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

• 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
• 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

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.

摘要 系统性硬化症(SSC；硬皮病)是一种特发性结缔组织疾病，其特征是 增加皮肤和内脏(如肺部)中胶原的产生和沉积。这个 SSC的病因尚不清楚，尽管有遗传影响、环境侮辱和异常的作用 免疫功能是积极研究的对象。间质性肺病(ILD)是SSc的并发症。 目前是这种疾病患者的主要死亡原因。特发性肺纤维化(IPF)是 也是一种发病率和死亡率都很高的纤维化疾病。我们有一个独特的资源，由肺组织组成 取自正常供者、SSc患者和IPF患者以及匹配的原代肺成纤维细胞。我们 已经使用肺组织来生成组织微阵列(TMA)，其中包括正常肺、SSC肺和 在同一TMA上的IPF肺核。我们推测，胶原蛋白组的改变，包括后 翻译修饰，代表了肺部并发症的一个新的和临床相关的特征 SSC和IPF。我们进一步假设，胶原羟化的非常特殊的部位调节着反应。 原代成人肺成纤维细胞。我们建议使用一种新的胶原靶向蛋白质组学方法。 定位和测量肺组织中的胶原类型和翻译后修饰 确定疾病(SSC与IPF)和表型(正常与纤维化)的变化。翻译后确定 将合成修饰的胶原肽，以测试正常、SSC和IPF成纤维细胞的反应 肺组织中的多肽。我们的发现将促进靶向治疗的发展，还将 支持识别肺纤维化的新生物标志物。