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

项目总结/摘要 这项拟议研究的总体目标是开发一种生物标志物， 镰状细胞病（SCD）疼痛的临床表现。严重的，使人衰弱的疼痛是最常见的 SCD的并发症是一种遗传性血红蛋白病，影响美国约10万人， States.尽管存在已知的遗传缺陷，但SCD患者的疼痛表达存在显著差异。 在临床上，有些患者经历频繁和复发性疼痛，而其他人只经历疼痛 在外面讹目前，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疼痛。 比其他病人更容易感到疼痛缺乏疼痛的预后生物标志物是一种 有针对性的个性化疼痛治疗的障碍。SCD与慢性炎症相关， 炎症介质（例如细胞因子、趋化因子、脂质）在基线时增加，在急性疼痛期间进一步增加。 然而，炎症的程度可能在患者之间存在很大差异。等多种因素 反复的血管闭塞、缺血再灌注损伤和溶血的持续影响促成SCD 炎症和疼痛。这个项目的核心概念是SCD中的疼痛是异质性和驱动性的 由炎症效应物和免疫调节物组成的复杂环境。一种预后生物标志物， 定量和全面地评估这些免疫效应物和调节物的组合， 与SCD疼痛的相关性将填补SCD疼痛研究的重大空白。理想情况下，这种生物标志物可以 为免疫调节药物的疼痛临床试验提供预后数据并确定入选标准。的 为R61阶段提出了以下目标：1）导出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， 健康对照、基线健康的SCD患者和急性疼痛的SCD患者，以及2）确定 来自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中的基因一致随后，为R33提出了以下目标 阶段：1）确定SCD患者I.I.com的可靠和有临床意义的变化，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患者报告结局。我们建议的工作将完善，复制和验证I.I.com作为预测 SCD疼痛的生物标志物。

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.