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

项目摘要/摘要 这项建议的目的是要研究导致骨质疏松症的分子机制 特发性肺纤维化与肺成纤维细胞纤维化表型的关系 肺纤维化(IPF)。IPF是一种破坏性的、慢性的、进行性的、纤维化的肺部疾病，在 未行肺移植3~5年。尽管这种疾病被认为是罕见的，影响大约- 美国10万人口--高昂的医疗成本和对质量和数量的重大影响 生命的一部分会给我们带来沉重的负担。重要的是，IPF的发病率正在增加，原因不明。治疗 选择仅限于支持性护理、肺移植或不能解决而是相反的药物治疗 延缓疾病的发展。这一局限性部分是由于对其病理生理机制的不完全理解。 IPF的基础生物学。因此，迫切需要提高对细胞和分子机制的了解。 在IPF的发病机制中起作用的异常现象，以开发新的治疗方案。 拟议的项目将通过研究多肽精氨酸脱亚胺酶4(PAD4)来满足这一需求， 一种催化肽基-精氨酸残基翻译后修饰为肽基-瓜氨酸的酶 最近，这与一个老年动物模型的器官纤维化的发展有关。穿过 功能获得和功能丧失实验，PAD4的S对IPF成纤维细胞促纤维化表型的贡献将是 下定决心。此外，通过使用小分子抑制剂，PAD4缺乏对发育迟缓的影响。 在博莱霉素小鼠模型和体外人类精密切割肺切片中治疗肺纤维化 已定义。通过阐明其在肺纤维化发展中的作用，这项工作将确定PAD4是否是一种 纤维肺疾病的可行治疗靶点。 该提案描述了一项为期三年的研究奖学金计划，该计划将允许首席调查员 开始了肺部疾病的学术研究生涯。他将在分部内承担这一项目 在他的密切指导下在布里格姆妇女医院的肺部和危重护理医学 赞助伊万·罗萨斯博士，间质性肺疾病和肺间质疾病临床前模型领域的专家 纤维化，共同赞助El-Chemaly博士，他也是间质性肺疾病和体外研究领域的专家 评估纤维化的技术。首席调查员还将受益于其他高度 他的科学咨询委员会有成就的成员，并有机会接触到全面的知识分子 以及该部门和哈佛生物医学社区内可用的物质资源。除了……之外 作为首席调查员职业发展的关键一步，该项目将为 未来的研究努力，随着他从团契到初级教员，并最终成为一名独立的 美国国立卫生研究院资助的调查员。

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.