Researches on novel techniques of organ-selective gene therapy in thoracic surgery

胸外科器官选择性基因治疗新技术研究

• 批准号: 11557100
• 负责人: MATSUDA Hikaru
• 金额: $ 8.64万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557100/
• 关键词: Hepatocyte growth factor (HGF); in vivo genetrausfection; HVJ-liposome; Dilated cardiomyopathy (DCM); Myocardial fibrosis; Apoptosis; Angiogenesis; Gene therapy; 虚血再灌流障害

Heart failure, caused by various cardiac disorders such as dilated cardiomyopathy (DCM) and myocardial infarction, is the leading cause of death in developed countries, but no effective treatment except for the *ardic transplantation has been existed. Heart failure is pathophysiologically characterized by structural *modeling of the myocardium associated with myocyte hypertrophy, cell death and excess deposition of extracellular matrix, which causes functional impairment. Therefore, such a remodeling has emerged as a new therapeutic target of heart failure to improve the morbidity and mortality of the disease. Hepatocyte growth factor, originally cloned as a potent mitogen for mature hepatocytes, has angiogenic, anti-apoptotic and anti-fibrotic activities in various disease models, albeit not proved in the heart. In this research, we elucidated the role of HGF in the heart in the following points ; 1) We newly identified HGF as an endogenous cardioprotective factor, as HGF and c-Met/HG … More F receptor was rapidly upregulated after ischemia-reperfusion injury and HGF-administration significantly suppressed the pathological progression in ischemia-reperfusion injury. 2) In end-stage of DCM hamsters, the myocardial TGF-β1 levels, that is thought to be a crucial fibrogenic factor in chronic fibrotic disorders, increased, whereas the myocardial HGF levels significantly decreased. When the hamsters received daily administration with recombinant human HGF for 3 weeks, myocardial fibrotic area were significantly decreased, whereas the myocyte cross-sectional area was significantly increased. Moreover, the level of TGF-β1 and type I and III collagen mRNA were down-regulated and the progression of cardiac dysfunction was significantly inhibited. 3) When HGF gene was transfected into canine myocardium of rapid-pacing induced DCM, promoted the recovery in LV function, LV wall thickness, cell diameter, and angiogenesis and decreased the fibrosis and cardiomyocytes apoptosis. Our findings suggest that HGF or HGF gene therapy may be a novel therapeutic strategy for heart failure. Less

心力衰竭是由扩张型心肌病（DCM）和心肌梗死等多种心脏疾病引起的，是发达国家的首要死亡原因，但除了心脏移植外，尚无有效的治疗方法。心力衰竭的病理生理学特征是与心肌细胞肥大、细胞死亡和细胞外基质过度沉积相关的心肌结构模型，从而导致功能障碍。因此，这种重塑已成为心力衰竭的新治疗靶点，以改善该疾病的发病率和死亡率。肝细胞生长因子最初被克隆为成熟肝细胞的有效有丝分裂原，在各种疾病模型中具有血管生成、抗凋亡和抗纤维化活性，尽管尚未在心脏中得到证实。在这项研究中，我们从以下几点阐明了 HGF 在心脏中的作用； 1）我们新发现HGF是一种内源性心脏保护因子，因为HGF和c-Met/HG F受体在缺血再灌注损伤后迅速上调，并且HGF给药显着抑制了缺血再灌注损伤的病理进展。 2)在DCM仓鼠的终末期，心肌TGF-β1水平升高，而心肌TGF-β1被认为是慢性纤维化疾病的关键纤维形成因子，而心肌HGF水平显着降低。当仓鼠每日给予重组人HGF连续3周时，心肌纤维化面积显着减少，而肌细胞横截面积显着增加。此外，TGF-β1以及I型和III型胶原mRNA的水平下调，心功能障碍的进展受到显着抑制。 3)将HGF基因转染至快节奏诱导的DCM犬心肌后，促进左心室功能、左心室壁厚度、细胞直径和血管生成的恢复，并减少纤维化和心肌细胞凋亡。我们的研究结果表明，HGF 或 HGF 基因治疗可能是心力衰竭的一种新型治疗策略。较少的

项目成果

Suzuki K et al.: "Reconstituted fusion liposomes for gene transfer in vivo and in vivo."Gene Therapy and Regulation.. 1. 65-77 (2000)

Suzuki K 等人：“用于体内和体内基因转移的重构融合脂质体。”基因治疗和调节.. 1. 65-77 (2000)

Nakamura T.Sawa Y.Matsuda H. et al.: "Myocardial protection from ischemia/reperfusion iujury by endogenous and exogenous HGF"J Clin Invest. 106. 1511-1519 (2000)

Nakamura T.Sawa Y.Matsuda H. 等人：“内源性和外源性 HGF 对心肌缺血/再灌注损伤的保护”J Clin Invest。

Kitagawa-Sakakida S.et al.: "Active Cell Migration in Retransplanted Rat Cardiac Allografts during the Course of Chronic Rejection"The Journal of Heart and Lung Transplantation. 19(6). 584-590 (2000)

Kitakawa-Sakakida S.et al.：“慢性排斥过程中重新移植的大鼠同种异体心脏移植物中的活性细胞迁移”心肺移植杂志。

Hayashi Y.et al.: "P-Selectin Monoclonal Antibody May Attenuate the Whole Body Inflammatory Response Induced by Cardiopulmonary Bypass."ASAIO J. 46. 334-337 (2000)

Hayashi Y.等人：“P-选择素单克隆抗体可以减弱心肺旁路引起的全身炎症反应。”ASAIO J. 46. 334-337 (2000)

Sawa Y.,Ohata T.,Takagi M.,Suhara H.,Matsuda H.: "Development of hybrid artificial lung with gene transfected biological cells."The Japanese Society for Artificial Organs. 3. 1-4 (2000)

Sawa Y.、Ohata T.、Takagi M.、Suhara H.、Matsuda H.：“用基因转染的生物细胞开发混合人工肺。”日本人工器官学会。