Genetic control of apoptosis in developing pulmonary fibrosis

肺纤维化过程中细胞凋亡的遗传控制

• 批准号: 11670591
• 负责人: SETOGUCHI Yasuhiro
• 金额: $ 2.3万
• 依托单位: JUNTENDO UNIVERSITY
• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670591/
• 关键词: Pulmonary fibrosis; apeptosis; Gene transfer; Gene therapy; Fas; Fas-L; FADD; Adenovirus vecror; アデノウイルスベクター; 間質性肺炎; 遺伝子導入; FasL; FADD

Upregulation of Fas and FasL expression in bronchiolar and alveolar epithelial cells Was found in patients with pulmonary fibrosis. In Bleomycin-treated experimental animal, apoptosis in lung tissue through the interaction of Fas-FasL contributes to development of pulmonary fibrosis. Fag are cell surface molecules that trigger apoptosis or inflammation upon engagement by specific receptor or antibody. FADD is recruited to the cytoplasmic domain of these receptors upon their activation and works as common mediator to induce apoptosis. Based upon these knowledge, we hypothesized that intracellular signals through Fas modified to be dominant-negative signal would suppress the development of pulmonary fibrosis. Tb evaluate this hypothesis, we constructed recombinant adenovirus vector coding FADD deletion mutant lacking the death effector domain. Bleomycin-induced pulmonary fibrosis was partially ameliorated by intratracheal FADD dominant negative transduction. This result would provide the basis for a novel therapeutic modality in pulmonary fibrosis.

肺纤维化患者细支气管和肺泡上皮细胞Fas和FasL表达上调。在博莱霉素处理的实验动物中，通过fasl - fasl相互作用导致肺组织凋亡参与肺纤维化的发生。Fag是一种细胞表面的分子，在特定受体或抗体的作用下引发细胞凋亡或炎症。FADD在这些受体激活后被募集到细胞质结构域，并作为诱导细胞凋亡的常见介质。基于这些知识，我们假设通过Fas修饰为显性负信号的细胞内信号会抑制肺纤维化的发展。为了验证这一假设，我们构建了重组腺病毒载体，编码缺乏死亡效应域的FADD缺失突变体。博莱霉素诱导的肺纤维化通过气管内FADD显性负转导得到部分改善。这一结果将为肺纤维化的新治疗模式提供基础。

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