A Protective Role for Fibroblast Activation Protein (FAP) in Pulmonary Fibrosis

描述（由申请人提供）：该提案描述了一个为期五年的培训计划，旨在促进过渡到肺部和重症医学的学术医师-科学家职业。首席研究员将于2009年12月完成肺部和重症监护奖学金培训，之后她将被任命为医学系讲师。她将在Wistar研究所继续她的科学研究，师从Ellen Puri博士。拟议的项目是在间质性肺疾病领域，目的是深入了解纤维化肺疾病如特发性肺纤维化（IPF）的发病机制，希望发现潜在的新治疗靶点。范博士将研究成纤维细胞活化蛋白（FAP）——一种II型整体细胞表面丝氨酸蛋白酶，具有二肽基肽酶、内肽酶和胶原酶活性——作为肺纤维化发展的关键因素。Ellen Pure博士将在范博士的整个研究过程中担任她的科学导师。Pure博士是CD44信号和调控领域的世界知名专家，对炎症、癌症生物学和纤维化有特殊兴趣。范博士还将得到一个科学咨询委员会的额外指导，该委员会包括Michael Beers博士，他是间质性肺病和表面活性物质生物学方面的专家，他将共同赞助这项资助，以及Steven Albelda博士，宾夕法尼亚大学医院肺部、过敏和重症监护室副主任兼肺部研究主任。范博士的项目将确定FAP防止肺损伤后肺纤维化发展的机制。初步数据显示，在两种肺纤维化模型（胸椎照射和气管内博莱霉素）中，与野生型相比，FAP缺陷小鼠的存活率降低，肺纤维化增加，这证实了FAP在疾病发病机制中的保护作用。具体目标1、2和3将决定发生这种情况的机制。特异性目的1将检查FAP缺陷小鼠是否因FAP已知特异性蛋白酶活性丧失而与野生型小鼠相比，肺纤维化增加。特异性目标2将检查1)成纤维细胞表型的改变，2)活性TGFb水平和信号的变化，和/或3)FAP缺乏时发生的ECM成分的改变，这些改变可能解释促纤维化表型。特异性目的3将探讨FAP可能的免疫调节作用。特异性目标4，通过使用新的药理学FAP抑制剂，将确定FAP活性急性丧失对肺损伤后肺纤维化发展的影响，补充我们早期的遗传学研究。虽然FAP作为抗肿瘤药物的潜在靶点在癌症生物学领域引起了浓厚的兴趣，但在纤维化研究领域，它是一种相对较少研究的蛋白质。我们的发现和实验计划代表了我们对这种蛋白的工作原理的理解的一个新的方向，对将来治疗间质性肺疾病具有潜在的意义。赞助机构——Wistar研究所和宾夕法尼亚大学——为范博士的科学发展提供了丰富的机会。她已经与宾夕法尼亚大学和费城医学与工程研究所的研究人员开展了合作。她得到了她的科学导师艾伦·普里（Ellen Puri）的全力支持，也得到了她所在院系的全力支持，支持她追求作为一名内科科学家的学术生涯。

DESCRIPTION (provided by applicant): This proposal describes a five-year training program designed to facilitate transition to an academic physician- scientist career in Pulmonary and Critical Care Medicine. The principal investigator will complete Pulmonary and Critical Care fellowship training in December 2009 after which she will be appointed to the title of Instructor in the Department of Medicine. She will pursue her scientific research at the Wistar Institute under the mentorship of Dr. Ellen Puri. The proposed project is in the field of interstitial lung disease, with the goal of gaining insight into the pathogenesis of fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF), with hopes of discovery of potential new therapeutic targets. Dr. Fan will study fibroblast activation protein (FAP)-a type II integral cell surface serine protease with dipeptidyl peptidase, endopeptidase, and collagenase activity-as a critical factor in the development of pulmonary fibrosis. Ellen Pure, PhD, will serve as Dr. Fan's scientific mentor throughout her investigations. Dr. Pure is a world-renowned expert in the field of CD44 signaling and regulation with a special interest in inflammation, cancer biology, and fibrosis. Dr. Fan will also have additional guidance from a scientific advisory committee, which includes Dr. Michael Beers, an expert in interstitial lung disease and surfactant biology who will co-sponsor this grant, as well as Dr. Steven Albelda, Vice Chief and Director of Lung Research of the Pulmonary, Allergy, and Critical Care Division at the Hospital of University of Pennsylvania. Dr. Fan's project will determine the mechanism(s) by which FAP protects against the development of pulmonary fibrosis after lung injury. Preliminary data demonstrates decreased survival and increased pulmonary fibrosis in FAP-deficient mice vs. wildtype in two pulmonary fibrosis models-thoracic irradiation and intratracheal bleomycin-establishing a protective role for FAP in the pathogenesis of the disease. Specific Aims 1, 2, and 3 will determine the mechanism(s) by which this occurs. Specific Aim 1 will examine whether increased pulmonary fibrosis is seen in FAP-deficient mice compared to wildtype due to loss of FAP's known specific protease activities. Specific Aim 2 will examine for 1) alterations in fibroblast phenotype, 2) changes in active TGFb levels and signaling, and/or 3) alterations in ECM components occurring in the setting of FAP deficiency that might explain the pro-fibrotic phenotype. Specific Aim 3 will explore a possible immuno- modulatory role for FAP. Specific Aim 4, through the use of novel pharmacologic FAP inhibitors, will determine the effect of acute loss of FAP activity on the development of pulmonary fibrosis after lung injury, complementing our earlier genetic studies. While FAP has generated intense interest in the field of cancer biology as a potential target for antitumor drugs, it is a relatively under-studied protein in the field of fibrosis research. Our findings and experimental plan represent a novel direction in our understanding of the workings of this protein with potential implications for the treatment of interstitial lung diseases in the future. The sponsoring institutions-the Wistar Institute and the University of Pennsylvania-provide a wealth of opportunities for Dr. Fan's scientific development. She has already developed collaborations with investigators at the University of Pennsylvania and the Institute of Medicine and Engineering in Philadelphia. She has the full support of her scientific mentor, Ellen Puri, as well as her department in her pursuit of an academic career as a physician-scientist. PUBLIC HEALTH RELEVANCE: This application aims to gain insight into the pathogenesis of fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF), with hopes of discovery of potential new therapeutic targets, through the study of fibroblast activation protein (FAP), a type II integral cell surface serine protease with dipeptidyl peptidase, endopeptidase, and collagenase activities. Our preliminary data demonstrates decreased survival and increased pulmonary fibrosis in FAP-deficient mice vs. wildtype in two pulmonary fibrosis models, establishing a protective role for FAP in the pathogenesis of the disease. Dr. Fan's project will determine the mechanism(s) by which FAP protects against the development of pulmonary fibrosis after lung injury.