Nociceptive Mechanisms Underlying Sickle Cell Pain

项目总结： 循环中的脂质代谢产物溶血磷脂酰胆碱(LysoPC)在 患有镰状细胞病(SCD)的患者和小鼠；其在红细胞膜中的过量导致红细胞镰状。 然而，目前尚不清楚溶血磷脂酶水平升高是否会导致SCD患者疼痛。目标是 这项建议的目的是研究LysoPC在急性和慢性SCD疼痛中所起的作用。血管注射时的急性疼痛- 闭塞危象(VOC)和慢性疼痛是SCD患者的主要并存疾病，严重影响患者的 患者的生活质量。SCD疼痛迫切需要改进的、机制定向的疼痛治疗 因为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反应、风险 上瘾，并不能完全缓解疼痛，而且在一些患者中，会进一步加剧疼痛。事实是， 急性和慢性SCD疼痛出现在许多身体部位，无论是深部的还是浅部的，这表明循环 溶血磷胆碱等因素可能驱动和维持SCD的疼痛。这项提议的科学前提是 在SCD中，源于红细胞的升高的血液携带的溶血PC通过 可渗透的血-神经屏障，然后敏化这些神经元中的各种受体，这些受体检测到 有害的刺激。我们推测，在急性VOC期间，可溶性溶血PC使G-蛋白受体4敏化 (GPR4)和/或酸敏离子通道3(ASIC3)到在组织中局部释放的质子 缺血，从而驱动SCD的急性机械敏化。其次，我们假设LysoPC 通过激活瞬时受体电位5(TRPC5)促进慢性机械性稳态疼痛 通道作用于感觉神经元，从而介导SCD的慢性机械性疼痛。三个具体目标将 质疑这一假设：1)全球抑制溶酶PC生成能防止急性危象和慢性疼痛吗？ 2)可溶性溶血磷脂酶是否通过敏化质子受体GPR4和/或ASIC3而导致急性危害性疼痛？ 3)LysoPC是否通过敏化拉伸激活的通道TRPC5而导致慢性稳定期疼痛？ 我们假设以一种调节失调的脂质为靶点的治疗方法可以预防急性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、独特的 治疗SCD疼痛的新药开发机会。到目前为止，LysoPC还没有被直接与疼痛联系在一起 机制，尽管它已被证明在包括类风湿在内的各种疾病中调节失调 关节炎、骨性关节炎、牛皮癣、偏头痛、痛经、多发性硬化症和心绞痛。因此，这项提议 也可能揭示LysoPC在这些疾病中驱动疼痛的机制。更广泛地说，我们的 实验将揭示脂质调节感官中离子通道和受体的基本机制 来改变它们的机械反应特性。

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.