Biomarkers to stratify pain severity and type in pancreatic disease

用于对胰腺疾病疼痛严重程度和类型进行分层的生物标志物

• 批准号: 10707763
• 负责人: Jami Lynn Saloman
• 金额: $ 77.81万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707763
• 关键词: Address; Antibodies; Arthritis; Biological; Biological Assay; Biological Markers; Blood; Calcitonin Gene-Related Peptide; Chronic; Clinical; Cohort Studies; Complications of Diabetes Mellitus; Data; Decision Making; Dedications; Diabetes Mellitus; Disease; Endoscopy; Enrollment; Evaluation; Exocrine pancreatic insufficiency; Fibrosis; Funding; Hand; Home; IL6ST gene; Inflammation; Interstitial Cystitis; Intervention; Knowledge; Leadership; Letters; Malignant neoplasm of pancreas; Maps; Mass Spectrum Analysis; Methods; Monitor; Multiomic Data; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Nerve Growth Factors; Neuropathy; Neuropeptides; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Pain; Pain management; Pancreas; Pancreatic Diseases; Pancreatitis; Participant; Patients; Pelvis; Phase; Phenotype; Physicians; Plasma; Plasma Proteins; Platelet-Derived Growth Factor; Proteins; Proteomics; Quality of life; Recurrence; Research Personnel; Resources; Sampling; Sampling Studies; Serum; Set protein; Severities; Site; Symptoms; Syndrome; Testing; Transforming Growth Factor beta; Up-Regulation; Urine; Validation; Visceral pain; acute pancreatitis; biomarker identification; biomarker validation; candidate marker; chemokine; chronic pain management; chronic pancreatitis; clinically relevant; cohort; cytokine; debilitating pain; design; diagnostic criteria; epidemiology study; experience; improved; insight; liquid chromatography mass spectrometry; member; molecular marker; pain relief; patient population; potential biomarker; prospective; secondary analysis; standard of care; success; translational study; treatment response; urinary; validation studies

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.

项目概要 慢性胰腺炎 (CP) 由进行性炎症和纤维化引起，最常见的是急性胰腺炎 胰腺炎 (AP) 和 AP 复发 (RAP)，并与糖尿病的长期并发症相关 和胰腺外分泌功能不全。疼痛是 AP 的三个诊断标准之一，多项研究表明 目前证实疼痛也是 CP 患者最显着的症状（77-93%）。在那里 有多种干预措施可用于治疗疼痛，其中许多对 CP 患者无效：仅约 25% 慢性胰腺炎患者通过当前的疼痛护理标准实现有意义的疼痛缓解 管理。截至目前，还没有慢性胰腺炎疼痛生物标志物可以根据严重程度对疼痛进行分层 和/或类型，这将指导医生决策或监测治疗反应。这有助于 脑瘫患者群体承受着巨大的痛苦。 为了弥补这一知识差距，我们将利用慢性胰腺炎的前瞻性评估来 流行病学和转化研究 (PROCEED) 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)。 PROCEED 将成为该提案的关键资源，是第一个前瞻性纵向 CP 队列 美国已招募了 1638 名（仍在增加）CP、AP 和 RAP 参与者，以及健康和非健康参与者 胰腺炎症状控制。这个独特队列的所有参与者都经过深度表型分析，提供 有关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 记录提供有关疼痛类型、严重程度和干预措施的详细信息。由于尺寸和 PROCEED 的多站点性质，该队列被分为独立的发现和验证队列，以便能够 符合 FDA 要求的生物标志物验证。在该提案的具体目标 1 和 2 中，我们将使用血浆和尿液 来自 PROCEED 发现队列（n > 500）的样本，以生成定量多组学数据集 蛋白质、趋化因子、细胞因子和神经肽。基于质谱的发现蛋白质组学和 基于多重抗体的测定将用于生物标志物鉴定。 在发现有希望的疼痛生物标志物后，我们将过渡到验证阶段（具体目标 3 和 4）。 在此阶段，我们将使用来自独立 PROCEED 验证队列的尿液和血浆样本（n >500）来验证特定目标 1 和 2 中确定的潜在生物标志物。我们将使用目标液体 色谱/质谱方法以及基于抗体的验证方法。大的 大量的 PROCEED 样本及其出色的注释将允许以精细的粒度为中心的疼痛 分析由此产生的大规模蛋白质组学和细胞因子/趋化因子测定数据。