The Role of Chemokine Signaling in Sickle Cell Pain

 描述(由申请人提供)：本项目的总体目标是确定趋化因子CCL2在镰状细胞病(SCD)疼痛感觉中的作用。SCD是一种常见的遗传性疾病，在急性血管闭塞危象期间会出现严重的疼痛；此外，大约50%的患者在成年后会出现慢性疼痛。这种疼痛既有神经性疼痛也有炎症性疼痛，患者报告对触摸和寒冷都有明显的过敏反应。先前的证据表明，在镰刀患者的危象期间和危象之间，趋化因子CCL2都会升高。重要的是，在其他神经病理性疼痛的动物模型中，CCL2与寒冷和机械过敏有关。然而，很少有研究研究CCL2等炎症介质如何参与SCD疼痛。因此，这项建议将探索炎症介质影响SCD疼痛产生和维持的机制。为了实现这一目标，这些研究将使用与人类SCD疼痛表型非常相似的镰状细胞疾病的小鼠模型。就像人类SCD患者报告冷痛和敏化的冷阈值一样，镰刀鼠表现出行为冷过敏，镰刀鼠的感觉神经元对寒冷敏感。目的1将确定作用于CCR2的趋化因子CCL2是否与SCD的感冒敏感性增加有关。以前的研究也注意到镰刀鼠有强烈的机械过敏反应。目的2将确定CCL2是否驱动在SCD中观察到的机械敏化。为了实现这些目标，将进行膜片钳电生理学和被梳理的神经纤维记录，以及钙成像和行为分析。这些相互关联的目标提供了一种定向的、但又是多方面的方法来解决CCL2在与SCD相关的复杂疼痛综合征中的作用。通过解决镰状细胞疾病频繁和严重疼痛的潜在机制，这项提案的目标与NINDS减轻神经和痛苦疾病负担的使命保持一致。

 DESCRIPTION (provided by applicant): The overall goal of this project is to determine the contribution of the chemokine CCL2 to the sensation of pain in Sickle Cell Disease (SCD). SCD is a common genetic disorder that involves crippling pain during acute vaso-occlusive crises; moreover, approximately 50% of patients develop chronic pain by adulthood. This pain has elements of both neuropathic and inflammatory pain, and patients report pronounced hypersensitivity to both touch and cold. Previous evidence has shown that the chemokine CCL2 is elevated both during and between crises in sickle patients. Importantly, CCL2 has been linked to both cold and mechanical hypersensitivity in other animal models of neuropathic pain. However, there has been little research investigating how inflammatory mediators such as CCL2 may contribute to SCD pain. Thus, this proposal will explore mechanisms through which inflammatory mediators influence the generation and maintenance of pain in SCD. To achieve this goal, these studies will use a mouse model of sickle cell disease that closely mimics the human SCD pain phenotype. Just as human patients with SCD report cold pain and sensitized cold thresholds, sickle mice exhibit behavioral cold hypersensitivity and the sensory neurons from sickle mice are sensitized to cold. Aim 1 will determine whether the chemokine CCL2 acting at CCR2 is responsible for the increased cold sensitization in SCD. Previous research has also noted a strong mechanical hypersensitivity in sickle mice. Aim 2 will determine whether CCL2 drives the mechanical sensitization observed in SCD. To achieve these aims, patch clamp electrophysiology and teased nerve fiber recordings will be performed, along with calcium imaging and behavioral assays. These interrelated aims provide a directed, yet multifaceted, approach to address the role of CCL2 in the complex pain syndromes associated with SCD. By addressing the mechanisms underlying the frequent and severe pain of sickle cell disease, this proposal's aims align with the mission of the NINDS to reduce the burden of neurological and painful diseases.