Proteomics of Pancreatic Fluid and Urine in Chronic Pancreatitis

慢性胰腺炎胰液和尿液的蛋白质组学

• 批准号: 7913684
• 负责人: Joao A Paulo
• 金额: $ 5.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913684
• 关键词: Address; Biological Assay; Body Fluids; Chronic; Cicatrix; Clinical; Control Groups; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Endocrine; Etiology; Evaluation; Functional disorder; Goals; Health Care Costs; Image; Inflammation; Inflammatory; Investigation; Liquid substance; Mass Spectrum Analysis; Methodology; Mission; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Pancreas; Pancreatic Diseases; Pancreatic carcinoma; Pancreatitis; Pathogenesis; Pathway interactions; Patients; Physiological; Proteins; Proteome; Proteomics; Relative (related person); Research Proposals; Therapeutic; Urine; Wages; advanced disease; base; chronic abdominal pain; chronic pancreatitis; clinical Diagnosis; cohort; innovation; protein profiling; public health relevance; response

DESCRIPTION (provided by applicant): Chronic pancreatitis (CP) is a progressively debilitating disease for which only moderate to advanced diagnosis is possible. In addition, the evaluation of chronic abdominal pain under the suspicion of CP results in millions of dollars in healthcare costs and lost wages annually. CP is characterized by chronic inflammation and progressive scarring leading to irreversible damage to the pancreas, resulting in loss of exocrine and endocrine function and in some cases pancreas carcinoma. The diagnosis of CP within a "therapeutic window" has remained elusive due to our poor understanding of the disease and scarce morphological changes on imaging studies in early and mild disease. The understanding of CP pathogenesis is paramount in early diagnosis. Furthermore, pathophysiology based therapy focused on inflammation could modify or retard disease progression. The health-related topics that I address in this research proposal are: (1) CP pathogenesis is currently poorly understood and (2) clinical diagnosis of CP detects only moderate to advanced disease. I hypothesize that CP-specific proteins can be identified by comprehensive, quantitative proteomic profiling of pancreatic fluid (PF) and that such perturbations of the pancreatic protein secretome is reflected in excreted urine. In Specific Aim 1 (SA1), I will determine if inflammatory proteins in PF are etiology-specific. Using quantitative mass spectrometry, we will evaluate the PF from 6 different etiologies of advanced CP, plus a non-diseased control group and compare the inflammatory protein profile to generate an inclusion list to be used in Specific Aim 2 (SA2). This list of proteins will be validated in SA2 using two large cohorts (1) non-pancreatic disease and (2) CP with varying degrees of pancreatic deficiency. These results will be important in assessing the value of the proteins discovered in SA1 for diagnostic applications. In Specific Aim 3 (SA3), I will investigate inflammation-related proteins in the urine of CP subjects using directed quantitative mass spectrometry. I hypothesize that proteins discovered in SA1 and validated in SA2 can also be identified in urine in SA3. CP- specific, inflammatory-related proteins identified using the strategy outlined herein will originate from: (1) Pancreatic fluid-a proximal body fluid which is ideal for investigation of physiological pathways of pancreatic dysfunction and (2) Urine-a noninvasively collected fluid that is well-suited for clinical diagnostics. While there are many classes of proteins that can be investigated with proteomics in PF, I chose to focus on inflammatory proteins because characterization of their expression may have both diagnostic and therapeutic implications. In conforming with the mission of the NIDDK, I aim to determine the identity, relative quantity, cellular origin, and molecular function of distinct sets of CP-specific, inflammatory proteins with the long-term goals of (1) understanding the inflammatory protein response of CP with respect to etiology, (2) identifying candidate diagnostic markers, and (3) discovering targets for directed therapy. PUBLIC HEALTH RELEVANCE: Chronic pancreatitis pathogenesis is currently poorly understood and its clinical diagnosis is limited to moderate to advanced disease. I hypothesize that etiology-specific inflammatory proteins are present in the pancreatic fluid and urine of chronic pancreatitis patients and that these proteins can be used in a mass spectrometry-based assay with diagnostic and therapeutic potential. I aim to comprehensively investigate and comparatively analyze the inflammatory proteome of non-pancreatitis and CP cohorts of different etiologies using cutting-edge and innovative mass spectrometric methodologies.

描述（由申请人提供）：慢性胰腺炎（CP）是一种逐渐使人衰弱的疾病，只能进行中度至晚期诊断。此外，对疑似慢性腹痛的慢性腹痛进行评估每年会导致数百万美元的医疗费用和工资损失。 CP 的特点是慢性炎症和进行性疤痕形成，导致胰腺不可逆损伤，导致外分泌和内分泌功能丧失，在某些情况下甚至导致胰腺癌。由于我们对这种疾病了解甚少，并且早期和轻度疾病的影像学研究很少有形态学变化，因此在“治疗窗口”内对 CP 的诊断仍然难以捉摸。了解 CP 发病机制对于早期诊断至关重要。此外，基于病理生理学的针对炎症的治疗可以改变或延缓疾病进展。我在本研究提案中讨论的与健康相关的主题是：(1) 目前对 CP 发病机制知之甚少，(2) CP 的临床诊断仅检测到中度至晚期疾病。我假设可以通过对胰液 (PF) 进行全面、定量的蛋白质组学分析来鉴定 CP 特异性蛋白，并且胰腺蛋白分泌组的这种扰动反映在排泄的尿液中。在特定目标 1 (SA1) 中，我将确定 PF 中的炎症蛋白是否具有病因学特异性。我们将使用定量质谱法评估 6 种不同病因的晚期 CP 以及非患病对照组的 PF，并比较炎症蛋白谱，以生成用于特定目标 2 (SA2) 的包含列表。该蛋白质列表将在 SA2 中使用两个大型队列进行验证：(1) 非胰腺疾病和 (2) 具有不同程度胰腺缺陷的 CP。这些结果对于评估 SA1 中发现的蛋白质的诊断应用价值非常重要。在特定目标 3 (SA3) 中，我将使用定向定量质谱法研究 CP 受试者尿液中与炎症相关的蛋白质。我假设在 SA1 中发现并在 SA2 中验证的蛋白质也可以在 SA3 中的尿液中被识别。使用本文概述的策略鉴定的CP特异性炎症相关蛋白将源自：(1)胰液——一种近端体液，非常适合研究胰腺功能障碍的生理途径；(2)尿液——一种非侵入性收集的液体，非常适合临床诊断。虽然可以通过 PF 蛋白质组学研究许多类别的蛋白质，但我选择关注炎症蛋白，因为它们表达的特征可能具有诊断和治疗意义。根据 NIDDK 的使命，我的目标是确定不同 CP 特异性炎症蛋白组的身份、相对数量、细胞起源和分子功能，长期目标是 (1) 了解 CP 相对于病因的炎症蛋白反应，(2) 识别候选诊断标记物，以及 (3) 发现定向治疗的靶点。 公共卫生相关性：目前对慢性胰腺炎的发病机制知之甚少，其临床诊断仅限于中度至晚期疾病。我假设慢性胰腺炎患者的胰液和尿液中存在病因特异性炎症蛋白，并且这些蛋白可用于具有诊断和治疗潜力的基于质谱的测定。我的目标是使用尖端和创新的质谱方法全面研究和比较分析不同病因的非胰腺炎和 CP 队列的炎症蛋白质组。