感染PANC-1细胞并有效抑制ORAI1基因的转录水平。Lenti-ORAI1-shRNA鼻腔滴入可成功感染小鼠鼻黏膜细胞,感染后第3天对ORAI1基因的转录抑制效率达到最高。变应性鼻炎小鼠Lenti-ORAI1-shRNA鼻腔干预后可有效下调其鼻黏膜与脾脏中Orai1表达水平,并减轻其鼻炎症状。下调鼻黏膜中Orai1表达不仅可降低变应性鼻炎小鼠鼻黏膜中肥大细胞、嗜酸性粒细胞、B细胞与Th2细胞中相关炎性介质的转录与释放,也可降低全身如脾脏与血清中上述免疫细胞炎性介质的转录与释放。Lenti-ORAI1-shRNA鼻腔干预对小鼠变应性鼻炎炎症的抑制作用可能与其阻碍了鼻黏膜上皮细胞中IL-33与TSLP蛋白的合成和表达有关
Objective:To construct and produce the recombinant lentivirus Lenti-Orai1-shRNA which can inhibit the transcription of murine ORAI1gene through RNA interference, and to detect its infection efficacy and inhibition efficacy of ORAI1transcription of the recombinant lentivirus. To establish the murine model of Lenti-ORAI1-shRNA infection in the nasal cavity in vivo, and to determine the kinetics of the inhibition efficacy of Orail transcription in the nasal mucosas by this method. To set up the establishment of the model of Lenti-ORAI1-shRNA infection in the nasal cavity of AR mice and assess its impact on AR symptoms, functions in the immune cells in the nasal mucosa and the spleen and to study its mechanisms primarily.
Methods:The interfering sequence that corresponded to the ORAI1gene was designed, chemically synthesized and then inserted into the lentiviral vector pLVTHM which had been restriction digested by the restriction enzymes MluI and Clal. The resultant clones were verified by sequencing. The recombinant lentiviruses were produced by co transfection of293T cells with the interferential plasmid, the pRsv-REV plasmid, the pMDLg-pRRE plasmid, and the pMD2.G plasmid according to standard protocols. the PANC cells were infected with lenti-ORAI1-shRNA and the viral infection efficacy was determined by fluorescence-activated cell sorting for GFP expressed in the transfected cells. The viral inhibition efficacy of ORAI1transcription was analyzed by Real-time RT PCR. Twenty-one BALB/c mice were randomly devided into seven groups, one of which was normal control group and the other6groups were Lenti-ORAI1-shRNA intervention groups. On day0, after the mice in the intervention groups were anesthetized,8μl lysophosphatidylcholine (in PBS,0.3%w/v) was delivered into the nasal airway via inhalation-driven instillation. The lentivirus (1×109tu/ml) were delivered into the nostrils of the mice1h after LPC delivery. The transfected mice were sacrificed on day1, day3, day7, day14, day21, day28, the mRNA levels of ORAI1in their nasal mucosas were measured using real-time RT-PCR. The mice were ramdomly devided into five groups:normal group (normal), normal mice with Lenti-ORAI1-shRNA intervention (NLI), AR mice (AR), AR mice with Lenti-GFP intervention (AR-GFP), AR mice with Lenti-ORAI1- shRNA intervention (AR-LI). The mice in the last three groups were sensitized by intraperitoneal injection with0.2ml of0.5mg/ml OVA/20mg/ml Al(OH)3solution for3times, and then were challenged by inhalation-driven instillation with20μl of40mg/ml OVA solution for8times. NLI and AR-LI mice accepted nasal instillation with20μl of Lenti-ORAI1-shRNA (1×109tu/ml)3days before the first challenge. AR-GFP mice received nasal instillation with the same dose of Lenti-GFP. The nasal symptoms of each mouse were evaluated by counting the number of sneezes and episodes of nasal rubbing during the10min immediately after the last intranasal challenge. The level of ORAI1, LTC4S, EAR3, germline Cε and IL-4mRNA in the nasal mucosa and spleen in each mice were measured using real-time RT-PCR. The level of Orai1, IL-33, IL-17E and TSLP expressions in the nasal mucosas and Orail expression in spleen in each mice were detected using Western Blotting. The distribution and intensity of Orai1expression in the nasal mucosa, NALT, and spleen in each mice were determined using immunohistochemical staining. Total and differential cell (epithelial cell, lympocyte, eosinophil and neutrophil) numbers were counted in nasal lavage fluid (NLF) obtained from each mice. The concentration of LTC4, ECP, OVA-IgE and IL-4in the NLF and serum in each mice were detected using ELISA.
Resutls:The expression of GFP could be detected in PANC cells48hours after infected with Lenti-ORAI1-shRNA. When the multiplicity of infection is10, the transfection efficacy of Lenti-ORAI1is98.28%, and the transfection efficacy of Lenti-GFP is98.75%; and the inhibition efficacy of Lenti-ORAI1is90.5%, and that of lenti-GFP is-1.4%. After nasal infection with Lenti-ORAI1-shRNA, the ORAI1mRNA in the nasal mucosas of the mice reached the lowest level3days after the infection, and was still lower than the normal control group1month after the infection. The levels of ORAI1mRNA in the nasal mucosas and spleens of AR-LI mice were lower compared with the AR mice, and the Orail expression level in the nasal mucosas was also lower than AR mice, and their counts of sneezes and nasal rubbing were also fewer compared to AR mice. The expressions of Orai1in the cells in the epithelial layer and lamina propria of nasal mucosa, NALT and the germinal center of spleen of the AR-LI mice were decreased compared to the AR mice. The levels of LTC4S, EAR3, germline Cε and IL-4mRNA in the nasal mucosas and spleens of AR-LI mice were reduced compared with the AR mice, and the concentrations of LTC4, OVA-IgE and IL-4in NLF, the concentrations of LTC4, ECP, OVA-IgE and IL-4in serum were also decrease compared to AR mice. The expression levels of IL-33, IL-17E and TSLP were all higer in AR mice compared with normal controls, and the expressions of IL-33and TSLP were reduced in AR-LI mice.
Conclusion:The recombinant lentivirus Lenti-Orail-shRNA was successfully produced, and it could effectively infect PANC cells and inhibit the transcription of murine ORAI1gene through RNA interference. Innasal instillation with Lenti-ORAI1-shRNA could effectively infect the cells in the epithelial layer of nasal mucosa. The inhibition efficacy of ORAI1transcription in nasal mucosa reached the highest level3days after the infection. Lenti-ORAI1-shRNA intervention in the nasal cavities of AR mice could downregulate the Orai1expressions in their nasal mucosas and spleens, and alleviated their AR symptoms. Downregulation of Orai1expression in the nasal mucosa of AR mice not only could reduce the inflammatory cells in NLF, but also could reduce the inflammatory mediators synthesis and release in mast cells, eosinophils, B cells and Th2cells. The inhibition of IL-33and TSLP synthesis in the nasal epithelial cells by Lenti-ORAI1-shRNA might be the reasons for its effect of reducing the immune cells responses in AR mice.
引文
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[1]Zhang SL, Yu Y, Roos J et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature, 2005,437:902-905.
[2]Park CY, Hoover PJ, Mullins FM et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1[J]. Cell,2009,136: 876-890.
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[4]Feske S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol,2007,7:690-702.
[5]Gwack Y, Feske S, Srikanth S et al. Signaling to transcription:store-operated Ca2+ entry and NFAT activation in lymphocytes [J]. Cell Calcium,2007,42:145-156.
[6]Feske S. ORAI1 and STIM1 deficiency in human and mice:roles of store-operated Ca2+ entry in the immune system and beyond[J]. Immunol Rev,2009, 231:189-209.
[7]Lin L, Zheng C, Zhang L et al.2-Aminoethoxydiphenyl borate administration into the nostril alleviates murine allergic rhinitis[J]. Am J Otolaryngol,2011, 32:318-328.
[8]Vig M, Peinelt C, Beck A et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry[J]. Science,2006,312:1220-1223.
[9]Vig M, DeHaven WI, Bird GS et al. Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels[J]. Nat Immunol,2008,9:89-96.
[10]Gwack Y, Srikanth S, Oh-Hora M et al. Hair loss and defective Tand B-cell function in mice lacking ORAI1 [J]. Mol Cell Biol,2008,28:5209-5222.
[11]Kim VN. RNA interference in functional genomics and medicine[J]. J Korean Med Sci,2003,18:309-318.
[12]Elbashir SM, Harborth J, Lendeckel W et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J]. Nature,2001,411: 494-498.
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