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.

（申请人的摘要）尽管有越来越多的证据表明， 正常肺分隔是支气管肺发育不良（BPD）的组成部分 目前在小型早产儿中发现， 仍然是造成许多肺部疾病的 功能虽然这种反应背后的致病机制是 复杂，很可能许多有害的方面是由 TGF-β作为最终共同途径的多种作用。有力的证据表明 TGF-β对成纤维细胞增殖和细胞外增殖的许多作用， 基质的产生由结缔组织生长因子（CTGF）介导。的 初步数据表明，CTGF表达培养的人胎肺， 成纤维细胞和气道平滑肌细胞受到TGF-β 1的极大刺激， CTGF在发育中的肺中表达。调查人员建议， 以下假设：（1）TGF-β超家族成员刺激表达 CTGF作为下游介质调节分支， 正常肺发育过程中的其他形态学事件。(2)信令 TGF-B上调CTGF表达的途径涉及细胞 除此之外，还有Smads。(3)CTGF是一种主要的效应分子， 肺纤维化的发病机制。为了验证这些假设， 他们将：（1）确定时间和空间表达的CTGF在 发育小鼠和人肺，并确定其在肺中的潜在作用 条件性消融的发展。(2)定义信号通路， TGF-β 1上调CTGF表达并调节CTGF表达的机制 基质蛋白的表达。(3)制定战略， 由TGF-β和CTGF介导的纤维化反应。这项工作将在 与项目5和项目6密切合作， 与项目1和4，将利用组织培养核心， 小鼠肺芽模型的实施，并将获得人肺样品 临床核心的。CTGF作用机制的鉴定 并且调节其表达的途径是相当重要的， 由于CTGF可能在正常肺发育中起关键作用， 异常的产生可以改善BPD中所见的纤维化反应。