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

描述（由申请人提供）：本提案描述了一项为期五年的培训计划，旨在促进向肺部和重症监护医学领域的学术医师-科学家职业生涯的过渡。主要研究者将于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Ellen Puri博士的指导下在Wistar研究所进行科学研究。该项目涉及间质性肺病领域，旨在深入了解纤维化肺病（如特发性肺纤维化（IPF））的发病机制，并希望发现潜在的新治疗靶点。Fan博士将研究成纤维细胞活化蛋白（FAP）-一种II型整合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CD 44信号传导和调节领域的世界知名专家，对炎症、癌症生物学和纤维化特别感兴趣。Fan博士还将获得科学咨询委员会的额外指导，该委员会包括间质性肺病和表面活性剂生物学专家Michael Beers博士，他将共同赞助这项资助，以及宾夕法尼亚大学医院肺部，过敏和重症监护部肺部研究副主任兼主任Steven Albelda博士。Fan博士的项目将确定FAP保护肺损伤后肺纤维化发展的机制。初步数据表明，在两种肺纤维化模型中，FAP缺陷型小鼠与野生型小鼠相比，存活率降低，肺纤维化增加-胸部照射和肺内博莱霉素-确立了FAP在疾病发病机制中的保护作用。具体目标1、2和3将决定这种情况发生的机制。特异性目的1将检查与野生型相比，在FAP缺陷型小鼠中是否由于FAP已知的特异性蛋白酶活性的丧失而观察到肺纤维化增加。具体目标2将检查1）成纤维细胞表型的改变，2）活性TGF b水平和信号传导的改变，和/或3）在FAP缺乏情况下发生的ECM组分的改变，其可能解释促纤维化表型。特异性目的3将探索FAP可能的免疫调节作用。具体目标4，通过使用新的药理学FAP抑制剂，将确定急性FAP活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强烈的兴趣，但它在纤维化研究领域是一种相对研究不足的蛋白质。我们的研究结果和实验计划代表了我们对这种蛋白质工作原理的理解的一个新方向，对未来间质性肺病的治疗具有潜在意义。赞助机构--威斯塔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。她有她的科学导师，埃伦普里，以及她的部门在她追求的学术生涯作为一个物理学家，科学家的全力支持。

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.