In vivo gene transfer into the lung Application in lung transplantation and therapeutic potential of HGF

体内基因转移到肺中 HGF 在肺移植中的应用和治疗潜力

基本信息

  • 批准号:
    11671320
  • 负责人:
  • 金额:
    $ 2.43万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2000
  • 项目状态:
    已结题

项目摘要

In vivo gene transfer into the lungThe aims of this study are 1) to determine the effect of retransfection of HVJ liposome system and 2) to compare the distribution of gene expression in the transtracheal and transplanted approaches in the setting of lung transplantation. Methods: Plasmid DNA of β-galactosidase (β-gal) were co-encapsulated in liposomes with high mobility group 1 (HMG1) protein, and were introduced into lung tissues by HVJ-mediated membrane fusion. Two groups of SD rats received intratracheal instillation of 0.3 ml of HVJ liposome solution containing 30μg of β-gal gene once on Day 0 (Group Tb-1, n = 4) and 3 times on Day 0-2 (Group Tb-3, n = 4). In another group, (Group Tx n = 3) orthotopic left lung transplantation was performed All isografts were flushed with PBS solution of 20 ml and preserved for 4 hours. HVJ-liposome complex (1.0 ml) containing β-gal gene was added to the flushing solution just before harvesting. Respective controls received HVJ-liposome with empty … More gene cassettes in a corresponding fashion. Two days after administration of β-gal gene, the transfected lungs were fixed and stained with X-Gal. The gene expression and distribution in the lung tissue was quantified by counting the staining cells. Results: There were no gene expression in the control animals. Three repetitive administrations via airway increased the expression in alveolar or airway epithelial cells by 2- to 4 fold compared to the single administration, indicating that the repeated transfection using HVJ-liposome system did not result in reduction of gene transfer efficiency without any inflammatory reaction. Compared to the transtracheal approach, successful gene transfer into the pulmonary endothelial cells using flushing solution as well as moderate degree of transfection into the airway and alveolar cells.Therapeutic potential of HGFHepatocyte growth factor (HGF) was initially identified as a potent mitogen for mature hepatocytes. Recent extensive and diverse studies have demonstrated that HGF has "tropic" roles in regeneration and maintenance First, HGF is a growth factor which promotes cell recovery following damage such as that associated with ischemia and drug toxicity. Second, in an experimental model of fulminant hepatic failure, HGF abrogated Fas-induced hepatocyte damage by eliciting of anti-apoptotic effect. Increased level of anti-apoptic protein BAG-1 (Bcl-2 functional partner) was also found to be associated with increased expression of HGF receptor, which: prevents cell death. Third, HGF may have therapeutic potential by its antifibtotic effects for the liver-fibrosis/cirrhosis, chronic glomelurosclerosis and pulmonary fibrosis.We first investigated the possible role of HGF on compensatory lung growth in mice. The endogenous HGF level in plasma peaked with 2.5 fold increase at day 3 after pneynibectiny, prior to the peak of the PCNA index at day 5. The expression and protein level of HGF in the remaining lungs also increased during this period. The PNCA index was significantly higher at day 3 in the recombinant human (rH)-HGF-treated group and was significantly lower in the antibody (a)-HGF group than in the corresponding controls. These results suggest that the supplement of HGF may accelerate postoneumonectomy compensatory alveolar regeneration while neutralizing HGF may delay this process. Less
本研究的目的是:1)确定HVJ脂质体系统的再转染效果; 2)比较肺移植中经气管和移植途径的基因表达分布。研究方法:将β-半乳糖苷酶(β-gal)质粒DNA与高迁移率族1(HMG 1)蛋白共包封在脂质体中,通过HVJ介导的膜融合将其导入肺组织。Tb-1组(n = 4)和Tb-3组(n = 4)分别于第0天和第0-2天腹腔内滴注含β-gal基因30μg的HVJ脂质体溶液0.3ml。另一组(Tx组n = 3)进行原位左肺移植。所有同种移植物用20 ml PBS溶液冲洗并保存4小时。在收获前将含有β-gal基因的HVJ-脂质体复合物(1.0 ml)添加到冲洗液中。相应的对照接受HVJ-脂质体, ...更多信息 以相应的方式表达基因盒。在给予β-gal基因后两天,固定转染的肺并用X-Gal染色。通过计数染色细胞来定量肺组织中的基因表达和分布。结果:对照组动物无基因表达。与单次给药相比,通过气道重复三次给药使肺泡或气道上皮细胞中的表达增加2至4倍,表明使用HVJ-脂质体系统的重复转染不会导致基因转移效率降低,而不会产生任何炎症反应。与经气管途径相比,使用冲洗液成功地将基因转移到肺内皮细胞中,以及中等程度地转染到气道和肺泡细胞中。HGF的治疗潜力肝细胞生长因子(HGF)最初被鉴定为成熟肝细胞的有效有丝分裂原。最近广泛和多样的研究表明,HGF在再生和维持中具有“向性”作用。首先,HGF是一种生长因子,其促进损伤后的细胞恢复,例如与缺血和药物毒性相关的损伤。第二,在暴发性肝衰竭的实验模型中,HGF通过引发抗凋亡作用来消除Fas诱导的肝细胞损伤。还发现抗凋亡蛋白BAG-1(Bcl-2功能伴侣)水平的增加与HGF受体表达的增加相关,HGF受体防止细胞死亡。第三,HGF对肝纤维化/肝硬化、慢性肾小球硬化和肺纤维化具有潜在的治疗作用。我们首先研究了HGF对小鼠肺代偿性生长的可能作用。血浆中的内源性HGF水平在pneynibectiny后第3天达到峰值,增加2.5倍,在第5天PCNA指数达到峰值之前。在此期间,其余肺中HGF的表达和蛋白水平也增加。与相应的对照组相比,重组人(rH)-HGF治疗组在第3天的PNCA指数显著更高,而抗体(a)-HGF组显著更低。这些结果表明,肝细胞生长因子的补充可能会加速肺切除术后的代偿性肺泡再生,而中和肝细胞生长因子可能会延迟这一过程。少

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Shin-ichi Takeda, E. Wagner, E. R. Weibel, Connie CW. Hsia: "Complete compensatory alveolar growth after right pneumonectomy in immature canines"J. Appl. Physiol..
武田真一、E. 瓦格纳、E. R. 韦贝尔、康妮 CW。
  • DOI:
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  • 影响因子:
    0
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  • 通讯作者:
Kenichi Omori, Shin-ichi Takeda, Shinichiro Miyoshi, Hikaru Matsuda et al.: "Gene expression after HVJ-liposome mediated transfection into the lung: A novel approach lung transplantation"J. Heart Lung Transplant.. 19. 79-79 (2000)
Kenichi Omori、Shin-ichi Takeda、Shinichiro Miyoshi、Hikaru Matsuda 等:“HVJ 脂质体介导的肺转染后的基因表达:一种新的肺移植方法”J.
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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  • 通讯作者:
Yasushi Sakamaki et al.: "Hepatocyte growth factor stimulates proliferarion of respiratory epithelium Cells during postpneumonectomy compensatory lung growth in mice"Am. J. Respir. Mol. Biol.. (in press).
Yasushi Sakamaki 等人:“肝细胞生长因子在小鼠肺切除术后代偿性肺生长过程中刺激呼吸道上皮细胞的增殖”Am。
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Y Sakamaki: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am J Respir Cell Mol Biology. (in press).
Y Sakamaki:“肝细胞生长因子在小鼠肺切除术后代偿性肺生长过程中刺激呼吸道上皮细胞的增殖”Am J Respir Cell Mol Biology。
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    0
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TAKEDA Shin-ichi其他文献

TAKEDA Shin-ichi的其他文献

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{{ truncateString('TAKEDA Shin-ichi', 18)}}的其他基金

Endocrine activity of metanephric xenograft : its potential as a novel donor source for kidney transplantation
后肾异种移植物的内分泌活性:其作为肾移植新供体来源的潜力
  • 批准号:
    19790589
  • 财政年份:
    2007
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
A Fundamental Study on Environmentally Benign Wet-Type Forming Process of Ceramics by Ultrasonic Attenuation Spectroscopy
超声衰减光谱法陶瓷环保湿式成型工艺基础研究
  • 批准号:
    12650671
  • 财政年份:
    2000
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
In vivo gene transfer study for pathogenesis of lung injury. Endothelin and development of obliterative bronchiolitis
肺损伤发病机制的体内基因转移研究。
  • 批准号:
    09671378
  • 财政年份:
    1997
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular genetic research on the peculiar form of Becker Muscular Dystrophy (BMD), where cardiac muscle is preferentially involved
针对贝克尔肌营养不良症(BMD)这一特殊形式的分子遗传学研究,其中心肌优先受累
  • 批准号:
    06670680
  • 财政年份:
    1994
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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Targeting Autocrine Hepatocyte Growth Factor (HGF) Production as a Therapeutic Modality in Acute Myeloid Leukemia (AML)
靶向自分泌肝细胞生长因子 (HGF) 的产生作为急性髓系白血病 (AML) 的治疗方式
  • 批准号:
    10589002
  • 财政年份:
    2022
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    $ 2.43万
  • 项目类别:
Hepatocyte Growth Factor Signaling and Airspace Maintenance
肝细胞生长因子信号传导和空域维护
  • 批准号:
    10316452
  • 财政年份:
    2021
  • 资助金额:
    $ 2.43万
  • 项目类别:
Hepatocyte Growth Factor Signaling and Airspace Maintenance
肝细胞生长因子信号传导和空域维护
  • 批准号:
    10470865
  • 财政年份:
    2021
  • 资助金额:
    $ 2.43万
  • 项目类别:
Hepatocyte Growth Factor Signaling and Airspace Maintenance
肝细胞生长因子信号传导和空域维护
  • 批准号:
    10626872
  • 财政年份:
    2021
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    $ 2.43万
  • 项目类别:
A Hepatocyte Growth Factor In A Spinal Cord Ischemia
脊髓缺血中的肝细胞生长因子
  • 批准号:
    18K16402
  • 财政年份:
    2018
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Protective effects of hepatocyte growth factor during ex vivo lung perfusion on ischemia-reperfusion injury in lung transplantation
离体肺灌注过程中肝细胞生长因子对肺移植缺血再灌注损伤的保护作用
  • 批准号:
    18K16416
  • 财政年份:
    2018
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Immune Microenvironments and Hepatocyte Growth Factor Signaling Interactions in Breast Cancer Disparities
乳腺癌差异中的免疫微环境和肝细胞生长因子信号传导相互作用
  • 批准号:
    10708080
  • 财政年份:
    2017
  • 资助金额:
    $ 2.43万
  • 项目类别:
Immune Microenvironments and Hepatocyte Growth Factor Signaling Interactions in Breast Cancer Disparities
乳腺癌差异中的免疫微环境和肝细胞生长因子信号传导相互作用
  • 批准号:
    10556581
  • 财政年份:
    2017
  • 资助金额:
    $ 2.43万
  • 项目类别:
Hepatocyte growth factor to Improve Functioning in PAD: the HI-PAD Study
肝细胞生长因子可改善 PAD 功能:HI-PAD 研究
  • 批准号:
    9373019
  • 财政年份:
    2017
  • 资助金额:
    $ 2.43万
  • 项目类别:
Establishment of regenerative therapy for dogs using delivery system of hepatocyte growth factor secreted from novel canine mesenchymal stem cells
利用新型犬间充质干细胞分泌的肝细胞生长因子输送系统建立犬再生疗法
  • 批准号:
    16H05037
  • 财政年份:
    2016
  • 资助金额:
    $ 2.43万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
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