CTGF in Normal and Deranged Lung Morphogenesis

CTGF 在正常和紊乱的肺形态发生中的作用

• 批准号: 6984834
• 负责人: SHU WU
• 金额: $ 12.98万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984834
• 关键词: bronchopulmonary dysplasia; cell growth regulation; connective tissue growth factor; dissection; embryo /fetus tissue /cell culture; gene expression; genetically modified animals; inhibitor /antagonist; laboratory mouse; lung development; mesenchyme; protein structure function; respiratory epithelium; transforming growth factors

The applicant's goal is to become an independent physician-scientist who engages in basic research that has clinical relevance. The applicant has obtained research training in molecular and cellular biology, and completed her fellowship training in Neonatology, and now is a faculty member in the Division of Neonatology. This proposal will provide the applicant with the opportunity to expand her scientific skills through a unique integration of interdepartmental resources. Her research will focus on understanding the role of connective tissue growth factor (CTGF) in normal and deranged lung morphogenesis. Bronchopulmonary dysplasia (BPD), a common long-term pulmonary sequelae of premature infants, is thought to arise as a consequence of developmental arrest of the immature lung in response to injury and abnormal repair. Transforming growth factor-beta (TGF-beta)is a key negative regulator of branching morphogenesis and is increased in lungs of infants at risk for BPD. CTGF expression is selectively induced by TGF-beta in fibroblast cells. Inhibition of CTGF synthesis or action can completely block TGF-beta stimulated fibroblast proliferation, collagen synthesis and induction of alpha-smooth muscle actin (alpha-SMA), a characteristic marker of myofibroblasts. Our preliminary studies using a mouse embryonic lung explant culture model have demonstrated that CTGF inhibits branching morphogenesis, TGF-beta induces CTGF protein expression in mesenchymal cells and concomitantly inhibits branching morphogenesis. Blocking of CTGF action with an anti-CTGF antibody attenuated TGF-13 inhibition of branching morphogenesis. Our hypothesis is that CTGF is a negative regulator of branching morphogenesis and mediates TGF-beta inhibition of branching morphogenesis. We speculate that inhibition of CTGF biological activity may be of therapeutic benefit to premature infants at risk of BPD. The specific aims are: 1). To determine the molecular and cellular responses involved in CTGF inhibition of branching morphogenesis in lung explant culture. 2). To evaluate the effects of blocking CTGF action or synthesis on TGF-beta inhibition of branching morphogenesis. 3). To investigate the role of CTGF in lung morphogenesis in vivo by over-expression of CTGF in airway epithelium of transgenic mice. The results of this proposal will expand our fundamental knowledge of developmental lung biology and provide the foundation for experiments to evaluate the role of CTGF in an animal model of BPD. This may contribute new insights into the prevention and management of BPD. The proposed research training plan will also include participation in didactic courses, seminars, formal presentations at local and national meetings, as well as regular reviewing of the candidate's progress by the advisory committee. It is expected that this award will allow the PI to become an independent investigator in the area of perinatal lung biology.

申请人的目标是成为一名独立的医师科学家，他们从事具有临床意义的基础研究。申请人已经获得了分子和细胞生物学的研究培训，并完成了她在新生儿学方面的研究金培训，现在是新生儿学系的教职员工。该建议将为申请人提供机会通过独特的部门间资源整合来扩大她的科学技能。 她的研究将集中在理解结缔组织生长因子（CTGF）在正常和破坏肺形态发生中的作用。支气管肺发育不良（BPD）是早产婴儿的常见长期肺后遗症，被认为是由于造成损伤和异常修复的未成熟肺部发育而产生的。转化生长因子β（TGF-β）是分支形态发生的关键负调节剂，并且在有BPD风险的婴儿的肺中增加。 CTGF表达是 通过TGF-β在成纤维细胞中有选择地诱导。 CTGF合成或作用的抑制可以完全阻止TGF-β刺激的成纤维细胞增殖，胶原蛋白合成和诱导α-光滑肌肉肌动蛋白（Alpha-SMA），这是肌纤维细胞的特征标记。我们使用小鼠胚胎肺外植体培养模型的初步研究表明，CTGF抑制了分支形态发生，TGF-beta在间充质细胞中诱导CTGF蛋白表达，并同时抑制分支形态发生。阻塞CTGF 抗CTGF抗体的作用减弱了TGF-13分支形态发生的抑制作用。我们的假设是CTGF是分支形态发生的负调节剂，并介导了TGF-β对分支形态发生的抑制。我们推测，抑制CTGF生物学活性可能对有BPD风险的早产婴儿具有治疗益处。具体目的是：1）。确定参与CTGF抑制肺外植体培养中分支形态发生的分子和细胞反应。 2）。评估阻断CTGF作用或合成对TGF-β抑制分支形态发生的影响。 3）。通过过度表达CTGF在转基因小鼠的气道上皮中，CTGF在体内的肺形态发生中的作用。该提案的结果将扩大我们对发育肺的基本知识 生物学并为实验提供了评估CTGF在BPD动物模型中的作用的基础。这可能会给BPD的预防和管理提供新的见解。 拟议的研究培训计划还将包括参加教学课程，研讨会，正式演讲，并在本地和国家会议上进行正式演讲，以及咨询委员会对候选人的进步进行定期审查。预计该奖项将使PI成为围产期肺生物学领域的独立研究者。