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: 8638624
• 负责人: DAVID Clement WHITCOMB
• 金额: $ 26.3万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638624
• 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; Genotype; Glycine Receptors; Goals; Hospitalization; Human; Hydroxyprostaglandin Dehydrogenases; Image; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Lead; Link; Machine Learning; Maps; Measures; Medical; Messenger RNA; Methods; Morphology; NTF3 gene; Nature; North America; Obstruction; Outcome; 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; improved; inflammatory pain; insight; islet; lifestyle factors; novel; novel strategies; protein expression; public health relevance; rare variant; response; sex

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 pain 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.

慢性胰腺炎（CP）是一种进行性和破坏性的胰腺炎性疾病。之一 最令人痛苦的特征是疼痛，约90%的患者发生疼痛，其中约一半的患者持续疼痛， 这与住院治疗增加和生活质量降低有关。由于有多处疼痛 由于没有标准化的方法来评估CP患者的疼痛， 需要更好地了解CP疼痛的机制以及如何适当治疗。北 美国胰腺炎研究2（NAPS 2）从美国最大的胰腺炎研究中心招募、分型和获得生物标本。 胰腺炎队列，我们已经完成了一项全基因组关联研究（GWAS），包括1171 NAPS 2 CP病例，其详细的表型疼痛数据可用。我们建议分析NAPS 2数据 集和生物标本（DNA，血清，胰腺组织），以确定遗传风险和潜在的机制， 持续疼痛，识别炎症性疼痛的标志物，并描述临床疼痛复合物， 病人管理我们已经通过完整的和嵌套的GWAS鉴定了8个候选基因， “持续”疼痛。目的1将确定这些变异是否与基因的功能变化有关 与持续疼痛表型相关。有针对性的SNP基因分型和基因表达研究将在 进行的研究，包括mRNA的研究和免疫组织化学染色的人类样本。目标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。疼痛是一 活动性炎症的指标，促炎细胞因子增加疼痛，抗炎 减少疼痛的细胞因子。我们将检测500个NAPS 2样本的CRP升高和10种Th 1/Th 2细胞因子， 炎症的生物标志物。对于阳性对照，我们将纳入40例急性胰腺炎患者的血液样本 因疼痛或炎症住院> 4天的患者。Aim 3将应用机器学习 检测基因型、生物标志物和形态学（阻塞）与定量 疼痛模式、严重程度和特征的测量以及SF 12 v2生活质量评分（精神和身体） 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，为疼痛的正确分类提供决策规则 临床试验此外，预计机器学习的使用将通过以下方式提供对疼痛机制的洞察： 将症状特征、生物标志物、成像研究和遗传学与复杂机制最佳地联系起来 在疼痛性脑瘫患者中可见。本研究的目的是利用现有的NAPS 2数据和生物标本 为未来的临床研究构建一个框架，以测试个性化疼痛管理的有效性 基于我们的机器学习预测的病因，而不仅仅是症状。