CTGF in lung development and BPD

CTGF 在肺发育和 BPD 中的作用

• 批准号: 6655312
• 负责人: JOEL ROSENBLOOM
• 金额: $ 24.35万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655312
• 关键词: age difference; antisense nucleic acid; bronchopulmonary dysplasia; embryo /fetus tissue /cell culture; extracellular matrix proteins; growth factor; human fetus tissue; human tissue; immediate early protein; immunocytochemistry; immunoelectron microscopy; in situ hybridization; laboratory mouse; lung; lung development; mammalian embryology; mitogens; molecular pathology; protein biosynthesis; tissue /cell culture; transforming growth factors

(Applicant's Abstract) Although there is increasing evidence that failure of normal lung septation is a component of bronchopulmonary dysplasia (BPD) currently seen in small premature infants, a fibroproliferative response remains responsible for many of the untoward alterations in pulmonary function. While the pathogenic mechanisms underlying this response are complex, it is likely that many of the harmful aspects are mediated by the manifold effects of TGF-B as a final common pathway. Strong evidence suggests that many of the effects of TGF-B on fibroblast proliferation and extracelluar matrix production are mediated by connective tissue growth factor (CTGF). The preliminary data demonstrate that CTGF expression by cultured human fetal lung fibroblasts and airway smooth muscle cells is greatly stimulated by TGF-B1 and that CTGF is expressed in the developing lung. The investigators propose the following hypotheses: (1) A TGF-B superfamily member stimulates the expression of CTGF which acts as a downstream mediator in the regulation of branching and other morphologic events during normal lung development. (2) The signaling pathway by which TGF-B up-regulates CTGF expression involves cellular components in addition to the Smads. (3) CTGF is a major effector molecule in the pathogenesis of pulmonary fibrosis seen in BPD. To test these hypotheses, they will: (1) Determine the temporal and spatial expression of CTGF in the developing mouse and human lung and determine its potential role in lung development by conditional ablation. (2) Define the signaling pathway and mechanisms whereby TGF-B1 up-regulates the expression of CTGF and modulates expression of matrix proteins. (3) Develop strategies for inhibiting the fibrotic response mediated by TGF-B and CTGF. This work will be carried out in close collaboration with Projects 5 & 6, will interact significantly with Projects 1 and 4, will utilize the Tissue Culture Core for the implementation of the mouse lung bud model and will obtain human lung samples from the Clinical Core. Identification of the mechanisms of action of CTGF and the pathways regulating its expression are of considerable importance, since CTGF may play a key role in normal lung development and blocking its abnormal production may ameliorate the fibrotic response seen in BPD.

（申请人摘要）尽管越来越多的证据表明 正常肺间隔是支气管肺发育不良 (BPD) 的一个组成部分 目前在早产儿中观察到，这是一种纤维增殖反应 仍然是导致肺部许多不良变化的原因 功能。虽然这种反应背后的致病机制是 复杂，许多有害方面可能是由 TGF-B 作为最终共同途径具有多种作用。强有力的证据表明 TGF-B 对成纤维细胞增殖和细胞外基质的许多影响 基质的产生是由结缔组织生长因子（CTGF）介导的。这 初步数据表明，培养的人胎肺中存在 CTGF 表达 成纤维细胞和气道平滑肌细胞受到 TGF-B1 的极大刺激， CTGF 在发育中的肺中表达。调查人员提出 以下假设：(1) TGF-B 超家族成员刺激表达 CTGF 作为分支调节的下游介质 正常肺部发育过程中的其他形态事件。 (2) 信令 TGF-B 上调 CTGF 表达的途径涉及细胞 除 Smad 之外的组件。 (3) CTGF是主要的效应分子 BPD 中肺纤维化的发病机制。为了检验这些假设， 他们将： (1) 确定 CTGF 在细胞中的时间和空间表达 开发小鼠和人肺并确定其在肺中的潜在作用 通过条件消融进行发育。 (2) 定义信号通路和 TGF-B1 上调 CTGF 表达并调节的机制 基质蛋白的表达。 (3) 制定抑制策略 TGF-B 和 CTGF 介导的纤维化反应。这项工作将进行 与项目 5 和 6 密切合作，将产生显着的互动 与项目 1 和 4 一起，将利用组织培养核心 实施小鼠肺芽模型并将获得人体肺样本 来自临床核心。 CTGF 作用机制的鉴定 调节其表达的途径非常重要， 因为 CTGF 可能在正常肺部发育中发挥关键作用并阻止其 异常的产生可能会改善 BPD 中出现的纤维化反应。