Evaluation of Pain in Chronic Pancreatitis using the NAPS2 cohorts

使用 NAPS2 队列评估慢性胰腺炎的疼痛

• 批准号: 8876665
• 负责人: DAVID Clement WHITCOMB
• 金额: $ 14.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876665
• 关键词: Alcohol consumption; Alcohols; American; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Biological; Biological Assay; Biological Markers; Blood specimen; C-reactive protein; Candidate Disease Gene; Categories; Classification; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Complication; DNA; Data; Data Set; Detection; Development; Discrimination; Distress; Effectiveness; Etiology; Evaluation; Failure; Frequencies; Funding; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Transcription; Genetic study; Genotype; Glycine Receptors; Goals; Health; Hospitalization; Human; Image; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Lead; Link; Machine Learning; Maps; Measures; Medical; Messenger RNA; Methods; Morphology; NTF3 gene; Nature; North America; Obstruction; Outcome; Oxidoreductase; Pain; Pain Map; Pain Origin; Pain management; Pancreas; Pancreatic Diseases; Pancreatitis; Patients; Pattern; Phenotype; Physicians; Predisposition; Preventive; Procedures; Proteins; Psyche structure; Quality of life; Recruitment Activity; Reporting; Research; Research Design; Risk; SNP genotyping; Sampling; Serum; Severities; Smoking; Staining method; Stains; Symptoms; TLR4 gene; Testing; Therapeutic Agents; Tissue Sample; Tissues; Total Pancreatectomy; Validation; Variant; X-Ray Computed Tomography; acute pancreatitis; base; chronic pain; chronic pancreatitis; cohort; cytokine; design; disability; effective therapy; exome; exome sequencing; genetic variant; genome wide association study; genome-wide; imaging biomarker; improved; inflammatory pain; insight; islet; lifestyle factors; novel; novel strategies; protein expression; rare variant; response; sex

DESCRIPTION (provided by applicant): Chronic pancreatitis (CP) is a progressive and destructive inflammatory disorder of the pancreas. One of the most distressing features is pain, which occurs in ~90% of patients, about half of whom have constant pain, which is associated with increased hospitalization and lower quality of life. Since there are multiple pain etiologies and since no standardized method exists to assess pain in patients with CP, novel approaches are needed to better understand the mechanisms of pain in CP and how it can be appropriately treated. The North American Pancreatitis Study 2 (NAPS2) recruited, phenotyped, and obtained biospecimens from the largest US cohort of pancreatitis, and we have completed a genome-wide association study (GWAS) that includes 1,171 NAPS2 CP cases for whom detailed phenotypic pain data are available. We propose to analyze the NAPS2 data set and biospecimens (DNA, serum, pancreas tissue) to define genetic risks and potential mechanisms of constant pain, identify markers of inflammatory pain, and characterize clinical pain complexes that can guide patient management. We have already identified through the full and a nested GWAS 8 candidate genes for "constant" pain. Aim 1 will determine whether these variants are associated with functional changes in genes associated with the constant pain phenotype. Targeted SNP genotyping and gene expression studies will be conducted, including mRNA studies and immunohistochemical staining in human samples. Aim 2 will determine whether c-reactive protein (CRP) or cytokine biomarkers correlate with constant pain. Pain is an indicator of active inflammation, with pro-inflammatory cytokines increasing pain, and anti-inflammatory cytokines diminishing pain. We will test 500 NAPS2 samples for elevated CRP and 10 Th1/Th2 cytokines as biomarkers of inflammation. For positive controls we will include blood samples from 40 acute pancreatitis patients who remain hospitalized for > 4 days for pain or inflammation. Aim 3 will apply machine-learning approaches to test for correlation of genotype, biomarkers, and morphology (obstruction) with quantitative measures of pain pattern, severity, and character as well as SF12 v2 quality of life scores (mental and physical) while controlling for sex, smoking, and alcohol. We anticipate that our machine learning approaches will provide decision rules for the proper classification of pain according to etiology worthy of formal testing in clinical trials. In addition, use of machine learning is anticipated to provide insight into pai mechanism by optimally linking the symptoms signatures, biomarkers, imaging studies, and genetics to complex mechanisms that are seen in patients with painful CP. The goal of this study is to use existing NAPS2 data and biospecimens to construct a framework for future clinical studies that test the effectiveness of personalized pain management based on our machine-learning-predicted etiology rather than symptoms alone.

描述（由申请人提供）：慢性胰腺炎（CP）是胰腺的进行性和破坏性炎症性疾病。最令人痛苦的特征之一是疼痛，疼痛发生在约90％的患者中，其中一半持续疼痛，这与住院增加和生活质量下降有关。由于存在多种疼痛病因，并且由于没有标准化的方法来评估CP患者的疼痛，因此需要采用新颖的方法来更好地了解CP疼痛的机制以及如何适当治疗。北美胰腺炎研究2（NAPS2）从美国最大的胰腺炎群中募集，表型和获得了生物测量，我们已经完成了全基因组范围的关联研究（GWAS），其中包括1,171个NAPS2 CP案例，其中详细表型疼痛数据可用。我们建议分析NAPS2数据集和生物测量（DNA，血清，胰腺组织），以定义遗传风险和恒定疼痛的潜在机制，鉴定炎症性疼痛的标志，并表征可以指导患者管理的临床疼痛复合体。我们已经通过完整的和嵌套的GWAS 8候选基因确定了“恒定”疼痛。 AIM 1将确定这些变体是否与与恒定疼痛表型相关的基因的功能变化相关。将进行靶向的SNP基因分型和基因表达研究，包括人类样品中的mRNA研究和免疫组织化学染色。 AIM 2将确定C反应蛋白（CRP）或细胞因子生物标志物是否与持续疼痛相关。疼痛是主动炎症的指标，促炎细胞因子会增加疼痛，抗炎细胞因子减轻疼痛。我们将测试500个NAPS2样品的CRP升高和10个TH1/TH2细胞因子作为炎症的生物标志物。对于阳性对照，我们将包括来自40名急性胰腺炎患者的血液样本，这些患者在疼痛或炎症中住院率超过4天。 AIM 3将采用机器学习方法来测试基因型，生物标志物和形态学（梗阻）的相关性，并使用定量的疼痛模式，严重性和特征以及SF12 V2 V2 V2的生活质量得分（心理和身体）进行控制，同时控制 性，吸烟和酒精。我们预计我们的机器学习方法将根据值得正式测试的病因为适当分类疼痛提供决策规则 在临床试验中。此外，预计使用机器学习可以通过最佳地将症状特征，生物标志物，成像研究和遗传学与复杂机制联系起来，从而提供对PAI机制的见解，这些机制在疼痛CP的患者中可见。这项研究的目的是使用现有的NAPS2数据和生物测量来为未来的临床研究构建一个框架，以基于我们的机器学习预测的病因来测试个性化疼痛管理的有效性，而不是仅症状。