锌指蛋白转录活化因子治疗下肢缺血及对骨骼肌肌纤维重塑的研究
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摘要
第一部分体外制备锌指蛋白转录活化因子
目的：合成与血管内皮生长因子(VEGF)的启动子结合的锌指蛋白转录活化因子(ZFP-ATF).方法：利用锌指蛋白(ZFP)软件工具根据VEGF启动子序列合成ZFP结合区,通过基因克隆实验将合成的ZFP结合区及P65激活区的目的基因克隆到PVAX1质粒中,采用双酶切及DNA测序方法进行目的基因检测。结果：ZFP软件合成的ZFP含有6个锌指基序,酶切方法证实克隆构建的位点在BamHl和Xholl间。测序的目的基因的长度是1100bP,PVAX1是3.0KB。结论：成功合成了PVAX1-ZFP-P65质粒；ZFP-ATF结构包括DNA的特异性结合区及转录激活区,可以特异性的与VEGF启动子结合并激活内源性VEGF基因表达。
第二部分体外细胞实验检测ZFP-ATF对VEGF的作用
目的：在体外细胞水平检测ZFP-ATF对VEGF基因的作用。方法：通过细胞转染的方法将ZFP-ATF、VEGF165转染入Hy926细胞内,之后检测VEGF剪接体形式及蛋白的相对表达浓度。结果：ZFP-ATF主要促进VEGF的主要三种剪接体形式的产生,同时VEGF的蛋白相对浓度要显著高于VEGF165组和对照组(P<0.05)。结论：通过体外细胞实验证实ZFP-ATF可以促进VEGF主要剪接体的生成及更高浓度的VEGF蛋白产生,这种显著的促VEGF作用可能在体内的治疗性血管生成方面会成为有潜力的治疗作用。
第三部分大鼠肠系膜血管生成实验
目的：研究ZFP-ATF在体内对新生血管生成及血管成熟度的作用。方法：将ICR大鼠随机分组(n=8)。在体式显微镜下将大鼠的部分肠系膜取出并拍摄。之后在肠系膜脂肪层内分别注入ZFP-ATF、VEGF165及0.9%的生理盐水,14天后在体式显微镜下对同部位肠系膜血管拍照观察。之后将肠系膜切下进行肠系膜免疫荧光实验,观察新生血管的成熟度。结果：ZFP-ATF组的新生毛细血管数量和功能性血管要显示高于VEGF165、空白组(P<0.05)。在肠系膜免疫荧光实验中,ZFP-ATF组的新生血管为少分支、有完整的外膜覆盖率且直径粗；而VEGF165组的新生血管是分支多、外膜覆盖率不完整且直径细。结论：ZFP-ATF可以促进更多的新生血管的形成,且生成血管因有完整的外膜细胞覆盖而成熟度更佳。
第四部分：构建小鼠缺血模型后构建PLGA优化载体以及对ZFP-ATF在小鼠下肢缺血中的治疗性血管生成作用及对骨骼肌肌纤维类型研究。
目的：研究聚乳酸羟基乙酸共聚物(PLGA)纳米粒子包封肝素优化质粒载体,并检测ZFP-ATF对缺血下肢的促血管生成及对骨骼肌纤维类型的影响。方法：通过单侧股动脉结扎构建小鼠缺血模型。采用高速乳化搅拌法制备PLGA-肝素,检测纳米粒子粒径大小、体外释放时间并对其促血管生成效果进行研究。之后将缺血小鼠随机分成三组(n=8),术后7天在缺血肌肉内注入ZFP-ATF, VEGF165及生理盐水。注入后7天取肌肉组织检测VEGF蛋白,14天后取肌肉组织行免疫组化实验,在21天后取肌肉组织行肌球蛋白重链(MHC)mRNA Real-time实验及肌纤维ATPase染色。
结果：PLGA作为一种优化的纳米粒子载体粒径大小在298nm,体外释放时间长达14天,且在缺血肌肉中发现可以促进侧枝血管的生成。ZFP-ATF中检测到的VEGF蛋白相对表达量明显高于VEGF165、对照组(P<0.05); ZFP-ATF的CD31染色的血管密度要多于其他组(P<0.05)；Real-time PCR显示ZFP-ATF. VEGF165组的腓肠肌和比目鱼肌中的MHC-I型增多, MHC-Iib减少(P<0.05),且ATPase染色显示相同的转变。结论：PLGA与质粒相比是一种良好的体外载体,可以优化载体的转染效率,具有良好的促血管生成效果。且ZFP-ATF的VEGF蛋白高表达和毛细血管浓度增加显示ZFP-ATF在缺血疾病中可能有更强的治疗性血管生成作用；同时骨骼肌肌纤维二型向一型的重塑可能对肌肉的耐久性改善有潜在的临床意义。
Part I Construct the Engineered Zinc Finger Protein-Activating Transcription Factor
Objective:To synthesize the Zinc Finger Protein-Activating Transcription Factor (ZFP-ATF) combining with the Vascular Endothelial Growth Factor (VEGF) promoter. Methods:Firstly, the purposed genes of ZFP binding domain were constructed according to the VEGF promoter sequences with ZFP tools and were cloned into the PVAXI plasmid with P65activating domain. After that, the accuracy and validity were verified with the Endonuclease digestion method and the DNA sequence. Results:The structure of ZFP-ATF contained the DNA binding and activation domain, of which the DNA binding domain was the genes of six ZFP binding domains; the transcription activation domain was from p65unit of the NF-κB in human nuclear factor. Besides, endonuclease digestion results showed the multiple cloning site located between the BamHI and XholI; mealwhile, the DNA sequence results suggested the length of the purposed gene of purposed gene was1000bp, the plasmid was about3.0kb. Conclusion:It is important to choose the correct DNA binding domain and activation domain when constructing the engineered ZFP transcription factor successfully. The innovative and potential point in ZFP-ATF was the specificity of combining with VEGF promoter to stimulate the endogenous VEGF expression.
Part II The effect of ZFP-ATF stimulating the VEGF expression with cell experiment in vitro
Objective:To test the effect of ZFP-ATF influencing the VEGF gene expression with cell experiment in vitro. Methods:the relative amount of VEGF mRNA and VEGF protein were tested after.transfecting the ZFP-ATF and VEGF165into the HY926cells. Results:ZFP-ATF mainly stimulated the main VEGF isoforms, m(?)reover, the relative amount of VEGF protein in ZFP-ATF group was dramatically higher than the sole VEGF165and control groups (P<0.05).Conclusion:ZFP-ATF can promote the main VEGF splice variants and higher VEGF protein with the HY926cell experiment, which illustrated that the powerful effect in endogenous VEGF expression may promote potential and effective therapeutic angiogenesis.
PartⅢ The rat mesenteric angiogenesis experiment
Objective:To research the capillary density and maturity of angiogenesis in ZFP-ATF group in vivo with mesentery. Methods:The ICR rats were randomly divided into three groups(N=8). The mesentery were taken out from abdominal cavity and photoed under stereomicroscope, which was performed again after14days when injected the ZFP-ATF, VEGF165and saline, respectively. In addition to, the same mesenteric artery beds were resected and stained with fluorescence antibody (NG2and Ki-67) to observe the maturity of the neovessels. Results:the capillary density and fractional vessel area in ZFP-ATF group were obviously higher than the VEGF165, saline groups (P<0.05).In mesenteric immunofluorescence experiment, the neovessels in ZFP-ATF group had less branch, integrated pericyte coverage and wide diameter, however, the neovessels in VEGF165group had more branch, incomplete pericyte coverage and narrow diameter.
Conclusion:The ZFP-ATF may dramatically stimulate the increase of the neovessels; more importantly, the maturity of the neovessels in ZFP-ATF group was optimal and effective because of the intergrated pericyte coverage.
Part IV The effect of PLGA nano material as a better carrier and ZFP-ATF stimulating the therapeutic angiogenesis in ischemic limb mice and influencing the skeletal muscle fiber remodeling.
Objective:To study the effect of the PLGA nanomaterial as a better carrier and ZFP-ATF stimulating the angiogenesis in ischemic limb mice model and influencing the skeletal muscle fiber remodeling. Methods:The unilateral ischemic limb mice model were performed with the resection and ligation of femoral artery. Double emulsion-solvent evaporation method was used to synthesize PLGA-heparin nanoparticles. Then test the surface morphology, the average diameter, the loading efficiency and the release time in vitro; then inject the PLGA-heparin into mouse ischemic limbs to observe the perfusion recovery with LDPI at the time of post-ischemic7,14,21, and28days; and finally, test the expression of VEGF and HGF and the number of the neo-vessels in ischemic limbs. After that, the mice were randomly divided into three groups (N=8). The ZFP-ATF, VEGF165and saline were respectively injected into the ischemic muscle7days after the femoral artery resection operation. The relative amount of VEGF protein was evaluated7days after injection, the capillary density was analyzed with immunohistochemical experiment including the CD31and PCNA14days after injection. Besides, the skeletal muscle fiber type was firstly observed21days after receiving the injection according to the MHC mRNA Real-time PCR and ATPase staining. Results:The surface morphology of the PLGA-heparin was smooth, the average diameter was290nm, the loading efficiency was5.35%, and the release period maintained for14days. In animal experiment, the perfusion recovery, VEGF and HGF levels, and capillary density in PLGA-heparin group were significantly higher than the control group. The relative amount of VEGF protein in ZFP-ATF group was higher in ischemic muscle than the VEGF165, salinel groups (P<0.05). The immunohistochemical experiment results showed the capillary density in ZFP-ATF group was obviously more than the VEGF165, saline groups (P<0.05). Besides that, the relative amount of MHC isoforms mRNA showed the increase of MHC-I isoform and decrease of MHC-IIb isoform in Gastrocnemius and Soleus in both ZFP-ATF and VEGF165groups compared with the salinel group(P<0.05), of course, the ATPase staining suggested the constituent ratio of muscle fiber type-I was increased.however, the muscle type-II was reduced by ZFP-ATF and VEGF165groups compared with the salinel group (P<0.05) both in Gastrocnemius and Soleus, though the differences between the ZFP-ATF group and VEGF165group had no statistical significance.. Conclusion:Nanoparticle encapsulating heparin could be successful and efficient in ischemic disease with prolongation its therapeutic effects and stimulating growth factors expression. The ZFP-ATF was of importance in therapeutic angiogenesis in terms of the ischemic disease according to supplying enough neovessels and promoting mature neovessels. Moreover, it was the first research on skeletal muscle fiber type remodeling with the gene therapy. The changes from the type-II to type-I indicated a potential clinical therapy for development of the muscle tolerance activity for the ischemic limb.
目的：合成与血管内皮生长因子(VEGF)的启动子结合的锌指蛋白转录活化因子(ZFP-ATF).方法：利用锌指蛋白(ZFP)软件工具根据VEGF启动子序列合成ZFP结合区,通过基因克隆实验将合成的ZFP结合区及P65激活区的目的基因克隆到PVAX1质粒中,采用双酶切及DNA测序方法进行目的基因检测。结果：ZFP软件合成的ZFP含有6个锌指基序,酶切方法证实克隆构建的位点在BamHl和Xholl间。测序的目的基因的长度是1100bP,PVAX1是3.0KB。结论：成功合成了PVAX1-ZFP-P65质粒；ZFP-ATF结构包括DNA的特异性结合区及转录激活区,可以特异性的与VEGF启动子结合并激活内源性VEGF基因表达。
第二部分体外细胞实验检测ZFP-ATF对VEGF的作用
目的：在体外细胞水平检测ZFP-ATF对VEGF基因的作用。方法：通过细胞转染的方法将ZFP-ATF、VEGF165转染入Hy926细胞内,之后检测VEGF剪接体形式及蛋白的相对表达浓度。结果：ZFP-ATF主要促进VEGF的主要三种剪接体形式的产生,同时VEGF的蛋白相对浓度要显著高于VEGF165组和对照组(P<0.05)。结论：通过体外细胞实验证实ZFP-ATF可以促进VEGF主要剪接体的生成及更高浓度的VEGF蛋白产生,这种显著的促VEGF作用可能在体内的治疗性血管生成方面会成为有潜力的治疗作用。
第三部分大鼠肠系膜血管生成实验
目的：研究ZFP-ATF在体内对新生血管生成及血管成熟度的作用。方法：将ICR大鼠随机分组(n=8)。在体式显微镜下将大鼠的部分肠系膜取出并拍摄。之后在肠系膜脂肪层内分别注入ZFP-ATF、VEGF165及0.9%的生理盐水,14天后在体式显微镜下对同部位肠系膜血管拍照观察。之后将肠系膜切下进行肠系膜免疫荧光实验,观察新生血管的成熟度。结果：ZFP-ATF组的新生毛细血管数量和功能性血管要显示高于VEGF165、空白组(P<0.05)。在肠系膜免疫荧光实验中,ZFP-ATF组的新生血管为少分支、有完整的外膜覆盖率且直径粗；而VEGF165组的新生血管是分支多、外膜覆盖率不完整且直径细。结论：ZFP-ATF可以促进更多的新生血管的形成,且生成血管因有完整的外膜细胞覆盖而成熟度更佳。
第四部分：构建小鼠缺血模型后构建PLGA优化载体以及对ZFP-ATF在小鼠下肢缺血中的治疗性血管生成作用及对骨骼肌肌纤维类型研究。
目的：研究聚乳酸羟基乙酸共聚物(PLGA)纳米粒子包封肝素优化质粒载体,并检测ZFP-ATF对缺血下肢的促血管生成及对骨骼肌纤维类型的影响。方法：通过单侧股动脉结扎构建小鼠缺血模型。采用高速乳化搅拌法制备PLGA-肝素,检测纳米粒子粒径大小、体外释放时间并对其促血管生成效果进行研究。之后将缺血小鼠随机分成三组(n=8),术后7天在缺血肌肉内注入ZFP-ATF, VEGF165及生理盐水。注入后7天取肌肉组织检测VEGF蛋白,14天后取肌肉组织行免疫组化实验,在21天后取肌肉组织行肌球蛋白重链(MHC)mRNA Real-time实验及肌纤维ATPase染色。
结果：PLGA作为一种优化的纳米粒子载体粒径大小在298nm,体外释放时间长达14天,且在缺血肌肉中发现可以促进侧枝血管的生成。ZFP-ATF中检测到的VEGF蛋白相对表达量明显高于VEGF165、对照组(P<0.05); ZFP-ATF的CD31染色的血管密度要多于其他组(P<0.05)；Real-time PCR显示ZFP-ATF. VEGF165组的腓肠肌和比目鱼肌中的MHC-I型增多, MHC-Iib减少(P<0.05),且ATPase染色显示相同的转变。结论：PLGA与质粒相比是一种良好的体外载体,可以优化载体的转染效率,具有良好的促血管生成效果。且ZFP-ATF的VEGF蛋白高表达和毛细血管浓度增加显示ZFP-ATF在缺血疾病中可能有更强的治疗性血管生成作用；同时骨骼肌肌纤维二型向一型的重塑可能对肌肉的耐久性改善有潜在的临床意义。
Part I Construct the Engineered Zinc Finger Protein-Activating Transcription Factor
Objective:To synthesize the Zinc Finger Protein-Activating Transcription Factor (ZFP-ATF) combining with the Vascular Endothelial Growth Factor (VEGF) promoter. Methods:Firstly, the purposed genes of ZFP binding domain were constructed according to the VEGF promoter sequences with ZFP tools and were cloned into the PVAXI plasmid with P65activating domain. After that, the accuracy and validity were verified with the Endonuclease digestion method and the DNA sequence. Results:The structure of ZFP-ATF contained the DNA binding and activation domain, of which the DNA binding domain was the genes of six ZFP binding domains; the transcription activation domain was from p65unit of the NF-κB in human nuclear factor. Besides, endonuclease digestion results showed the multiple cloning site located between the BamHI and XholI; mealwhile, the DNA sequence results suggested the length of the purposed gene of purposed gene was1000bp, the plasmid was about3.0kb. Conclusion:It is important to choose the correct DNA binding domain and activation domain when constructing the engineered ZFP transcription factor successfully. The innovative and potential point in ZFP-ATF was the specificity of combining with VEGF promoter to stimulate the endogenous VEGF expression.
Part II The effect of ZFP-ATF stimulating the VEGF expression with cell experiment in vitro
Objective:To test the effect of ZFP-ATF influencing the VEGF gene expression with cell experiment in vitro. Methods:the relative amount of VEGF mRNA and VEGF protein were tested after.transfecting the ZFP-ATF and VEGF165into the HY926cells. Results:ZFP-ATF mainly stimulated the main VEGF isoforms, m(?)reover, the relative amount of VEGF protein in ZFP-ATF group was dramatically higher than the sole VEGF165and control groups (P<0.05).Conclusion:ZFP-ATF can promote the main VEGF splice variants and higher VEGF protein with the HY926cell experiment, which illustrated that the powerful effect in endogenous VEGF expression may promote potential and effective therapeutic angiogenesis.
PartⅢ The rat mesenteric angiogenesis experiment
Objective:To research the capillary density and maturity of angiogenesis in ZFP-ATF group in vivo with mesentery. Methods:The ICR rats were randomly divided into three groups(N=8). The mesentery were taken out from abdominal cavity and photoed under stereomicroscope, which was performed again after14days when injected the ZFP-ATF, VEGF165and saline, respectively. In addition to, the same mesenteric artery beds were resected and stained with fluorescence antibody (NG2and Ki-67) to observe the maturity of the neovessels. Results:the capillary density and fractional vessel area in ZFP-ATF group were obviously higher than the VEGF165, saline groups (P<0.05).In mesenteric immunofluorescence experiment, the neovessels in ZFP-ATF group had less branch, integrated pericyte coverage and wide diameter, however, the neovessels in VEGF165group had more branch, incomplete pericyte coverage and narrow diameter.
Conclusion:The ZFP-ATF may dramatically stimulate the increase of the neovessels; more importantly, the maturity of the neovessels in ZFP-ATF group was optimal and effective because of the intergrated pericyte coverage.
Part IV The effect of PLGA nano material as a better carrier and ZFP-ATF stimulating the therapeutic angiogenesis in ischemic limb mice and influencing the skeletal muscle fiber remodeling.
Objective:To study the effect of the PLGA nanomaterial as a better carrier and ZFP-ATF stimulating the angiogenesis in ischemic limb mice model and influencing the skeletal muscle fiber remodeling. Methods:The unilateral ischemic limb mice model were performed with the resection and ligation of femoral artery. Double emulsion-solvent evaporation method was used to synthesize PLGA-heparin nanoparticles. Then test the surface morphology, the average diameter, the loading efficiency and the release time in vitro; then inject the PLGA-heparin into mouse ischemic limbs to observe the perfusion recovery with LDPI at the time of post-ischemic7,14,21, and28days; and finally, test the expression of VEGF and HGF and the number of the neo-vessels in ischemic limbs. After that, the mice were randomly divided into three groups (N=8). The ZFP-ATF, VEGF165and saline were respectively injected into the ischemic muscle7days after the femoral artery resection operation. The relative amount of VEGF protein was evaluated7days after injection, the capillary density was analyzed with immunohistochemical experiment including the CD31and PCNA14days after injection. Besides, the skeletal muscle fiber type was firstly observed21days after receiving the injection according to the MHC mRNA Real-time PCR and ATPase staining. Results:The surface morphology of the PLGA-heparin was smooth, the average diameter was290nm, the loading efficiency was5.35%, and the release period maintained for14days. In animal experiment, the perfusion recovery, VEGF and HGF levels, and capillary density in PLGA-heparin group were significantly higher than the control group. The relative amount of VEGF protein in ZFP-ATF group was higher in ischemic muscle than the VEGF165, salinel groups (P<0.05). The immunohistochemical experiment results showed the capillary density in ZFP-ATF group was obviously more than the VEGF165, saline groups (P<0.05). Besides that, the relative amount of MHC isoforms mRNA showed the increase of MHC-I isoform and decrease of MHC-IIb isoform in Gastrocnemius and Soleus in both ZFP-ATF and VEGF165groups compared with the salinel group(P<0.05), of course, the ATPase staining suggested the constituent ratio of muscle fiber type-I was increased.however, the muscle type-II was reduced by ZFP-ATF and VEGF165groups compared with the salinel group (P<0.05) both in Gastrocnemius and Soleus, though the differences between the ZFP-ATF group and VEGF165group had no statistical significance.. Conclusion:Nanoparticle encapsulating heparin could be successful and efficient in ischemic disease with prolongation its therapeutic effects and stimulating growth factors expression. The ZFP-ATF was of importance in therapeutic angiogenesis in terms of the ischemic disease according to supplying enough neovessels and promoting mature neovessels. Moreover, it was the first research on skeletal muscle fiber type remodeling with the gene therapy. The changes from the type-II to type-I indicated a potential clinical therapy for development of the muscle tolerance activity for the ischemic limb.
引文
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