TRANSFORMING GROWTH FACTOR ALPHA AND LUNG INJURY

本应用旨在确定转化生长因子α(TGFα)在肺损伤炎症反应中的作用。转化生长因子α是一种在整个肺发育过程中发现的蛋白质，它由肺中的大多数细胞产生，并专门与表皮生长因子受体(EGF-R)结合。与野生型(Wt)对照组相比，使用SP-C启动子在远端肺组织表达人TGFα的转基因小鼠在暴露于加热的特氟龙超细颗粒(UFP)引起的急性肺损伤后显示出更高的存活率和更少的炎症。目前的应用验证了TGFAlpha减少急性肺损伤炎症反应的假设。为了直接确定转化生长因子α在体内的作用，我们将在UFP暴露之前和期间通过腺病毒基因载体将转化生长因子α通过腹膜、气管内给wt小鼠，并与未治疗的对照组相比评估肺炎症和损伤的程度。为了确定TGFα的抗炎作用机制，我们将检测TGFAlpha对损伤后炎症介质表达、抗氧化酶活性以及细胞增殖和凋亡部位的影响。为了确定TGFAlpha在炎症中的作用所需的细胞间隔，我们将比较UFP暴露后仅II型细胞EGF-R信号缺乏的小鼠和所有细胞EGF-R信号缺乏的小鼠的炎症反应。这一应用将确定TGFα减轻损伤后肺损伤和炎症的作用和机制，并可能在未来治疗和预防临床上显著的急性肺损伤方面有价值。这项建议的首席研究员(PI)已经完成了儿科肺部医学的研究，并开始了他作为肺内科和生物系助理教授的第一年，他在基础研究方面的努力超过75%。在他的整个训练过程中，他表现出了持续的兴趣和能力，完成了他的出版物中所表明的基础科学研究。RCA将允许PI在杰夫·惠特塞特博士指导的儿童医院肺生物科继续发展。肺生物学分部由高度互动的独立高级研究人员组成，他们资助了表面活性物质生物学、肺发育、肺损伤机制和囊性纤维化方面的研究工作。拟议中的实验将允许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.