CTGF in lung development and 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 目前见于小早产儿，一种纤维增生性反应 仍然是许多令人不快的肺部改变的罪魁祸首 功能。而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 转化生长因子-β作为最终共同途径的多种作用。强有力的证据表明 转化生长因子-β对成纤维细胞增殖和细胞外的许多作用 基质的产生是由结缔组织生长因子(CTGF)介导的。这个 初步数据表明培养的人胎肺表达CTGF 转化生长因子-β1对成纤维细胞和气道平滑肌细胞的刺激作用 CTGF在发育中的肺中表达。调查人员建议 假设：(1)一个转化生长因子-β超家族成员刺激其表达 CTGF在分枝和分枝的调节中起下游中介作用 正常肺发育过程中的其他形态事件。(2)信令 转化生长因子β上调CTGF表达的途径涉及细胞 除了SMADS之外，还包括其他组件。(3)CTGF是一种主要的效应分子。 肺纤维化的发病机制可见于BPD。为了检验这些假设， 他们将：(1)确定CTGF在脑内的时空表达。 小鼠和人肺的发育及其在肺中的潜在作用 通过有条件的消融来发展。(2)明确信号传导途径， 转化生长因子-β1上调结缔组织生长因子表达及调控的机制 基质蛋白的表达。(3)制定策略，以抑制 转化生长因子-β和结缔组织生长因子介导的纤维化反应。这项工作将会进行 在与项目5和6的密切合作中，将进行重大互动 在项目1和4中，将利用组织培养核心 实施小鼠肺芽模型并将获得人肺标本 来自临床核心中心。结缔组织生长因子作用机制的鉴定 调节其表达的途径是相当重要的， 由于CTGF可能在正常的肺发育和阻断其 异常的生产可能会改善BPD的纤维化反应。

(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.