TRANSFORMING GROWTH FACTOR ALPHA AND LUNG INJURY

本申请试图确定转化生长因子α（TGF α）对肺损伤的炎症反应的作用。 TGF α是一种在肺发育过程中发现的蛋白质，它由肺中的大多数细胞产生，并仅与表皮生长因子受体（EGF-R）结合。 使用SP-C启动子在远端肺中表达人TGF α的转基因小鼠在暴露于加热的特氟隆超细颗粒（UFP）引起的急性肺损伤后，与野生型（wt）对照相比，表现出增加的存活率和减少的炎症。 本申请检验了TGF α减少急性肺损伤中的炎症反应的假设。 为了直接确定TGF α在体内的作用，我们将在UFP暴露之前和期间通过腹腔内、肝内和腺病毒基因载体向野生型小鼠施用TGF α，并与未处理的对照组相比评估肺部炎症和损伤的程度。 为了确定TGF α的抗炎特性的机制，我们将确定TGF α对炎症介质的表达、抗氧化酶活性以及损伤后增殖和凋亡的细胞位点的影响。 为了确定TGF α对炎症作用所需的细胞区室，我们将比较仅在II型细胞中缺乏EGF-R信号传导的小鼠与在所有细胞中缺乏EGF-R信号传导的小鼠中暴露于UFP后的炎症反应。 该应用将确定TGF α减少损伤后肺损伤和炎症的作用和机制，并可能在治疗和预防临床显著的急性肺损伤方面具有未来价值。该提案的主要研究者（PI）已经完成了儿科肺部医学的奖学金，并开始了他作为肺部医学和生物学部门助理教授的第一年，基础研究的努力超过75%。 在他的培训过程中，他表现出了持续的兴趣和能力，以完成基础科学调查，如他的出版物所示。 RCA将允许PI在Jeff惠特塞特博士指导的儿童医院肺生物学部门继续发展。 肺生物学部由一组高度互动的独立高级研究人员组成，他们在表面活性剂生物学，肺发育，肺损伤机制和囊性纤维化方面进行了资助研究。 所提出的实验将允许P.I.在一个致力于了解各种肺部疾病的基本病理生物学的部门中发展一条独立的研究路线。

The present application seeks to determine the effects of transforming growth factor alpha (TGFalpha) on the inflammatory response to lung injury. TGFalpha is a protein found throughout lung development where it is produced by most cells in the lung and binds exclusively to the epidermal growth factor receptor (EGF-R). Transgenic mice expressing human TGFalpha in distal lung using the SP-C promoter demonstrate increased survival and reduced inflammation compared with wild type (wt) controls following acute lung injury caused by exposure to heated Teflon ultrafine particles (UFP). The present application tests the hypothesis that TGFalpha reduces the inflammatory response in acute lung injury. To directly determine the role of TGFalpha in vivo, we will administer TGFalpha to wt mice intraperitoneally, intratracheally, and through adenoviral gene vectors before and during UFP exposure and assess the degree of lung inflammation and injury compared with untreated controls. To determine the mechanisms of TGFalpha's anti-inflammatory properties we will determine TGFalpha's effects on the expression of inflammatory mediators, antioxidant enzyme activity, and cellular sites of proliferation and apoptosis following injury. To determine the cellular compartments required for TGFalpha's effects on inflammation, we will compare the inflammatory response following UFP exposure in mice with deficiency of EGF-R signaling in type II cells only, to mice with deficiency of EGF-R signaling in all cells. This application will determine the role and delineate mechanisms by which TGFalpha reduces lung damage and inflammation following injury, and may be of future value in treating and preventing clinically significant acute lung injury. The principal investigator (PI) for this proposal has completed a fellowship in pediatric pulmonary medicine and is beginning his first year as an Assistant Professor in the Divisions of Pulmonary Medicine and Biology with greater than 75 percent effort in basic research. Throughout his training he has demonstrated a continued interest and ability to accomplish basic science investigation as indicated in his publications. The RCA will allow the PI to continue to develop in the Division of Pulmonary Biology at Children's Hospital directed by Dr. Jeff Whitsett. The Pulmonary Biology Division consists of a highly interactive group of independent senior investigators with funded research efforts in surfactant biology, lung development, mechanisms of lung injury, and cystic fibrosis. The experiments proposed will permit the P.I. to develop an independent line of research in a division dedicated to understanding the basic pathobiology of various lung diseases.