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.

项目概要/摘要该提案的目的是研究发展的分子机制特发性纤维化肺疾病中的肺纤维化和肺成纤维细胞的促纤维化表型肺纤维化 (IPF) 是一种破坏性、慢性、进行性纤维化肺部疾病，可导致死亡。尽管这种疾病被认为是罕见的，但如果不进行肺移植，则需要 3-5 年。美国大约有 100,000 人——护理成本高昂，对质量和数量产生重大影响重要的是，IPF 的发病率正在增加，原因尚不清楚。选择仅限于支持性护理、肺移植或无法解决问题但更有效的药物治疗减缓疾病进展的部分原因是对病理生理学的不完全理解。因此，迫切需要提高对 IPF 的细胞和分子机制的了解。有助于 IPF 发病机制的动物学研究，以便开发新的治疗选择。拟议的项目将通过研究肽基精氨酸脱亚胺酶 4 (PAD4) 来满足这一需求，催化肽基精氨酸残基翻译后修饰为肽基瓜氨酸的酶最近，这与老年动物模型器官纤维化的发展有关。在功能获得和功能丧失实验中，PAD4 对 IPF 成纤维细胞促纤维化表型的贡献将是此外，通过使用小分子抑制剂，确定了 PAD4 缺陷对发育的影响。博莱霉素小鼠模型和离体人体精密切割肺切片中肺纤维化的研究将通过阐明其在肺纤维化发展中的作用，这项工作将确定 PAD4 是否是一种纤维化肺病的可行治疗靶点。该提案描述了一项为期三年的研究奖学金计划，该计划将允许主要研究者他将在肺部疾病部门开展该项目。在他的密切指导下，布莱根妇女医院的肺科和重症监护医学赞助人Ivan Rosas博士是间质性肺疾病和肺病临床前模型领域的专家纤维化，共同发起人 El-Chemaly 博士，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也将受益于其他高度专业人士的专业知识。其科学咨询委员会的成就卓著的成员可以接触到全面的知识除了该部门和更大的哈佛生物医学界内可用的物质资源。作为首席研究员职业发展的关键一步，该项目将为未来的研究工作，随着他从研究员晋升为初级教师，并最终成为独立的 NIH 资助的调查员。