Protein Biomarkers in Lung Allograft Rejection

肺同种异体移植排斥反应中的蛋白质生物标志物

• 批准号: 7394488
• 负责人: CHRIS H WENDT
• 金额: $ 41.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394488
• 关键词: Acute; Allografting; Archives; Area; Arts; Biological Markers; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Chronic; Clara cell; Clara cell-specific protein; Clinical; Complex; Databases; Defensins; Detection; Deuterium; Development; Diagnostic; Disease; Goals; Graft Rejection; Human; Individual; Inflammation; Label; Lung; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Mass Spectrum Analysis; Metalloproteins; Methodology; Methods; Minnesota; Morbidity - disease rate; Numbers; Organ Transplantation; Outcome; Patients; Peptides; Predictive Value; Procedures; Prospective Studies; Proteinase 3; Proteins; Proteome; Proteomics; Relative (related person); Research; Risk; Sampling; Serum; Set protein; Signal Transduction; Site; Solid; Sputum; Staging; Survival Rate; Syndrome; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; Universities; White Blood Cell Count procedure; cohort; lung allograft; mortality; neutrophil; tool

DESCRIPTION (provided by applicant): Lung transplantation is an effective therapy for many end stage lung diseases. Despite advances in immunosuppressive therapy, chronic rejection remains a leading cause of morbidity and mortality. While certain markers of inflammation have been identified currently no set of biomarkers predictably identify patients who are at risk of or currently have chronic rejection. We theorize that there are distinct and reproducible sets of protein products within the lung that characterize chronic rejection and can be characterized into a biosignature of rejection. We chose broncho-alveolar lavage fluid as a starting point to identify a biosignaure of rejection since the small airways are the observable site of chronic rejection and are likely to yield a strong signal. The goal of this project is to identify and validate effective biomarkers for eventual use as diagnostic tools for the detection of chronic lung allograft rejection. This proposal begins with a discovery made during our mass spectrometric analysis of archived bronchoalveolar lavage (BALF) samples of a cohort of well-characterized lung transplant recipients. Samples from patients who subsequently developed chronic rejection or bronchiolitis obliterans syndrome (BOS) had multiple peaks on their mass spectrometry spectrum compared to controls, i.e. those that did not develop BOS. We subsequently identified elevated levels of human neutrophil peptide (HNP) and the decline of Clara Cell Protein as potential biomarkers of BOS. These changes occurred up to 20 months prior to the onset of clinical onset of BOS. In addition, we identified peak ratios by profile analysis of the MALDI-TOF spectrum, including unidentified peaks that predicted those that would develop BOS. Consequently, this proposal focuses on developing diagnostic tools using state-of-the-art proteomics to identify those at risk for developing chronic rejection. We have proposed two major areas of research. One is to validate HNP, Clara Cell Protein and the identified protein ratios as biomarkers of chronic lung transplant rejection in a prospective study of lung transplant recipients. The second is to increase the number of biomarkers for chronic rejection, creating a panel of protein biomarkers that ultimately predicts those with or are at risk for chronic lung transplant rejection.

描述（由申请人提供）：肺移植是许多终末期肺部疾病的有效治疗方法。尽管免疫抑制治疗取得了进展，但慢性排斥反应仍然是发病率和死亡率的主要原因。虽然目前已经确定了某些炎症标志物，但没有一组生物标志物可预测地识别处于慢性排斥风险或目前患有慢性排斥的患者。我们的理论是，在肺内有不同的和可重复的蛋白质产物集，这些蛋白质产物表征慢性排斥反应，并且可以表征为排斥反应的生物特征。我们选择支气管肺泡灌洗液作为识别排斥反应生物信号的起点，因为小气道是慢性排斥反应的可观察部位，并且可能产生强信号。本项目的目标是识别和验证有效的生物标志物，最终用作检测慢性肺移植排斥反应的诊断工具。这项建议始于我们对一组特征良好的肺移植受者的存档支气管肺泡灌洗（BALF）样本进行质谱分析时的发现。与对照组（即未发生BOS的患者）相比，来自随后发生慢性排斥反应或闭塞性细支气管炎综合征（BOS）的患者的样品在其质谱谱上具有多个峰。随后，我们将人中性粒细胞肽（HNP）水平升高和克拉拉细胞蛋白下降确定为BOS的潜在生物标志物。这些变化发生在BOS临床发作前20个月。此外，我们通过MALDI-TOF光谱的轮廓分析确定了峰比，包括预测将发展BOS的未识别峰。因此，这项建议的重点是开发诊断工具，使用最先进的蛋白质组学，以确定那些处于发展慢性排斥反应的风险。我们提出了两个主要的研究领域。一是在肺移植受者的前瞻性研究中验证HNP、Clara细胞蛋白和所鉴定的蛋白质比率作为慢性肺移植排斥反应的生物标志物。第二个是增加慢性排斥反应的生物标志物的数量，创建一组蛋白质生物标志物，最终预测那些患有慢性肺移植排斥反应或有慢性肺移植排斥反应风险的人。