CTGF in Normal and Deranged Lung Morphogenesis

申请人的目标是成为一个独立的医生，科学家谁从事基础研究，具有临床相关性。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医学的奖学金培训，现在是新生儿医学部的一名教员。该提案将为申请人提供通过跨部门资源的独特整合来扩展其科学技能的机会。 她的研究将集中在了解结缔组织生长因子（CTGF）在正常和紊乱的肺形态发生中的作用。支气管肺发育不良（BPD）是早产儿常见的长期肺部后遗症，被认为是由于未成熟肺对损伤和异常修复的反应而发生发育停滞的结果。转化生长因子-β（TGF-β）是分支形态发生的关键负调节因子，在BPD风险婴儿的肺部增加。CTGF表达是 在成纤维细胞中由TGF-β选择性诱导。CTGF合成或作用的抑制可以完全阻断TGF-β刺激的成纤维细胞增殖、胶原蛋白合成和α-平滑肌肌动蛋白（α-SMA）（肌成纤维细胞的特征性标志物）的诱导。我们使用小鼠胚胎肺外植体培养模型的初步研究表明，CTGF抑制分支形态发生，TGF-β诱导CTGF蛋白在间充质细胞中的表达，并伴随抑制分支形态发生。CTGF阻断 与抗CTGF抗体的作用减弱了TGF-13对分支形态发生的抑制。我们的假设是CTGF是分支形态发生的负调节因子，并介导TGF-β抑制分支形态发生。我们推测，CTGF生物活性的抑制可能是治疗BPD风险的早产儿的好处。具体目标是：1）。确定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）。评价阻断CTGF作用或合成对TGF-β抑制分支形态发生的影响。3）。通过转基因小鼠气道上皮CTGF的过表达，探讨CTGF在体内肺形态发生中的作用。这一建议的结果将扩大我们对发育肺的基本知识 生物学的研究，并为评价CTGF在BPD动物模型中的作用的实验提供基础。这可能为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、在地方和国家会议上的正式发言，以及咨询委员会对候选人的进展情况进行定期审查。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。

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.