PAD4 Contributes to the Profibrotic Phenotype of Fibroblasts from Patients with IPF and Promotes Lung Fibrosis

项目总结/摘要 本提案的目的是研究发展的分子机制， 肺纤维化和肺成纤维细胞的促纤维化表型在纤维化肺疾病如特发性 肺纤维化（IPF）。IPF是一种破坏性、慢性、进行性、纤维化肺病， 3-5在没有肺移植的情况下，虽然这种疾病被认为是罕见的影响， 美国10万人--护理成本高、质量和数量影响大 生活的重担。重要的是，IPF的发病率正在增加，原因尚不清楚。治疗 选择仅限于支持性治疗、肺移植或不能解决问题但 减缓疾病的发展。这种局限性部分是由于对病理生理学的不完全理解- IPF基础疾病。因此，迫切需要提高对细胞和分子机制的理解， 有助于IPF发病机制的疾病，以开发新的治疗选择。 拟议的项目将通过研究肽基精氨酸脱亚胺酶4（PAD 4）来解决这一需求， 一种催化肽基精氨酸残基翻译后修饰为肽基瓜氨酸的酶 并且最近在老年动物模型中发现其与器官纤维化的发展有关。通过 在功能获得和丧失实验中，PAD 4对IPF成纤维细胞的促纤维化表型的贡献将是 测定此外，通过使用小分子抑制剂，PAD 4缺乏对发育的影响， 肺纤维化在博来霉素小鼠模型和离体人精确切割的肺切片中的进展将是 定义了通过阐明其在肺纤维化发展中的作用，这项工作将确定PAD 4是否是一个与肺纤维化相关的基因。 纤维化肺病的可行治疗靶点。 该提案描述了一个为期三年的研究奖学金计划，将允许主要研究者 开始肺部疾病的学术研究生涯。他将在该司内开展这一项目， 在他的密切指导下，布里格姆妇女医院的肺部和重症监护医学 申办者Ivan罗萨斯博士是间质性肺病和肺疾病临床前模型领域的专家， El-Chemaly博士也是间质性肺病和体外研究领域的专家， 评估纤维化的技术。首席研究员还将受益于其他高度专业化的专家， 他的科学顾问委员会的成员，并获得全面的知识 和物理资源可利用的部门和更大的哈佛生物医学界。除了 作为主要研究者职业发展的关键一步，该项目将为以下方面提供基础： 未来的研究努力，因为他从奖学金，初级教师，并最终，一个独立的进步 NIH资助的研究员。

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to investigate the molecular mechanisms underlying the development of pulmonary fibrosis and the profibrotic phenotype of pulmonary fibroblasts in fibrotic lung diseases like idiopathic pulmonary fibrosis (IPF). IPF is a devastating, chronic, progressive, fibrotic lung disease that leads to death in 3-5 years in the absence of lung transplantation. Although the disease is considered rare—affecting approxi- mately 100,000 people in the United States—the high cost of care and significant impact on quality and quantity of life imparts a significant burden. Importantly, the incidence of IPF is increasing for unclear reasons. Treatment options are limited to supportive care, lung transplantation, or medical therapies that do not resolve but rather slow the progression of disease. This limitation is in part due to an incomplete understanding of the pathophysi- ology underlying IPF. There is thus an urgent need to improve understanding of the cellular and molecular mech- anisms contributing to the pathogenesis of IPF in order to develop new therapeutic options. The proposed project will address this need through investigation of peptidylarginine deiminase 4 (PAD4), an enzyme that catalyzes the post-translational modification of peptidyl-arginine residues to peptidyl-citrulline and that has recently been implicated in the development of organ fibrosis in an aged animal model. Through gain- and loss-of-function experiments, PAD4’s contribution to the profibrotic phenotype of IPF fibroblasts will be determined. Moreover, through use of a small molecule inhibitor, the effect of PAD4 deficiency on the develop- ment of pulmonary fibrosis in a bleomycin mouse model and in ex vivo human precision-cut lung slices will be defined. By elucidating its role in the development of pulmonary fibrosis, this work will determine if PAD4 is a viable therapeutic target for fibrotic lung disease. This proposal describes a three-year research fellowship program that will allow the principle investigator to begin an academic research career in pulmonary disease. He will undertake this project within the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital under the close mentorship of his sponsor Dr. Ivan Rosas, an expert in the field of interstitial lung disease and pre-clinical models of pulmonary fibrosis, and co-sponsor Dr. El-Chemaly, also an expert in the field of interstitial lung disease and in in vitro techniques for assessing fibrosis. The principle investigator will also benefit from the expertise of other highly accomplished members of his Scientific Advisory Committee and have access to the comprehensive intellectual and physical resources available within the Division and greater Harvard biomedical community. In addition to serving as a critical step in the principle investigator’s career development, this project will provide a basis for future research endeavors, as he advances from fellowship, to junior faculty, and, ultimately, to an independent NIH-funded investigator.