Biomarkers to stratify pain severity and type in pancreatic disease

项目总结 慢性胰腺炎(CP)是由进行性炎症和纤维化引起的，最常见的是急性胰腺炎 胰腺炎(AP)和AP的反复发作(RAP)，并与糖尿病的长期并发症有关 和胰腺外分泌功能不全。疼痛是AP的三个诊断标准之一，多项研究已经 现在证实，疼痛也是CP患者最显著的症状(77%-93%)。在那里的时候 是否有多种干预措施可用于治疗疼痛，其中许多对CP患者无效：只有25% 慢性胰腺炎患者通过目前的疼痛护理标准实现有意义的疼痛缓解 管理层。到目前为止，还没有根据疼痛的严重程度对疼痛进行分层的慢性胰腺炎疼痛生物标志物 和/或类型，这将指导医生决策或监测治疗反应。这有助于 CP患者群体中巨大的痛苦负担。 为了解决这一知识差距，我们将利用慢性胰腺炎的前瞻性评估 流行病学和转化性研究(继续进行)已在NIDDK的支持下实现-/ NCI资助的慢性胰腺炎、糖尿病和胰腺癌研究联盟(CPDPC)。 继续进行，这将是这项提议的关键资源，是 美国它已经招募了1638名(还在增加)患有CP、AP和RAP的参与者，以及健康和非 胰腺炎症状性对照。这一独特队列的所有参与者都进行了深入的表型鉴定，提供 关于临床症状和一般生活质量变量的详细信息。此外，10个与疼痛相关的变量 记录了有关疼痛类型、严重程度和干预措施的详细信息。由于大小和 多站点性质的继续，队列被拆分为独立的发现和验证队列，以实现 符合FDA标准的生物标记物验证。在本提案的具体目标1和2中，我们将使用血浆和尿液 来自继续发现队列(n&gt；500)的样本，以生成 蛋白质、趋化因子、细胞因子和神经肽。基于质谱学的发现蛋白质组学和 生物标志物的鉴定将使用基于多重抗体的检测方法。 一旦发现有前景的疼痛生物标记物，我们将过渡到验证阶段(具体目标3和4)。 在这一阶段，我们将使用来自独立进行验证队列(N)的尿样和血浆样本 验证特定目标1和2中确定的潜在生物标志物。我们将使用目标液体 用气相色谱/质谱法以及基于抗体的方法进行验证。大的 一些连续的样本及其出色的注释将允许精致的粒状疼痛聚焦 对由此产生的大规模蛋白质组和细胞因子/趋化因子检测数据进行分析。

PROJECT SUMMARY Chronic pancreatitis (CP) results from progressive inflammation and fibrosis, most commonly from acute pancreatitis (AP) and recurrent episodes of AP (RAP), and is associated with long term complications of diabetes and exocrine pancreatic insufficiency. Pain is one of three diagnostic criteria for AP and multiple studies have now confirmed that pain is also the most significant symptom for patients with CP (77-93%). While there are a variety of interventions available to treat pain, many of which are not efficacious in CP patient: only ~25% chronic pancreatitis patients achieve meaningful pain relief with current standard of care for pain management. As of now, there are no chronic pancreatitis pain biomarkers to stratify pain based on severity and/or type, which would guide physician decision making or monitor therapeutic responses. This contributes to the immense burden of pain in this CP patient population. To address this gap in knowledge, we will leverage the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) which has been realized under the auspice of the NIDDK-/ NCI-funded Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). PROCEED, which will be a key resource for this proposal, is the first prospective longitudinal CP cohort in the U.S. It has enrolled 1638 (and counting) participants with CP, AP, and RAP, as well as healthy and non- pancreatitis symptomatic controls. All participants of this unique cohort undergo deep phenotyping, provide detailed information on clinical symptoms, and general QoL variables. Furthermore, 10 pain-associated variables are recorded providing detailed information about pain types, severities and interventions. Due to the size and multi-site nature of PROCEED, the cohort was split into independent discovery and validation cohorts to enable FDA-compliant biomarker validation. In Specific Aims 1 and 2 of this proposal, we will use plasma and urine samples from the PROCEED discovery cohort (n >500) to generate quantitative multi-omics datasets of the proteins, chemokines, cytokines and neuropeptides. Mass spectrometry-based discovery proteomics and multiplexed antibody-based assays will be used for the biomarker identification. Upon discovery of promising pain biomarkers, we will transition to the validation phase (Specific Aims 3 and 4). In this phase, we will use the urine and plasma samples from the independent PROCEED validation cohort (n >500) to validate the potential biomarkers identified in the Specific Aims 1 and 2. We will use targeted liquid chromatography/mass spectrometry methods as well as antibody-based method for the validation. The large number of PROCEED samples and their superb annotation will allow for an exquisitely granular pain-focused analysis of the resulting large scale proteomic and cytokine/chemokine assay data.