Molecular mechanism and targeting of chronic pain in sickle cell disease

我们的长期目标是推进神经生物学和分子机制的知识， 镰状细胞病（SCD）的慢性疼痛，并开发有效的药物治疗。疼痛不仅是一种 对于10万名患有SCD的美国人来说， 1 - 3疼痛和SCD是如此紧密地交织在一起，非洲部落的话， 在Herrick在西方文献中描述SCD之前的几百年里， 止痛药尽管现在认识到SCD疼痛的特征在于慢性疼痛伴急性疼痛发作， 疼痛，4 - 5慢性疼痛的神经生物学研究很少，没有很好的表征，并且目前难以治疗。 在Herrick的开创性论文发表后的世纪，人们进行了大量的研究 9 - 10已经开发了几种SCD的转基因模型，包括人源化的 Berkeley（BERK）11和Townes的镰状细胞转基因小鼠（TOW）12，两者都代表SCD表型， 密切模仿人类严重SCD的许多特征。13 - 20我们建议使用这些良好表征的 镰状细胞转基因小鼠模型用于研究慢性粒细胞白血病的分子和表观遗传机制 疼痛，这可以为更彻底地了解SCD中的疼痛机制提供更多的希望， 指导开发有效的治疗方法。这个R35计划将推进分子生物学的知识， SCD中慢性疼痛的潜在机制，并应用新知识设计和检查实验 SCD小鼠模型中的治疗剂。该计划旨在具有灵活性，扩大或新的 当有新的发现或新兴技术出现时，可以迅速确定研究方向。我们 研究应用分子和细胞生物学，药理学，神经生物学，表观遗传学， 有针对性的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 用于在分子、细胞和系统水平上研究镰状疼痛问题。该计划将在方法上 使用几种新开发的创新方法研究SCD中的慢性疼痛，并开始填补我们 了解SCD的慢性疼痛。在确定了SC疼痛的CaMKII α靶点后， CaMKII α抑制剂从实验室到SCD患者的I期研究，我们的团队非常适合开展 在R35项目中。我们的创新有一个成功的概率很高，鉴于我们出色的轨道 记录，充满活力的正在进行的研究计划，并在追求新的研究方向设计的灵活性。

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.