The Inflammatory Index as a Biomarker for Pain in Patients with Sickle Cell Disease

炎症指数作为镰状细胞病患者疼痛的生物标志物

• 批准号: 10618737
• 负责人: Amanda M Brandow
• 金额: $ 69.61万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-26 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618737
• 关键词: Acute Pain; Affect; Biological Assay; Biological Markers; Biological Response Modifiers; Biology; Cells; Chronic; Clinical; Clinical Trials; Complex; Complication; Data; Genes; Genetic Transcription; Goals; Health; Hemoglobinopathies; Hemolysis; Heterogeneity; Immune; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Link; Lipids; Measures; Mutation; Ontology; Pain; Pain Research; Pain management; Pathway Analysis; Patient Outcomes Assessments; Patients; Pattern; Persons; Phase; Plasma; Population; Prognostic Marker; Recurrence; Recurrent pain; Regulator Genes; Reperfusion Injury; Reporter; Research; Sickle Cell Anemia; Sickle Hemoglobin; Signal Transduction; Testing; Training; Transcript; United States; Validation; Work; beta Globin; chemokine; clinical heterogeneity; clinical pain; cohort; cytokine; debilitating pain; differential expression; effective therapy; experience; genome-wide; health care service utilization; immune modulating agents; immunoregulation; inclusion criteria; indexing; individual variation; inflammatory milieu; inter-individual variation; multidisciplinary; novel; prognostic; prognostication; prospective; response

PROJECT SUMMARY/ABSTRACT The overall goal of this proposed research is to develop a biomarker that prognosticates and correlates with the clinical expression of pain in sickle cell disease (SCD). Severe, debilitating pain is the most common complication of SCD, an inherited hemoglobinopathy affecting approximately 100,000 people in the United States. Despite the known genetic defect, there is significant variability in pain expression in patients with SCD. Clinically, some patients experience frequent and recurrent pain while others experience pain only occasionally. Currently, there is no plasma biomarker, linked to pain biology, that can prognosticate patients who are likely to experience more pain than other patients. The lack of a prognostic biomarker for pain is a barrier to targeted, personalized pain treatment. SCD is associated with chronic inflammation with elevated inflammatory mediators (e.g. cytokines, chemokines, lipids) at baseline that increase further during acute pain. However, the degree of inflammation is likely highly variable among patients. Multiple factors, including ongoing effects of recurrent vaso-occlusion, ischemia-reperfusion injury, and hemolysis contribute to SCD inflammation and pain. This project is centered on the concept that pain in SCD is heterogeneous and driven by a complex milieu of inflammatory effectors and immune regulators. A prognostic biomarker that quantitatively and comprehensively assesses the combination of these immune effectors and regulators and correlates with pain in SCD will fill a significant gap in SCD pain research. Ideally, such a biomarker could provide prognostic data and define inclusion criteria for pain clinical trials of immunomodulatory drugs. The following aims are proposed for the R61 Phase: 1) Derive the inflammatory index (I.l.com) for pain in patients with SCD by identifying inflammatory and immune regulatory gene probe sets that will optimally distinguish healthy controls, patients with SCD in baseline health, and patients with SCD in acute pain and 2) Determine whether co-expressed gene modules from patients with SCD correlate with clinical pain data and are concordant with genes included in the I.I.com. Subsequently, the following aims are proposed for the R33 Phase: 1) Determine the reliable and clinically meaningful changes of the I.I.com in patients with SCD and 2) Investigate the preliminary clinical validity of the I.I.com as a prognostic biomarker for pain in patients with SCD. Our collaborative and multidisciplinary team brings research expertise in SCD pain biology, inflammation, and SCD patient-reported outcomes. Our proposed work will refine, replicate and validate the I.I.com as a prognostic biomarker for SCD pain.

项目概要/摘要 这项拟议研究的总体目标是开发一种生物标志物，可以预测并与 镰状细胞病（SCD）疼痛的临床表现。最常见的是严重的、令人衰弱的疼痛 SCD 的并发症，一种遗传性血红蛋白病，影响美国约 100,000 人 国家。尽管存在已知的遗传缺陷，但 SCD 患者的疼痛表达存在显着差异。 临床上，一些患者会经历频繁且反复的疼痛，而另一些患者则仅经历疼痛 偶尔。目前，还没有与疼痛生物学相关的血浆生物标志物可以预测患者的预后 他们可能比其他患者经历更多的疼痛。缺乏疼痛的预后生物标志物是一个问题 阻碍有针对性的、个性化的疼痛治疗。 SCD 与慢性炎症有关 基线时的炎症介质（例如细胞因子、趋化因子、脂质）在急性疼痛期间进一步增加。 然而，患者之间的炎症程度可能差异很大。多种因素，包括 反复血管闭塞、缺血再灌注损伤和溶血的持续影响导致 SCD 炎症和疼痛。该项目的核心概念是 SCD 中的疼痛是异质的且受驱动的 由炎症效应子和免疫调节子组成的复杂环境。一种预后生物标志物 定量、全面地评估这些免疫效应子和调节子的组合， 与 SCD 疼痛相关的研究将填补 SCD 疼痛研究的重大空白。理想情况下，这样的生物标志物可以 为免疫调节药物的疼痛临床试验提供预后数据并定义纳入标准。这 R61 阶段提出以下目标： 1) 推导患者疼痛的炎症指数 (I.l.com) 通过识别炎症和免疫调节基因探针组来最佳地区分 SCD 健康对照、基线健康状况的 SCD 患者以及急性疼痛的 SCD 患者，2) 确定 SCD 患者的共表达基因模块是否与临床疼痛数据相关？ 与 I.I.com 中包含的基因一致。随后，为R33提出了以下目标 阶段：1) 确定 SCD 患者中 I.I.com 的可靠且有临床意义的变化；2) 研究 I.I.com 作为 SCD 患者疼痛预后生物标志物的初步临床有效性。 我们的协作和多学科团队带来了 SCD 疼痛生物学、炎症和 SCD 患者报告的结果。我们提出的工作将完善、复制和验证 I.I.com 作为预测 SCD 疼痛的生物标志物。