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

PAD4 有助于 IPF 患者成纤维细胞的促纤维化表型并促进肺纤维化

基本信息

批准号：
9911164
负责人：
Anthony Joseph Esposito
金额：
$ 7.59万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-04 至 2022-07-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911164
关键词：
Address Adult Advisory Committees Affect Age Animal Model Apoptosis Bleomycin Cardiac development Cell Proliferation Cessation of life Chronic Citrulline Collagen Communities Critical Care Deoxyribonucleases Development Disease Disease Progression Enzymes Etiology Experimental Models Extracellular Matrix FDA approved Faculty Family Fellowship Fellowship Program Fibroblasts Fibrosis Functional disorder Funding Genes Goals Hospitals Human Hydroxyproline In Vitro Incidence Innate Immune Response Innovative Therapy Interstitial Lung Diseases Investigation Knockout Mice Knowledge Laboratories Learning Life Link Lung Lung Transplantation Lung diseases Medical Medicine Mentorship Modeling Molecular Morbidity - disease rate Mus Myofibroblast Organ Organ Model Partner in relationship Pathogenesis Pathologic Patients Phenotype Physicians Play Post-Translational Protein Processing Pre-Clinical Model Prevalence Process Production Protein-arginine deiminase Proteins Pulmonary Fibrosis Quality of life Regulation Research Research Personnel Resources Role Scientist Slice Structure Supportive care Techniques Testing Training Transfection United States United States National Institutes of Health Woman Work aged attenuation care costs career career development coronary fibrosis experimental study extracellular gain of function hospital admission rate human old age (65+)idiopathic pulmonary fibrosis improved in vivo indium-bleomycin inhibitor/antagonist loss of function lung injury member mortality mouse model neutrophil new therapeutic target novel novel therapeutics organ growth outcome forecast overexpression protein function skills small hairpin RNA small molecule inhibitor therapeutic target tissue repair treatment effect

项目摘要

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.

项目摘要/摘要该提案的目的是研究开发发展的分子机制肺纤维化和肺成纤维细胞的纤维化表型，例如特发性肺部疾病肺纤维化（IPF）。 IPF是一种毁灭性，慢性，进行性，纤维化肺部疾病，导致死亡在没有肺移植的情况下3 - 5年。尽管这种疾病被认为很少在美国，有100,000人是高度护理和对质量和数量的重大影响生命施加了重要的伯宁。重要的是，出于不清楚的原因，IPF的事件正在增加。治疗选择仅限于支持性护理，肺移植或无法解决的医疗疗法减慢疾病的进展。这种局限性部分是由于对病理学的不完全理解 IPF的基础。因此，迫切需要提高对细胞和分子机械的理解为了开发新的治疗选择，促成IPF发病机理的障碍。拟议的项目将通过研究肽氨酸脱节酶4（PAD4）的研究来满足这一需求。一种催化petidyl-精氨酸的翻译后修饰的酶保留至petidyl-Citrulline 最近，这与老年动物模型中器官纤维化的发展有关。通过获得功能丧失实验，PAD4对IPF成纤维细胞的纤维化表型的贡献将是决定。此外，通过使用小分子抑制剂，PAD4缺乏对发育的影响 - 在博来霉素小鼠模型中提及肺纤维化，并在体内精确切割肺切片中定义。通过阐明其在肺纤维化发展中的作用，这项工作将确定PAD4是否为可行的纤维化肺疾病的治疗靶标。该提案描述了一项为期三年的研究奖学金计划，该计划将允许主要研究者开始从事肺部疾病的学术研究职业。他将在在他的近亲心态下，杨百翰和妇女医院的肺和重症监护医学赞助商伊万·罗萨斯（Ivan Rosas）博士，他是间质性肺部疾病和肺部模型的专家纤维化和共同赞助者El-Pregaly博士也是间质性肺部疾病和体外领域的专家评估纤维化的技术。原则研究者还将受益于其他高度的专业知识他的科学咨询委员会成员很有成就，并有能力获得全面的知识分子以及该部门和大哈佛大学生物医学社区内的物理资源。此外作为主要研究者职业发展的关键一步，该项目将为随着他从奖学金发展到初级教师，未来的研究努力，最终努力 NIH资助的调查员。