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CCL 2对镰状细胞病（SCD）疼痛感觉的贡献。SCD是一种常见的遗传性疾病，在急性血管闭塞性危象期间涉及致残性疼痛;此外，大约50%的患者在成年后发展为慢性疼痛。这种疼痛具有神经性疼痛和炎性疼痛的元素，并且患者报告对触摸和寒冷都明显过敏。先前的证据表明，趋化因子CCL 2在镰状患者的危象期间和危象之间都升高。重要的是，在其他神经性疼痛的动物模型中，CCL 2与冷和机械超敏反应有关。然而，很少有研究调查CCL 2等炎症介质如何导致SCD疼痛。因此，这项建议将探讨炎症介质影响SCD疼痛的产生和维持的机制。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病小鼠模型。就像SCD患者报告冷痛和致敏冷阈值一样，镰状小鼠表现出行为冷超敏反应，并且镰状小鼠的感觉神经元对冷敏感。目的1将确定趋化因子CCL 2作用于CCR 2是否是SCD中增加的冷致敏的原因。以前的研究也注意到镰刀小鼠有强烈的机械超敏反应。目的2将确定CCL 2是否驱动SCD中观察到的机械致敏。为了实现这些目标，将进行膜片钳电生理学和梳理神经纤维记录，沿着钙成像和行为测定。这些相互关联的目标提供了一种定向的，但多方面的方法来解决CCL 2在与SCD相关的复杂疼痛综合征中的作用。通过解决镰状细胞病频繁和严重疼痛的潜在机制，该提案的目标与NINDS的使命一致，以减少神经和疼痛疾病的负担。

 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.