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

成纤维细胞激活蛋白 (FAP) 在肺纤维化中的保护作用

• 批准号: 7873669
• 负责人: Ming-Hui Fan
• 金额: $ 13.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873669
• 关键词: Acute; Adult; Advisory Committees; Beer; Biology; Bleomycin; Bronchoalveolar Lavage; CD44 gene; Cancer Biology; Cell surface; Cells; Cessation of life; Chest; Chronic lung disease; Cicatrix; Collaborations; Collagen; Complement; Critical Care; Data; Development; Diagnosis; Dipeptidyl Peptidases; Disease; Doctor of Philosophy; Endopeptidases; Engineering; Environment; Environmental Exposure; Etiology; Evolution; Extracellular Matrix; Family; Fellowship; Fibroblasts; Fibrosis; Foamy Macrophage; Future; Genetic; Goals; Grant; Hamman-Rich syndrome; Hypersensitivity; In Vitro; Inflammation; Inflammatory Infiltrate; Institute of Medicine (U.S.); Institutes; Institution; Interstitial Lung Diseases; Investigation; Leukocytes; Lung; Lung Transplantation; Lung diseases; Mediating; Medicine; Membrane Proteins; Mentors; Mentorship; Modeling; Mouse Strains; Mus; Mutant Strains Mice; Myofibroblast; Nature; Pathogenesis; Patients; Pennsylvania; Peptide Hydrolases; Phenotype; Philadelphia; Physicians; Play; Population; Principal Investigator; Process; Protein Deficiency; Proteins; Pulmonary Fibrosis; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Serine Protease; Severities; Signal Transduction; Staging; Staining method; Stains; Structure of parenchyma of lung; Testing; Tissue Stains; Training; Training Programs; Universities; University Hospitals; Work; antitumor drug; career; collagenase; design; effective therapy; fibroblast-activating factor; in vivo; inhibitor/antagonist; insight; instructor; interest; irradiation; lung injury; new therapeutic target; novel; prevent; public health relevance; research study; response; surfactant; therapeutic target

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.

描述（由申请人提供）：该提案描述了一项为期五年的培训计划，旨在促进向肺科和重症监护医学领域的学术医师科学家职业过渡。主要研究者将于 2009 年 12 月完成肺科和重症监护进修培训，之后她将被任命为医学系讲师。她将在威斯塔研究所 (Wistar Institute) 的艾伦·普里 (Ellen Puri) 博士的指导下进行科学研究。该项目属于间质性肺疾病领域，旨在深入了解特发性肺纤维化（IPF）等纤维化肺疾病的发病机制，并希望发现潜在的新治疗靶点。 Fan 博士将研究成纤维细胞激活蛋白 (FAP)——一种具有二肽基肽酶、内肽酶和胶原酶活性的 II 型整合细胞表面丝氨酸蛋白酶——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。范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疾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、过敏和重症监护部门肺脏研究副主任兼主任 Steven Albelda 博士。 Fan 博士的项目将确定 FAP 预防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（胸部照射和气管内博来霉素）中，与野生型相比，FAP 缺陷小鼠的存活率降低，肺纤维化增加，这表明 FAP 在疾病发病机制中发挥保护作用。具体目标 1、2 和 3 将确定发生这种情况的机制。具体目标 1 将检查与野生型相比，FAP 缺陷小鼠是否因 FAP 已知的特异性蛋白酶活性丧失而导致肺纤维化增加。具体目标 2 将检查 1) 成纤维细胞表型的变化，2) 活性 TGFb 水平和信号传导的变化，和/或 3) FAP 缺乏情况下发生的 ECM 成分的变化，这可能解释促纤维化表型。具体目标 3 将探索 FAP 可能的免疫调节作用。具体目标 4 通过使用新型药理学 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引起了癌症生物学领域的浓厚兴趣，但它在纤维化研究领域是一种相对未被充分研究的蛋白质。我们的发现和实验计划代表了我们对这种蛋白质作用的理解的新方向，对未来间质性肺疾病的治疗具有潜在的影响。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建立了合作。在她追求作为一名医师科学家的学术生涯时，她得到了她的科学导师 Ellen Puri 以及她的部门的全力支持。 公共健康相关性：本申请旨在通过研究成纤维细胞活化蛋白（FAP）（一种具有二肽基肽酶、内肽酶和胶原酶活性的 II 型完整细胞表面丝氨酸蛋白酶），深入了解特发性肺纤维化 (IPF) 等纤维化肺部疾病的发病机制，希望发现潜在的新治疗靶点。我们的初步数据表明，在两种肺纤维化模型中，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。 Fan 博士的项目将确定 FAP 预防肺损伤后肺纤维化发展的机制。