组织工程生物人工肌肉释放重组治疗性蛋白质的研究
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摘要
第一部分人生长激素基因表达载体的构建
目的:构建表达人生长激素(hGH)基因的重组载体,为实现hGH基因在鼠骨骼肌成肌细胞的表达奠定基础。
方法:将目的基因hGH亚克隆到载体pcDNA3.0、pLenti6 / V5-D-TOPO、pLgXSN载体上,构建重组载体pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN,并通过酶切,DNA测序鉴定构建载体是否正确。
结果:pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN,三个载体经限制性内切酶分析和DNA测序分析表明:hGH的基因片段和预期相符。
结论:表达人生长激素的重组载体pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN构建成功。
第二部分组织工程生物人工肌肉分泌和释放重组人生长激素
目的:实现人生长激素(hGH)基因在鼠骨骼肌成肌细胞的表达,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉。
方法:(1)建立鼠原代骨骼肌成肌细胞的分离和培养的方法。(2)用pcDNA-hGH转染鼠原代骨骼肌成肌细胞,使用放免的方法检测细胞培养液中hGH的含量,证实pcDNA-hGH转染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(3)用pLenti6/V5- hGH转染人胚肾上皮细胞(293T),blasticidin筛选,收集病毒上清,用高滴度的病毒上清感染鼠原代骨骼肌成肌细胞,使用放免的方法检测成肌细胞培养液中hGH的含量,证实pLenti6/V5-hGH感染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(4)采用二步转染转导法,用E-86和PT67包装细胞包装pLghGHSN, G418筛选,产生稳定的病毒生产细胞线。用高滴度的病毒上清感染鼠原代骨骼肌成肌细胞,使用放免的方法检测成肌细胞培养液中hGH的含量,证实pLghGHSN感染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(5)比较构建的三种载体转染成肌细胞后表达hGH的浓度。用高表达的载体转染成肌细胞,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉,用放射免疫和免疫印迹的方法检测生物人工肌肉的培养基中hGH的表达,验证基因修饰的生物人工肌肉是否能够合成和分泌hGH。
结果:(1)建立了鼠原代骨骼肌成肌细胞的分离和培养的方法。(2)三种载体转染成肌细胞后,hGH的表达浓度分别是:40.41±0.1 ng/L; 58.58±3.31ng/ml;680.58±3.31ng/ml。转染pLghGHSN的成肌细胞表达hGH的浓度最高。(3)用pLghGHSN转染鼠骨骼肌成肌细胞,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉,用放免的方法检测到生物人工肌肉分泌hGH的量为1-2μg/BAM /24h,免疫印迹检测生物人工肌肉分泌的hGH蛋白分子量为22KDa。
结论: pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN转染成肌细胞后可以在成肌细胞有效表达hGH。pLghGHSN转染成肌细胞后表达hGH的浓度最高。hGH基因修饰的生物人工肌肉能够合成和分泌hGH。
第三部分组织工程生物人工肌肉释放重组人生长激素对心肌梗死大鼠心功能的影响
目的:将人生长激素(hGH)基因修饰的生物人工肌肉(BAM)植入心肌梗死大鼠的皮下,观察hGH基因表达和释放对心肌梗死大鼠心功能的影响。
方法:(1)24只SD大鼠随机分为两组,心肌梗死组12只,假手术组12只。(2)心肌梗死组大鼠结扎冠状动脉前降支,建立鼠心肌梗死模型。假手术组只穿线,不结扎。(3)心肌梗死组随机分为治疗组(MI-GH组)和对照组(MI组),假手术组随机分为治疗组(S-GH组)和对照组(S组),结扎冠状动脉的前降支术后及假手术后即刻将基因修饰的BAM植入同种动物的皮下,治疗组植入GH-BAM,对照组植入GFP-BAM。(4)分别于皮下植入生物人工肌肉4周和8周后,用放免的方法检测大鼠血清中hGH和IGF-1的含量,(5)皮下植入生物人工肌肉8周后,用超声心动图检测各组大鼠EF、FS、LVEDD。
结果:(1)分别于4w和8w后用放免的方法检测血清中hGH的浓度:MI-GH组和S-GH组血清hGH和IGF-1的浓度显著高于相应的对照组, P<0.05。(2)8w后超声心动图检测结果:①EF:MI-GH组(65.0±6.5%)与MI组(48.1±6.8%)比较:P<0.05,S-GH组与S组比较:P>0.05;②FS:MI-GH组(41.3±7.4%)与MI组(26.5±7.1 %)比较:P<0.05。S-GH组与S组比较P>0.05;③LVEDD:MI-GH组(7.2±0.42)与MI组(8.25±0.31)比较:P<0.05。S-GH组与S组比较:P>0.05。
结论:(1) hGH基因修饰的生物人工肌肉植入同种动物的皮下后,能够在心肌梗死大鼠体内持续稳定地分泌和释放hGH,并改善心肌梗死大鼠的心功能。(2)基因修饰的生物人工肌肉可能作为一种新的基因治疗方法来调节性补充有生物活性的治疗性蛋白质,纠正某些疾病伴随的神经内分泌失衡状态。
Part one Study on construction of recombinant vector carrying human growth hormone gene
Objective: To construct a recombinant vector carrying human growth hormone (hGH) gene. To set the stage for achieving efficient and stable expression of hGH gene in primary rat skeletal myoblasts.
Methods: (1)The plasmid containing hGH fragment was cleaved by restriction enzyme digestion,and the resultant fragment hGHcDNA was inserted directionally into pcDNA3.0.(2)A pair of primers were designed and synthesized according to human hGH cDNA sequences. pZ12l-hGH-2 was used as a template of PCR reaction. (3)hGH cDNA was subcloned into the vector pLenti6/v5-D-TOPO and pLgXSN.(4)The recombinant vector was identified by restriction endonuclease analysis and DNA sequence analysis.
Results Restriction enzyme and DNA sequencing analysis revealed that hGH gene was correctly inserted into the blank vector pcDNA3.0、pLenti6/v5-D-TOP and pLgXSN.
Conclusions The recombinant vector pcDNA-hGH、PLghGHSN and pLenti6/V5 -hGH were constructed successfully.
Part two Tissue-Engineered Bioartificial muscles Secrete and delivere recombinant human growth hormone
Objective To achieve efficient and stable expression of human growth hormone ( hGH) gene in primary rat skeletal myoblasts. Genetically modified myoblast with hGH will be tissue-engineered into BAM which delivere recombinant protein.
Methods (1)To establish a practical method of isolation and culture of primary rat skeletal myoblasts. (2)Using a cationic polymer Sofast, primary rat myoblasts were transfected by pcDNA-hGH. hGH protein levels in culture medium from the myoblasts were measured with radioimmunoassay.(3)The plasmid pLenti6/V5-hGH was transfected into the human embryonic kideny 293T cells with Lipofectamine 2000,and blasticidin select positive colony, a high-titer retrovirus were obtained as a result.(4)pLghGHSN was packaged by PT67 and E86 packaging cells. Retroviral producer cell line were generated for pLghGHSN after a 2-step transfection. G418 select positive colony, a high-titer retrovirus were obtained.(5)Myoblast were infected by a high-titer lentiviral and retroviral supernatant. The expression of the hGH was detected with radioimmunoassay. To compare the expression of hGH in culture medium from pcDNA-hGH-myoblast、pLenti6/V5-hGH-myoblast、pLghGHSN-myoblast. (6)Myoblast expressed high level hGH were tissue-engineered into BAMs, and rhGH levels in culture medium from BAMs were measured by a radioimmunoassay technique that does not cross-react with rat GH. The expression of protein in culture medium from BAMs was detected by westerblot.
Results (1)The method of isolating and culture of primary rat skeletal myoblasts was established. The levels of the hGH in culture medium from pcDNA-hGH-myoblast、pLenti6/V5-hGH-myoblast、pLghGHSN-myoblast were 40.41±0.1ng/ml; 58.58±3.31 ng/ml; 680.58±3.31ng/ml, respectively. The hGH levels of culture medium were higher in pLghGHSN-myoblast than in pLenti6/V5–hGH-myoblast and pcDNA–hGH -myoblast. Proliferating rat skeletal myoblasts stably transduced with the pLghGHSN were tissue engineered in vitro into bioartificial muscles containing organized postmitotic myofibers secreting 1-2μg of rhGH/day in vitro.
Conclusions The primary rat skeletal muscle cells could be transfected efficiently with pcDNA-hGH、pLenti6/V5-hGH and pLghGHSN,and secreted hGH proteins.hGH gene modifing BAM could secrete and delivere recombinant protein.
Part three Recombinant human growth hormone Secreted From Tissue-Engineered Bioartificial muscle improves Ventricular function in AMI Rat
Objective Heart failure is characterized by a number of nurohormonal abnormalities, including derangements in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling axis. Studies showed that patients with heart failure exhibit a low serum GH and IGF-1 levels. GH administration might improve ventricular function. In the present study, we will examine a new method for delivery of rhGH using genetically modified bioartificial muscles (BAM). To investigate whether the rhGH delivered by this technique improved LV function in rats with CHF.
Methods (1)SD male rats underwent left anterior descending coronary artery so as to establish acute myocardial infarction (AMI) models. Similar surgery was performed in sham-operated rats but without coronary artery ligation.(2)Twelve rats that underwent ligation were randomly divided into 2 equal groups: MI group and MI-GH: MI group received GFP-BAM transplantation; MI-GH group received GH-BAM transplantation; Another 12 rats were used as sham operation group(S group). S group were also randomly divided into 2 equal groups: S group and S-GH, S group received GFP-BAM transplantation; S -GH group received GH-BAM transplantation; (3)Ligation of the left anterior descending branch or sham operation was performed with subcutane implantation of GFP-BAM or GH-BAM. (4)hGH and IGF-1 levels in rat serum were measured by a radioimmunoassay 4 and 8 weeks after treatment. Echocardiography was performed 4 and 8 weeks after treatment.
Results Serum GH and IGF-1 level were significantly higher in both CHF and sham rats treated with GH-BAMs than in those treated with GFP-BAMs. ( P<0.05 for both). There were significantly higher in LV ejection fraction (EF), fractional shortening (FS) in CHF rats treated with GH-BAM compared with CHF rats treated with GFP-BAM (65.0±6.5% verse 48.1±6.8%, 41.3±7.4% verse 26.5±7.1%. P<0.05). There were significantly lower in LV end-diastolic dimension (LVEDD) in CHF rats treated with GH-BAM compared with CHF rats treated with GFP-BAM (7.2±0.42 versus 8.25±0.31, P<0.05). There were no significant differences in EF,FS and LVEDD between S group and S-GH.
Conclusions(1)When implanted subcutaneously into syngeneic rat, genetically modified BAMs delivered a sustained physiologic dose of rhGH and improved LV myocardial function in AMI rat. (2)Genetically modified bioartificial muscles provides a new method delivering recombinant protein for gene therapy.
目的:构建表达人生长激素(hGH)基因的重组载体,为实现hGH基因在鼠骨骼肌成肌细胞的表达奠定基础。
方法:将目的基因hGH亚克隆到载体pcDNA3.0、pLenti6 / V5-D-TOPO、pLgXSN载体上,构建重组载体pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN,并通过酶切,DNA测序鉴定构建载体是否正确。
结果:pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN,三个载体经限制性内切酶分析和DNA测序分析表明:hGH的基因片段和预期相符。
结论:表达人生长激素的重组载体pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN构建成功。
第二部分组织工程生物人工肌肉分泌和释放重组人生长激素
目的:实现人生长激素(hGH)基因在鼠骨骼肌成肌细胞的表达,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉。
方法:(1)建立鼠原代骨骼肌成肌细胞的分离和培养的方法。(2)用pcDNA-hGH转染鼠原代骨骼肌成肌细胞,使用放免的方法检测细胞培养液中hGH的含量,证实pcDNA-hGH转染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(3)用pLenti6/V5- hGH转染人胚肾上皮细胞(293T),blasticidin筛选,收集病毒上清,用高滴度的病毒上清感染鼠原代骨骼肌成肌细胞,使用放免的方法检测成肌细胞培养液中hGH的含量,证实pLenti6/V5-hGH感染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(4)采用二步转染转导法,用E-86和PT67包装细胞包装pLghGHSN, G418筛选,产生稳定的病毒生产细胞线。用高滴度的病毒上清感染鼠原代骨骼肌成肌细胞,使用放免的方法检测成肌细胞培养液中hGH的含量,证实pLghGHSN感染鼠骨骼肌成肌细胞后能够合成和分泌hGH;(5)比较构建的三种载体转染成肌细胞后表达hGH的浓度。用高表达的载体转染成肌细胞,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉,用放射免疫和免疫印迹的方法检测生物人工肌肉的培养基中hGH的表达,验证基因修饰的生物人工肌肉是否能够合成和分泌hGH。
结果:(1)建立了鼠原代骨骼肌成肌细胞的分离和培养的方法。(2)三种载体转染成肌细胞后,hGH的表达浓度分别是:40.41±0.1 ng/L; 58.58±3.31ng/ml;680.58±3.31ng/ml。转染pLghGHSN的成肌细胞表达hGH的浓度最高。(3)用pLghGHSN转染鼠骨骼肌成肌细胞,并将hGH基因修饰的鼠骨骼肌成肌细胞组织工程为生物人工肌肉,用放免的方法检测到生物人工肌肉分泌hGH的量为1-2μg/BAM /24h,免疫印迹检测生物人工肌肉分泌的hGH蛋白分子量为22KDa。
结论: pcDNA-hGH、pLenti6/V5-hGH、pLghGHSN转染成肌细胞后可以在成肌细胞有效表达hGH。pLghGHSN转染成肌细胞后表达hGH的浓度最高。hGH基因修饰的生物人工肌肉能够合成和分泌hGH。
第三部分组织工程生物人工肌肉释放重组人生长激素对心肌梗死大鼠心功能的影响
目的:将人生长激素(hGH)基因修饰的生物人工肌肉(BAM)植入心肌梗死大鼠的皮下,观察hGH基因表达和释放对心肌梗死大鼠心功能的影响。
方法:(1)24只SD大鼠随机分为两组,心肌梗死组12只,假手术组12只。(2)心肌梗死组大鼠结扎冠状动脉前降支,建立鼠心肌梗死模型。假手术组只穿线,不结扎。(3)心肌梗死组随机分为治疗组(MI-GH组)和对照组(MI组),假手术组随机分为治疗组(S-GH组)和对照组(S组),结扎冠状动脉的前降支术后及假手术后即刻将基因修饰的BAM植入同种动物的皮下,治疗组植入GH-BAM,对照组植入GFP-BAM。(4)分别于皮下植入生物人工肌肉4周和8周后,用放免的方法检测大鼠血清中hGH和IGF-1的含量,(5)皮下植入生物人工肌肉8周后,用超声心动图检测各组大鼠EF、FS、LVEDD。
结果:(1)分别于4w和8w后用放免的方法检测血清中hGH的浓度:MI-GH组和S-GH组血清hGH和IGF-1的浓度显著高于相应的对照组, P<0.05。(2)8w后超声心动图检测结果:①EF:MI-GH组(65.0±6.5%)与MI组(48.1±6.8%)比较:P<0.05,S-GH组与S组比较:P>0.05;②FS:MI-GH组(41.3±7.4%)与MI组(26.5±7.1 %)比较:P<0.05。S-GH组与S组比较P>0.05;③LVEDD:MI-GH组(7.2±0.42)与MI组(8.25±0.31)比较:P<0.05。S-GH组与S组比较:P>0.05。
结论:(1) hGH基因修饰的生物人工肌肉植入同种动物的皮下后,能够在心肌梗死大鼠体内持续稳定地分泌和释放hGH,并改善心肌梗死大鼠的心功能。(2)基因修饰的生物人工肌肉可能作为一种新的基因治疗方法来调节性补充有生物活性的治疗性蛋白质,纠正某些疾病伴随的神经内分泌失衡状态。
Part one Study on construction of recombinant vector carrying human growth hormone gene
Objective: To construct a recombinant vector carrying human growth hormone (hGH) gene. To set the stage for achieving efficient and stable expression of hGH gene in primary rat skeletal myoblasts.
Methods: (1)The plasmid containing hGH fragment was cleaved by restriction enzyme digestion,and the resultant fragment hGHcDNA was inserted directionally into pcDNA3.0.(2)A pair of primers were designed and synthesized according to human hGH cDNA sequences. pZ12l-hGH-2 was used as a template of PCR reaction. (3)hGH cDNA was subcloned into the vector pLenti6/v5-D-TOPO and pLgXSN.(4)The recombinant vector was identified by restriction endonuclease analysis and DNA sequence analysis.
Results Restriction enzyme and DNA sequencing analysis revealed that hGH gene was correctly inserted into the blank vector pcDNA3.0、pLenti6/v5-D-TOP and pLgXSN.
Conclusions The recombinant vector pcDNA-hGH、PLghGHSN and pLenti6/V5 -hGH were constructed successfully.
Part two Tissue-Engineered Bioartificial muscles Secrete and delivere recombinant human growth hormone
Objective To achieve efficient and stable expression of human growth hormone ( hGH) gene in primary rat skeletal myoblasts. Genetically modified myoblast with hGH will be tissue-engineered into BAM which delivere recombinant protein.
Methods (1)To establish a practical method of isolation and culture of primary rat skeletal myoblasts. (2)Using a cationic polymer Sofast, primary rat myoblasts were transfected by pcDNA-hGH. hGH protein levels in culture medium from the myoblasts were measured with radioimmunoassay.(3)The plasmid pLenti6/V5-hGH was transfected into the human embryonic kideny 293T cells with Lipofectamine 2000,and blasticidin select positive colony, a high-titer retrovirus were obtained as a result.(4)pLghGHSN was packaged by PT67 and E86 packaging cells. Retroviral producer cell line were generated for pLghGHSN after a 2-step transfection. G418 select positive colony, a high-titer retrovirus were obtained.(5)Myoblast were infected by a high-titer lentiviral and retroviral supernatant. The expression of the hGH was detected with radioimmunoassay. To compare the expression of hGH in culture medium from pcDNA-hGH-myoblast、pLenti6/V5-hGH-myoblast、pLghGHSN-myoblast. (6)Myoblast expressed high level hGH were tissue-engineered into BAMs, and rhGH levels in culture medium from BAMs were measured by a radioimmunoassay technique that does not cross-react with rat GH. The expression of protein in culture medium from BAMs was detected by westerblot.
Results (1)The method of isolating and culture of primary rat skeletal myoblasts was established. The levels of the hGH in culture medium from pcDNA-hGH-myoblast、pLenti6/V5-hGH-myoblast、pLghGHSN-myoblast were 40.41±0.1ng/ml; 58.58±3.31 ng/ml; 680.58±3.31ng/ml, respectively. The hGH levels of culture medium were higher in pLghGHSN-myoblast than in pLenti6/V5–hGH-myoblast and pcDNA–hGH -myoblast. Proliferating rat skeletal myoblasts stably transduced with the pLghGHSN were tissue engineered in vitro into bioartificial muscles containing organized postmitotic myofibers secreting 1-2μg of rhGH/day in vitro.
Conclusions The primary rat skeletal muscle cells could be transfected efficiently with pcDNA-hGH、pLenti6/V5-hGH and pLghGHSN,and secreted hGH proteins.hGH gene modifing BAM could secrete and delivere recombinant protein.
Part three Recombinant human growth hormone Secreted From Tissue-Engineered Bioartificial muscle improves Ventricular function in AMI Rat
Objective Heart failure is characterized by a number of nurohormonal abnormalities, including derangements in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling axis. Studies showed that patients with heart failure exhibit a low serum GH and IGF-1 levels. GH administration might improve ventricular function. In the present study, we will examine a new method for delivery of rhGH using genetically modified bioartificial muscles (BAM). To investigate whether the rhGH delivered by this technique improved LV function in rats with CHF.
Methods (1)SD male rats underwent left anterior descending coronary artery so as to establish acute myocardial infarction (AMI) models. Similar surgery was performed in sham-operated rats but without coronary artery ligation.(2)Twelve rats that underwent ligation were randomly divided into 2 equal groups: MI group and MI-GH: MI group received GFP-BAM transplantation; MI-GH group received GH-BAM transplantation; Another 12 rats were used as sham operation group(S group). S group were also randomly divided into 2 equal groups: S group and S-GH, S group received GFP-BAM transplantation; S -GH group received GH-BAM transplantation; (3)Ligation of the left anterior descending branch or sham operation was performed with subcutane implantation of GFP-BAM or GH-BAM. (4)hGH and IGF-1 levels in rat serum were measured by a radioimmunoassay 4 and 8 weeks after treatment. Echocardiography was performed 4 and 8 weeks after treatment.
Results Serum GH and IGF-1 level were significantly higher in both CHF and sham rats treated with GH-BAMs than in those treated with GFP-BAMs. ( P<0.05 for both). There were significantly higher in LV ejection fraction (EF), fractional shortening (FS) in CHF rats treated with GH-BAM compared with CHF rats treated with GFP-BAM (65.0±6.5% verse 48.1±6.8%, 41.3±7.4% verse 26.5±7.1%. P<0.05). There were significantly lower in LV end-diastolic dimension (LVEDD) in CHF rats treated with GH-BAM compared with CHF rats treated with GFP-BAM (7.2±0.42 versus 8.25±0.31, P<0.05). There were no significant differences in EF,FS and LVEDD between S group and S-GH.
Conclusions(1)When implanted subcutaneously into syngeneic rat, genetically modified BAMs delivered a sustained physiologic dose of rhGH and improved LV myocardial function in AMI rat. (2)Genetically modified bioartificial muscles provides a new method delivering recombinant protein for gene therapy.
引文
1.董文甫,李艳红,岳文斌.上海畜牧兽医通讯. 2006;1:2-4.
2.王学东,吴永全,贾三庆.中国心血管杂志. 2002;7(5):367-369.
3. Weber E, Anderson WF, Kasahara N. Recent advances in retrovirus vector-mediated gene therapy: teaching an old vector new tricks. Curr Opin Mol Ther. 2001;3 (5): 439-53.
4. Romano G, Pacilio C, Giordano A. Gene transfer technology in therapy: current applications and future goals. Stem Cells.1999; 17(4): 191–202.
5. Levy JP, Muldoon RR, Zolotukhin S, et al. Retroviral transfer and expression of a humanized, red-shifted green fluorescent protein gene into human tumor cells. Nat Biotechnol.1996; 4:610-4.
6. Lybarger L, Dempsey D, Franek KJ, et al. Rapid generation and flowcytometric cytometric analysis of stable GFP-expressing cells. Cytometry. 1996; 25:211.
7. Muldoon RR, Levy JP, Kain SR, et al. Tracking and quantitation of retroviral retroviral mediated transfer using a completely humanized, red-shifted green fluorescent protein gene. Biotechniques.1997; 22:162.
8. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996; 272: 263- 267.
9. Naldini L, Blomer U, Gage F H, et al. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. ProcNat1 Acad Sci USA. 1996; 92(21): 11382- 1388.
10. Zufferey R, Nagy D, Mandel R J, et al. Mutiply attenuated lentiviral vector achieved efficient gene delivery in vivo. Nat Biotechnol .1997;15 (9): 871-875.
11. Miyoshi H, Takshashi M, Gage FH, et al. Stable and efficient gene transfer into the retina using an HIV– based lentiviral vector. Proc Natl Acad Sci USA. 1997; 94(19): 10319-10323.
12.Goldman M J, Lee P S, Yang J S, et al. Lentiviral vectors for gene therapy of cystic fibrosis. Hum Gene Thera. 1997; 8: 2261 - 2268.
13.伍志坚,黄海金,梁国栋.用于基因治疗的慢病毒载体.中华实验和临床病毒学杂志.1998; 12(2): 195-198.
14.查锡良.医学分子生物学.第1版.北京:人民卫生出版社.223-224.
15. Salle GL, Robert JJ, Berrard S, et al. An adenovirus vector for gene transfer into neurous and glia in the brain. Science.1993; 259(5097): 988-90.
16. Walther W, Stein U. Viral vectors for gene t ransfer: a review of their use in the treatment of human diseases. Drugs. 2000; 60 (2): 249-271.
17. Kafri T, Morgan D, Krahl T, et al. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: Implications for gene therapy. Proc Natl Acad Sci. 1998; 95: 11377-82.
18. Yang Y, Jooss KU, Su Q, et al. Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther. 1996;3: 137-44.
19.姚二梅,冯泽华,侯云德.腺病毒伴随病毒载体的研究进展.中华实验和临床病毒学杂志.1997;11(1):97-100.
20. Brown WR, Mee PJ, Hong SM. Artificial chromosomes: ideal vectors? Trends Biotechnol. 2000;18(5):218-23.
21.Woolf TM. Therapeutic repair of mutated nucleic acid sequences.Nat Biotechnol. 1998;16(4): 341-4.
22.杨丹,卓忠雄.基因治疗载体研究进展.临床超声医学杂志. 2006; 8(5):296-297.
23.刘娜,刘吉勇.基因治疗中载体的研究进展.山东医药. 2005;45(5):74-75.
24.孙自君,张子彬.心力衰竭的基因治疗进展.滨州医学院学报. 1998;21(4): 410-412.
25.潘君,王远亮,唐丽灵.组织工程研究进展.国外医学生物医学工程分册. 2000;23(5):257-261.
26.何峰颖,张英杰,刘仁光.组织工程在心血管病治疗中的应用.中国心血管病研究杂志.2006;4(5):397-399.
27. Vandenburgh H, Del Tatto MD, Shansky J, et al. Attenuation of skeletal muscle wasting with recombinant human growth hormone secreted from a tissue-engineered bioartificial muscle. Hum Gene Ther. 1998; 9:2555-2564.
28. Yl?-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nature Medicine. 2003; 9: 694-701.
29. Gounis MJ, Spiga MG , Graham R M , et a1.Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Therapy. 2005;12: 762–771.
30. Yongxin L, Shansky J, Del Tatto MD, et al. Recombinant vascular endothelial growth factor secreted from tissue-engineered bioartificial muscles promotes localized angiogenesis. Circulation. 2001; 104: 594-599.
31. Yongxin L, Shansky J, Del Tatto MD, et al. Therapeutic potential of implanted tissue-engineered bioartificial muscles delivering recombinant proteins to the sheep heart. Ann. N. Y. Acad. Sci. 2002; 961: 78-82.
1.曹雪涛,顾健人,刘德培.我国基因治疗的研究前景与战略重点.中华医学杂志. 2001;81(12):705-708.
2.王学东,吴永全,贾三庆.中国心血管杂志. 2002;7(5):367-369.
3.查锡良.医学分子生物学.第1版.北京:人民卫生出版社.223-224.
4. Weber E, Anderson WF, Kasahara N. Recent advances in retrovirus vector-mediated gene therapy: teaching an old vector new tricks. Curr Opin Mol Ther, 2001; 3 (5): 439-53.
5. Romano G, Pacilio C, Giordano A. Gene transfer technology in therapy: current applications and future goals. Stem Cells. 1999; 17(4): 191–202.
6. Levy JP, Muldoon RR, Zolotukhin S, et al. Retroviral transfer and expression of a humanized, red-shifted green fluorescent protein gene into human tumor cells. Nat Biotechnol. 1996; 4: 610-4.
7. Lybarger L, Dempsey D, Franek KJ, et al. Rapid generation and flowcytometric cytometric analysis of stable GFP-expressing cells. Cytometry. 1996, 25: 211-20.
8. Muldoon RR, Levy JP, Kain SR, et al. Tracking and quantitation of retroviral retroviral mediated transfer using a completely humanized, red-shifted green fluorescent protein gene. Biotechniques.1997, 22:162-7.
9. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996; 272: 263-267.
10. Naldini L, Blomer U, Gage FH, et al. Efficient transfe, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector.ProcNat1 Acad Sci USA. 1996; 92(21): 11382-11388.
11. Zufferey R, Nagy D, Mandel RJ, et al. Mutiply attenuated lentiviral vector achieved efficient gene delivery i n vivo. Nat Biotechnol .1997; 15 (9): 871-875.
12. Miyoshi H, Takshashi M, Gage FH, et al. Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. Proc Natl Acad Sci USA. 1997; 94(19): 10319- 0323.
13. Goldman MJ, Lee PS, Yang JS, et al. Lentiviral vectors for gene therapy of cystic fibrosis. Hum Gene Thera. 1997; 8: 2261-2268.
14.伍志坚,黄海金,梁国栋.用于基因治疗的慢病毒载体.中华实验和临床病毒学杂志.1998;12(2): 195-198.
15. Salle GL, Robert JJ, Berrard S, et al. An adenovirus vector for gene transfer into neurous and glia in the brain. Science.1993; 259(5097): 988-90.
16. Walther W, Stein U. Viral vectors for gene t ransfer: a review of their use in the t reatment of human diseases. Drugs. 2000; 60 (2): 249-271.
17. Kafri T, Morgan D, Krahl T, et al. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: Implications for gene therapy. Proc Natl Acad Sci. 1998; 95: 11377-82.
18. Yang Y, Jooss KU, Su Q, et al. Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther. 1996; 3: 137-44
19.姚二梅,冯泽华,侯云德.腺病毒伴随病毒载体的研究进展.中华实验和临床病毒学杂志.1997;11(1): 97-100.
20. Mountain A. Gene therapy: the first decade. Trends Biotechnol. 2000;18(3): 119-28.
21.董文甫,李艳红,岳文斌.上海畜牧兽医通讯. 2006;1: 2-4.
1.孙自君,张子彬.心力衰竭的基因治疗进展滨州医学院学报.1998;21(4)
2. Yl?-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nature Medicine. 2003; 9: 694– 701.
3. Gounis MJ, Spiga MG, Graham RM, et a1.Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Therapy. 2005; 12: 762–771.
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5. Mayer NJ and Rubin SA. Molecular and cellular prospects for repair, augmentation, and replacement of the failing heart. Am Heart J.1997; 134: 577-586.
6. Vandenburgh H, Del Tatto MD, Shansky J, et al. Attenuation of skeletal muscle wasting with recombinant human growth hormone secreted from a tissue-engineered bioartificial muscle. Hum Gene Ther. 1998; 9: 2555-2564.
7. Yongxin L, Shansky J, Del Tatto MD, et al. Recombinant vascular endothelial growth factor secreted from tissue-engineered bioartificial muscles promotes localized angiogenesis. Circulation. 2001; 104: 594-599.
8. Yongxin L, Shansky J, Del Tatto MD, et al. Therapeutic potential of implanted tissue-engineered bioartificial muscles delivering recombinant proteins to the sheep heart. Ann. N. Y. Acad. Sci. 2002; 961: 78-82.
9. Kotoku L and Shounan Y. Gene therapy theraphy by myoblast-mediated gene transfer. Somatic Gene Theraphy. 1995; 8:121-133.
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11.潘君,王远亮,唐丽灵.组织工程研究进展.国外医学生物医学工程分册. 2000;23(5):257-261.
12.何峰颖,张英杰,刘仁光.组织工程在心血管病治疗中的应用.中国心血管病研究杂志.2006;4(5):397-399
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3. Cittadini A, Stro¨mer H, Katz SE, et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and vitro evaluation. Circulation. 1996; 93: 800-829.
4. Jayasankar V, Pirolli TJ, Bish LT, et al. Targeted overexpression of growth hormone by adenoviral gene transfer preserves myocardial function and ventricular geometry in ischemic cardiomyopathy. J Mol and Cell Cardiol. 2004; 36: 531-8.
5. Duerr RL, McKirnan MD, Gim RD, et al. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation. 1996; 93: 2188-2196.
6. O’Driscoll IG, Green DJ, Ireland M, et al . Treatment of end-stage cardiac failure with growth hormone. Lancet, 1997,349:1068.
7. Melmed S, Jackson I, Kleinberg D, et al. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab. 1998; 83: 2646–52.
8. Fukuda I, Hizuka N, Murakami Y, et al. Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women’s Medical University. Intern Med. 2001; 40: 987–92.
9. Yl?-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nature Medicine.2003; 9: 694– 701.
10. Gounis MJ, Spiga MG , Graham RM , et a1.Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Therapy .2005;12: 762–771.
11. Vandenburgh H, Del Tatto MD, shansky J, et al. Attenuation of skeletal muscle wasting with recombinant human growth hormone secreted from a tissue -engineered bioartificial muscle. Hum Gene Ther. 1998; 9: 2555-2564.
12. Cittadini A, Grossman JD, Napo liR, et al. GH attenuates early LV remodeling and imp roves cardiac function in rats with large M I. J Am Coll Cardiol. 1997; 9: 1109.
13. Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996; 334: 809-814.
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20. Yongxin L, Shansky J, Del Tatto MD, et al. Recombinant vascular endothelial growth factor secreted from tissue-engineered bioartificial muscles promotes localized angiogenesis. Circulation. 2001; 104: 594-599.
21. Yongxin L, Shansky J, Del Tatto MD, et al. Therapeutic potential of implanted tissue-engineered bioartificial muscles delivering recombinant proteins to the sheep heart. Ann. N. Y. Acad. Sci. 2002; 961: 78-82.
1. McElhinney DB, Colan SD, Moran AM, et al. Recombinant human growth hormone treatment for dilated cardiomyopathy in children. Pediatrics. 2004; 114: e452-458.
2. Jayasankar V, Pirolli TJ, Bish LT, et al. Targeted overexpression of growth hormone by adenoviral gene transfer preserves myocardial function and ventricular geometry in ischemic cardiomyopathy. J Mol and Cell Cardiol. 2004; 36: 531-8.
3. Kontoleon PE, Anastasiou-Nana MI, Papapetrou PD, et al. Hormonal profile in patients with congestive heart failure. Int J Cardiol. 2003; 87: 179-183.
4. Cittadini A, Stro¨mer H, Katz SE, et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and vitro evaluation. Circulation. 1996; 93: 800-829.
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26. Yang R, Bunting S, Gillett N, et al. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995; 92: 262-7.
27. Duerr RL, Mckrnam D, Ronald D, et al. Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chrohic left ventricular failure in the rat. Circulation. 1996; 93: 2188-2196.
28. CittadiniA, Grossman JD, Napoli R, et al. GH attenuates early LV remodeling and improves cardiac function in rats with large M I. J Am Coll Cardiol. 1997; 29(5): 1109-16.
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50. Volterrani M, Desenzani P, Lorusso R, et al. Haemodynam ic effects of intravenous growth hormone in congestive heart failure. Lancet, 1997, 349(9058): 1067-8.
51. Osterziel KJ, Strohm O, Schuler J, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998; 351(9111): 1233-7.
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57. Yl?-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nature Medicine. 2003; 9: 694-701.
58. Gounis M J, Spiga M G , Graham R M , et a1. Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Therapy. 2005; 12: 762-771.
2.王学东,吴永全,贾三庆.中国心血管杂志. 2002;7(5):367-369.
3. Weber E, Anderson WF, Kasahara N. Recent advances in retrovirus vector-mediated gene therapy: teaching an old vector new tricks. Curr Opin Mol Ther. 2001;3 (5): 439-53.
4. Romano G, Pacilio C, Giordano A. Gene transfer technology in therapy: current applications and future goals. Stem Cells.1999; 17(4): 191–202.
5. Levy JP, Muldoon RR, Zolotukhin S, et al. Retroviral transfer and expression of a humanized, red-shifted green fluorescent protein gene into human tumor cells. Nat Biotechnol.1996; 4:610-4.
6. Lybarger L, Dempsey D, Franek KJ, et al. Rapid generation and flowcytometric cytometric analysis of stable GFP-expressing cells. Cytometry. 1996; 25:211.
7. Muldoon RR, Levy JP, Kain SR, et al. Tracking and quantitation of retroviral retroviral mediated transfer using a completely humanized, red-shifted green fluorescent protein gene. Biotechniques.1997; 22:162.
8. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996; 272: 263- 267.
9. Naldini L, Blomer U, Gage F H, et al. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. ProcNat1 Acad Sci USA. 1996; 92(21): 11382- 1388.
10. Zufferey R, Nagy D, Mandel R J, et al. Mutiply attenuated lentiviral vector achieved efficient gene delivery in vivo. Nat Biotechnol .1997;15 (9): 871-875.
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