CTGF in Normal and Deranged Lung Morphogenesis

申请者的目标是成为一名独立的内科科学家，从事与临床相关的基础研究。申请人接受过分子和细胞生物学的研究培训，并完成了新生儿科的研究员培训，现在是新生儿科的教员。这项建议将为申请者提供机会，通过独特的跨部门资源整合来扩大她的科学技能。 她的研究将集中于了解结缔组织生长因子(CTGF)在正常和错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，被认为是未成熟肺因损伤和异常修复而发育停滞的结果。转化生长因子-β(转化生长因子-β)是分支形态发生的关键负性调节因子，并在BPD风险婴儿的肺中增加。CTGF的表达是 转化生长因子-β选择性诱导成纤维细胞。抑制CTGF的合成或作用可以完全阻断转化生长因子-β刺激的成纤维细胞的增殖、胶原的合成和α-平滑肌肌动蛋白(α-SMA)的诱导，而α-SMA是肌成纤维细胞的特征标志。我们利用小鼠胚胎肺外植体培养模型的初步研究表明，CTGF抑制分枝形态发生，转化生长因子-β诱导间充质细胞CTGF蛋白表达，同时抑制分枝形态发生。CTGF的屏蔽 抗CTGF抗体的作用减弱了转化生长因子-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控因子，并介导转化生长因子-β抑制分支形态发生。我们推测，抑制CTGF生物活性可能对有BPD风险的早产儿有治疗作用。具体目标是：1)。目的：研究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)。探讨阻断CTGF的作用或合成对转化生长因子-β抑制分枝形态发生的影响。3)。目的通过在转基因小鼠呼吸道上皮细胞中过表达CTGF，探讨CTGF在体内肺形态发生中的作用。这项建议的结果将扩大我们对发育肺的基本知识。 并为实验评估CTGF在BPD动物模型中的作用提供了基础。这可能有助于对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陈述以及咨询委员会对候选人进展情况的定期审查。预计这一奖项将使PI成为围产期肺部生物学领域的独立研究员。

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.