Development of proteomic-based ECM signatures for lung fibrosis

基于蛋白质组学的肺纤维化 ECM 特征的开发

基本信息

批准号：
10284461
负责人：
Peggi M Angel
金额：
$ 36.49万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284461
关键词：
Adult Autopsy COL1A1 gene COL1A2 gene Cause of Death Cell physiology Chest Clinical Collagen Complication Connective Tissue Diseases Data Deposition Development Disease Etiology Extracellular Matrix Fibroblasts Fibrosis Genes Genetic Histopathology Human Hydroxylation Interstitial Lung Diseases Investigation Lung Lung Adenocarcinoma Lysine Measurement Measures Methods Modification Morbidity - disease rate Normal tissue morphology Onset of illness Organ Pathologic Pathology Patients Peptides Phenotype Physiology Pilot Projects Post-Translational Protein Processing Post-Translational Regulation Process Production Proline Proteome Proteomics Pulmonary Fibrosis Regulation Reporting Resolution Resources Role Sampling Scleroderma Signal Transduction Site Skin Structure of parenchyma of lung Systemic Scleroderma Testing Tissue Microarray Tissue imaging Tissues Translational Regulation Variant Virus Diseases Work X-Ray Computed Tomography base biomarker identification clinically relevant environmental agent idiopathic pulmonary fibrosis immune function migration molecular pathology mortality novel novel marker placebo controlled study response targeted treatment tumor microenvironment

Adult Autopsy COL1A1 gene COL1A2 gene Cause of Death Cell physiology Chest Clinical Collagen Complication Connective Tissue Diseases Data Deposition Development Disease Etiology Extracellular Matrix Fibroblasts Fibrosis Genes Genetic Histopathology Human Hydroxylation Interstitial Lung Diseases Investigation Lung Lung Adenocarcinoma Lysine Measurement Measures Methods Modification Morbidity - disease rate Normal tissue morphology Onset of illness Organ Pathologic Pathology Patients Peptides Phenotype Physiology Pilot Projects Post-Translational Protein Processing Post-Translational Regulation Process Production Proline Proteome Proteomics Pulmonary Fibrosis Regulation Reporting Resolution Resources Role Sampling Scleroderma Signal Transduction Site Skin Structure of parenchyma of lung Systemic Scleroderma Testing Tissue Microarray Tissue imaging Tissues Translational Regulation Variant Virus Diseases Work X-Ray Computed Tomography base biomarker identification clinically relevant environmental agent idiopathic pulmonary fibrosis immune function migration molecular pathology mortality novel novel marker placebo controlled study response targeted treatment tumor microenvironment

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项目摘要

ABSTRACT Systemic sclerosis (SSc; scleroderma) is an idiopathic disorder of connective tissue characterized by increased production and deposition of collagen in the skin and internal organs such as the lungs. The etiology of SSc is unknown, although the role of genetic influences, environmental insults and abnormal immune function are subjects of active investigation. Interstitial lung disease (ILD) is a complication of SSc and is currently the leading cause of death in patients with this disease. Idiopathic pulmonary fibrosis (IPF) is also a fibrotic disease with high morbidity and mortality. We have a unique resource consisting of lung tissues from normal donors, patients with SSc and patients with IPF as well as matching primary lung fibroblasts. We have used the lung tissues to generate tissue microarrays (TMAs) that include normal lung, SSc lung, and IPF lung cores on the same TMA. We hypothesize that alteration of the collagen proteomes, including post- translational modifications, represents a novel and clinically relevant signature of pulmonary complications of SSc and IPF. We further hypothesize that very specific sites of collagen hydroxylation regulate the response of primary adult human lung fibroblasts. We propose to use a novel collagen-targeting proteomic approach to localize and measure collagen types and post- translational modifications within the lung tissues and identify disease (SSc vs. IPF) and phenotype (normal vs. fibrosis) changes. Identified post-translationally modified collagen peptides will be synthesized to test the response of fibroblasts from normal, SSc and IPF lung tissues to the peptides. Our findings will facilitate the development of targeted therapies and will also support the identification of novel biomarkers for pulmonary fibrosis.

抽象的系统性硬化症（SSC;硬皮病）是一种以特征性组织为特征的特发性疾病胶原蛋白在皮肤和内脏（例如肺部）中的产生和沉积增加。这 SSC的病因尚不清楚，尽管遗传影响，环境侮辱和异常的作用免疫功能是主动研究的受试者。间质性肺疾病（ILD）是SSC的并发症目前是该疾病患者的主要死亡原因。特发性肺纤维化（IPF）为也是一种高发病率和死亡率的纤维化疾病。我们有一个由肺组织组成的独特资源来自正常供体，SSC患者和IPF患者以及原发性肺成纤维细胞。我们已经使用肺组织产生组织微阵列（TMA），包括正常肺，SSC肺和同一TMA上的IPF肺核。我们假设胶原蛋白组的改变，包括翻译修饰代表了肺部并发症的新颖且临床上相关的特征 SSC和IPF。我们进一步假设胶原蛋白羟基化非常具体的位点调节了反应原发性成年人肺成纤维细胞。我们建议使用一种新颖的胶原蛋白蛋白质组学方法在肺组织内定位和测量胶原蛋白类型和翻译后修饰鉴定疾病（SSC与IPF）和表型（正常与纤维化）变化。在翻译后确定将合成改良的胶原蛋白肽，以测试正常，SSC和IPF的成纤维细胞的响应肺组织到肽。我们的发现将促进目标疗法的发展，也将支持鉴定新的生物标志物用于肺纤维化。