Nociceptive Mechanisms Underlying Sickle Cell Pain

项目摘要： 循环脂质代谢物溶血磷脂酰胆碱（lysoPC）在以下患者的血液中显著上调： 镰状细胞病（SCD）患者和小鼠;其在RBC膜中的过量导致RBC镰状化。 然而，尚不清楚升高的lysoPC水平是否有助于SCD中的疼痛。客观 该建议的目的是研究lysoPC在急性和慢性SCD疼痛中的作用。血管手术期间的急性疼痛- 闭塞性危象（VOC）和慢性疼痛是SCD患者的主要合并症，严重影响患者的生活质量。 患者的生活质量。SCD疼痛迫切需要改进的、针对机制的疼痛治疗 由于目前使用的主要治疗药物是阿片类药物，这些药物具有严重的不良副作用， 成瘾，不能完全缓解疼痛，在一些患者中，甚至进一步加剧疼痛。的事实 急性和慢性SCD疼痛来自身体的许多部位，包括深部和浅表部位，这表明循环系统 因子，如lysoPC，可以驱动和维持SCD中的疼痛。这一建议的科学依据是 在SCD中，起源于RBC的升高的血液传播的lysoPC通过以下途径进入感觉神经元： 渗透性血神经屏障，然后使这些神经元内的各种受体敏感， 有害刺激我们假设在急性VOC期间，可溶性lysoPC使G蛋白受体4敏感 在一些实施方案中，所述方法包括将GPR 4和/或酸敏感离子通道3（ASIC 3）与在组织中局部释放的质子结合。 缺血，从而驱动SCD中的急性机械致敏。其次，我们假设lysoPC 通过激活瞬时受体电位5（TRPC 5）导致慢性机械稳态疼痛 通道上的感觉神经元，从而介导慢性机械性疼痛的SCD。三个具体目标将 质疑这一假设：1）全面抑制lysoPC的产生会预防急性危象和慢性疼痛吗？ 2)可溶性lysoPC是否通过致敏质子受体GPR 4和/或ASIC 3而导致急性危象痛？ 3)lysoPC是否通过致敏牵张激活通道TRPC 5而导致慢性稳态疼痛？ 我们假设治疗靶向一种失调的脂质来预防急性VOC和 慢性疼痛、VOC疼痛的缓解和慢性SCD疼痛的缓解将呈现单一的、独特的 为SCD疼痛的新药开发提供了机会。到目前为止，lysoPC尚未与疼痛直接相关 尽管它已被证明在各种疾病中失调，包括类风湿性关节炎， 关节炎、骨关节炎、牛皮癣、偏头痛、痛经、多发性硬化症和心绞痛。因此，本提案 还可能揭示lysoPC在这些疾病中驱动疼痛的机制。更广泛地说，我们 实验将揭示脂质调节感觉神经元中离子通道和受体的基本机制。 神经元改变其机械响应特性。

Project Summary: The circulating lipid metabolite lysophosphatidylcholine (lysoPC) is profoundly upregulated in the blood of patients and mice with sickle cell disease (SCD); its over-abundance in RBC membranes drives RBC sickling. However, nothing is known about whether the elevated lysoPC levels contributes to pain in SCD. The objective of this proposal is to investigate the role lysoPC plays in acute and chronic SCD pain. Acute pain during vaso- occlusive crisis (VOC) and chronic pain are major comorbidities for patients with SCD that severely impact the patients' quality of life. Improved, mechanism-targeted pain treatments are desperately needed for SCD pain because the main treatment currently used is opioid-class drugs, which have serious adverse side effects, risk addiction, do not fully alleviate the pain, and in some patients, exacerbate the pain even further. The fact that acute and chronic SCD pain arise from many body sites, both deep and superficial, suggests that a circulating factor, such as lysoPC, may drive and maintain the pain in SCD. The Scientific Premise of this proposal is that in SCD, the elevated blood borne lysoPC which originates in RBCs gains access to sensory neurons via the permeable blood-nerve barrier, and then sensitizes a variety of receptors within these neurons that detect noxious stimuli. We hypothesize that during an acute VOC, soluble lysoPC sensitizes the G-protein Receptor 4 (GPR4) and/or Acid Sensing Ion Channel 3 (ASIC3) to protons that are released locally in tissue during ischemia, thereby driving the acute mechanical sensitization in SCD. Second, we hypothesize that lysoPC contributes to chronic mechanical steady state pain by activating the Transient Receptor Potential 5 (TRPC5) channel on sensory neurons thereby mediating the chronic mechanical pain in SCD. Three Specific Aims will interrogate this hypothesis: 1) Will global inhibition of lysoPC generation prevent acute crisis and chronic pain? 2) Does soluble lysoPC contribute to acute crisis pain by sensitizing the proton receptors GPR4 and/or ASIC3? 3) Does lysoPC contribute to chronic steady state pain by sensitizing the stretch-activated channel TRPC5? We hypothesize that therapeutically targeting one dysregulated lipid for the prevention of acute VOC and chronic pain, alleviation of VOC pain, and alleviation of chronic SCD pain will present a single, unique opportunity for novel drug development for SCD pain. To date, lysoPC has not yet been linked directly to pain mechanisms even though it has been shown to be dysregulated in various diseases, including rheumatoid arthritis, osteoarthritis, psoriasis, migraine, dysmenorrhea, multiple sclerosis and angina. Thus, this proposal may also reveal the mechanism through which lysoPC drives the pain in these disorders. More broadly, our experiments will uncover basic mechanisms by which lipids modulate ion channels and receptors in sensory neurons to alter their mechanical response properties.