Molecular mechanism and targeting of chronic pain in sickle cell disease

我们的长期目标是促进对潜在的神经生物学和分子机制的了解 治疗镰状细胞病(SCD)的慢性疼痛，并开发有效的药物疗法。疼痛不仅仅是一种 终生伴侣，但也是10万美国SCD患者死亡率的预测因子，主要是人 1-3 Pain和SCD是如此紧密地交织在一起，以至于非洲部落的词汇 疾病，在赫里克描述西方文献中描述SCD的几百年前就被用来形容拟声词 止痛。尽管现在人们认识到SCD疼痛的特征是慢性疼痛并伴有急性发作 疼痛，4-5慢性疼痛的神经生物学研究很少，没有很好的特征，而且目前难以治疗 可用疗法，在赫里克的开创性论文发表一个世纪后的6-7个世纪。8进行了大量的研究 9-10已经建立了几种SCD的转基因模型，包括人源化的 伯克利(Berk)11和汤斯的镰状细胞转基因小鼠(TOW)，12都代表SCD表型 与人类严重的SCD的许多特征非常相似。13-20我们建议采用这些特征良好的 镰状细胞转基因小鼠模型研究慢性阻塞性肺疾病分子和表观遗传学机制 疼痛，可以为更彻底地了解SCD的疼痛机制带来很大希望，并可能 指导开发有效的治疗方法。这个R35计划将增进对分子的认识 SCD慢性疼痛的潜在机制并应用新知识设计和检验实验 SCD小鼠模型的治疗。该计划旨在具有扩展或新的灵活性 当新发现或新兴技术出现时，研究方向可以迅速确定。我们的 研究应用了分子和细胞生物学、药理学、神经生物学、表观遗传学、 定向交付和其他尖端工具，我们拥有现有的研究、专业知识和研究设施 用于从分子、细胞和系统层面研究镰刀痛问题。这个计划将在方法论上 使用几项新开发的创新技术研究SCD中的慢性疼痛，并开始填补我们 对SCD慢性疼痛的认识。在确定了SC Pain的CaMKIIα靶点后，最近移动了一个 CaMKIIα抑制剂在SCD患者中从BASE到I期研究，我们的团队是唯一适合进行 在R35计划中进行研究。鉴于我们卓越的业绩，我们的创新有很高的成功几率 记录，充满活力的持续研究计划，以及在追求新研究方向方面设计的灵活性。

Our long-term goal is to advance the knowledge of the neurobiological and molecular mechanisms underlying chronic pain in sickle cell disease (SCD) and develop effective pharmacologic treatments. Pain is not only a life-long companion but also a predictor of mortality for the 100,000 Americans living with SCD, people mainly of African or Latin descent.1-3 Pain and SCD are so intimately intertwined, that African tribal words for the disease, spoken hundreds of years before Herrick described SCD in the western literature, are onomatopoeic for pain. Though it is now appreciated that SCD pain is characterized by chronic pain with episodes of acute pain,4-5 the neurobiology of chronic pain is poorly studied, not well characterized, and is refractory to currently available therapies,6-7 a century after Herrick's seminal paper.8 A great deal of research has been carried on the disease itself.9-10 Several transgenic models of SCD have been developed, including the humanized Berkeley (BERK)11 and Townes' sickle cell transgenic mice (TOW),12 both representing SCD phenotypes that closely mimics many features of severe SCD in humans.13-20 We propose to employ these well-characterized sickle cell transgenic mouse models for studying molecular and epigenetic mechanisms underlying chronic pain, which can hold much promise for a more thorough understanding of pain mechanisms in SCD and may guide development of effective therapies. This R35 program will advance the knowledge of molecular mechanisms underlying chronic pain in SCD and apply new knowledge to design and examine experimental therapeutics in mouse models of SCD. The program is designed to have flexibility that expanded or new research directions can be rapidly taken when new findings or emerging technology become available. Our research applies the power of molecular and cellular biology, pharmacology, neurobiology, epigenetics, targeted delivery, and other cutting-edge tools and we have existing research, expertise and research facility for studying sickle pain problem at molecular, cellular, and systems levels. This program will methodologically investigate chronic pain in SCD using several newly developed innovations and start to fill the void in our understanding of chronic pain of SCD. Having identified the CaMKIIα target for SC pain and recently moved a CaMKIIα inhibitor from bench to a Phase I study in patients with SCD, our team is uniquely suited to carry out research in this R35 program. Our innovation has a high probability of success given our outstanding track record, vibrant ongoing research program, and the designed flexibility in pursuing new research directions.