Biomarker and Metabolomic Investigations in ALI

ALI 的生物标志物和代谢组学研究

• 批准号: 8466608
• 负责人: ANNETTE M. ESPER
• 金额: $ 9.62万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466608
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alveolar; Biological; Biological Assay; Biological Markers; Bronchoalveolar Lavage Fluid; Characteristics; Chromatography; Clinical; Complex; Critical Illness; Data; Databases; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Disease susceptibility; Epithelial; Exhalation; Fourier Transform; Goals; HMGB1 Protein; Human Biology; Immunoglobulins; Inflammatory; Injury; Investigation; Lead; Learning; Life; Light; Link; Lung; Mass Spectrum Analysis; Matrix Metalloproteinases; Measures; Medical; Metabolic; Metabolic Pathway; Monitor; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Plasma; Population Control; Process; Production; Protocols documentation; Research; Resolution; Risk; Sampling; Science; Sepsis; Specimen; Steroids; Stratification; Stromelysin 1; Survivors; Systems Biology; Techniques; Testing; Therapeutic; Time; Tissues; Work; base; biobank; cost effective; design; disease phenotype; drug development; effective therapy; improved; innovation; insight; lung injury; member; metabolomics; mortality; novel; outcome forecast; receptor for advanced glycation endproducts; repaired; repository; response; tool

DESCRIPTION (provided by applicant): The overall objective of this project is to enhance our understanding of acute lung injury (ALI) pathogenesis and to expand the potential utility of biomarkers and metabolomic analysis. Acute lung injury (ALI) is a life- threatening disease that affects 200,000 people each year in the US and, because there is no defined medical therapy, mortality rates remain high. Our ability to determine which at-risk patients will progress to ALI i limited, and although specific biomarkers have been identified, there remain unanswered questions about how these biomarkers contribute to ALI pathogenesis. RAGE is a marker of alveolar epithelial lung injury, and elevated levels of soluble RAGE (sRAGE) have been identified in the BALF of patients with ALI when compared to non-ALI patients. However, the RAGE activation pathway is complex and there is limited data explaining the mechanism of sRAGE entry into the alveolar space. HMGGB1 and MMPs have been implicated in the RAGE pathway; however, data showing that all these markers are concomitantly increased in ALI is unavailable. Analyzing specimens from the NHLBI biologic specimen repository allows us to confirm and extend our initial observations about sRAGE and active metabolite patterns. We propose to test the hypothesis that sRAGE, HMGB1 and MMP-3 and -13 work as a functioning unit and changes in levels over time in ALI patients will be associated with mortality. We will extend this data using metabolomics to show that specific metabolic pathways are associated with biomarker activation and survival status. The specific aims are designed to : 1) test the hypothesis that sRAGE, HMGB1 and MMPs are coordinately increased in the BALF of patients with ALI compared to controls at risk for ALI; and determine whether sustained increases in sRAGE, HMGB1 and MMP levels over time are associated with mortality in ALI patients; and 2) develop a high- resolution metabolomic database for ALI linked to outcomes in order to: determine the association between specific metabolomic pathways and biomarkers analyzed in Aim 1, and identify candidate metabolites that differentiate ALI survivors and non-survivors. To test our hypotheses we will analyze BAL samples from the NHLBI biorepository obtained from the ARDSnet LaSRS trial, which provides BALF collected at two different time points. As a control population, we will also obtain BALF from mechanically ventilated patients with an at- risk diagnosis for ALI. We will perform assays measuring HMGB1, MMP-3 and -13, and sRAGE both in BALF. Metabolomic profiling of ARDS patients will be performed via high-resolution mass spectrometry. The long- term goal is to develop an affordable approach that can be used for predicting disease susceptibility, diagnosis, risk stratification, response to therapy and prognosis.

描述（由申请人提供）：该项目的总体目的是增强我们对急性肺损伤（ALI）发病机理的理解，并扩大生物标志物和代谢组分分析的潜在效用。急性肺损伤（ALI）是一种威胁生命的疾病，每年在美国影响20万人，并且由于没有确定的医疗疗法，死亡率仍然很高。我们确定哪些高危患者将进展到ALI I有限的能力，尽管已经确定了特定的生物标志物，但仍未解决这些生物标志物如何对ALI发病机理的贡献。愤怒是肺泡上皮肺损伤的标志物，与非ALI患者相比，在ALI患者的BALF患者中已经确定了可溶性愤怒水平（SRAGE）。但是，愤怒的激活途径是复杂的，并且有限的数据解释了Srage进入肺泡空间的机制。 HMGGB1和MMP与愤怒途径有关。但是，数据表明，ALI中所有这些标记的同时增加是不可用的。分析来自NHLBI生物学标本存储库的标本使我们能够确认并扩展有关SRAGE和主动代谢物模式的初始观察结果。我们建议检验以下假设：Srage，HMGB1和MMP -3和-13作为功能单位起作用，而ALI患者随着时间的推移随时间的变化将与死亡率有关。我们将使用代谢组学扩展这些数据，以表明特定的代谢途径与生物标志物激活和生存状态有关。该特定目的旨在：1）检验以下假设：与有ALI风险的对照组相比，ALI患者的SRAGE，HMGB1和MMP在ALI患者的BALF中有协同增加；并确定随着时间的流逝，SRAGE，HMGB1和MMP水平的持续增加与ALI患者的死亡率有关； 2）为与结果相关的ALI开发一个高分辨率代谢组数据库，以确定AIM 1中分析的特定代谢组途径与生物标志物之间的关联，并确定分化Ali幸存者和非幸存者的候选代谢物。为了检验我们的假设，我们将分析从Ardsnet Lasrs试验中获得的NHLBI生物座位的BAL样品，该试验提供了在两个不同时间点收集的BALF。作为对照人群，我们还将从具有ALI风险诊断的机械通风患者那里获得BALF。我们将执行测量HMGB1，MMP -3和-13的测定法，并在BALF中进行SRAGE。 ARDS患者的代谢组分析将通过高分辨率质谱法进行。长期目标是开发一种可负担的方法，该方法可用于预测疾病的易感性，诊断，风险分层，对治疗和预后的反应。