Molecular mechanism and targeting of chronic pain in sickle cell disease

镰状细胞病慢性疼痛的分子机制和靶向

• 批准号: 10319980
• 负责人: Zaijie Jim Wang
• 金额: $ 66.14万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319980
• 关键词: Acute Pain; African; American; Chronic; Companions; Development; Disease; Emerging Technologies; Epigenetic Process; Goals; Human; Investigational Therapies; Knowledge; Life; Literature; Methodology; Molecular; Molecular and Cellular Biology; Neurobiology; Pain; Paper; Patients; Persons; Pharmacological Treatment; Pharmacology; Probability; Refractory; Reporting; Research; Seminal; Sickle Cell; Sickle Cell Anemia; Study models; System; Therapeutic; Transgenic Mice; Transgenic Model; chronic pain; design; disease phenotype; effective therapy; flexibility; inhibitor; innovation; mortality; mouse model; neurobiological mechanism; phase 1 study; programs; research facility; sickling; success; targeted delivery; tool

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.

我们的长期目标是促进对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。痛苦不仅是 终身伴侣，也是居住在SCD的100,000名美国人的死亡率的预测指标，人们主要是 1-3疼痛和SCD是如此紧密地交织，非洲部落的词 在赫里克（Herrick）描述西方文学中SCD之前数百年的疾病是拟声词 疼痛。虽然现在对SCD疼痛的特征是慢性疼痛和急性发作的特征。 疼痛，4-5慢性疼痛的神经生物学研究很差，没有很好的特征，对当前的难治性 可用的疗法，在赫里克（Herrick）开创性论文后一个世纪以6-7世纪。8进行了大量研究 疾病本身。9-10已经开发了几种SCD的转基因模型，包括人源化 伯克利（Berk）11和Townes的镰状细胞转基因小鼠（TOW），12都代表SCD表型 密切模仿人类严重SCD的许多特征。13-20我们建议采用这些良好的特征 镰状细胞转基因小鼠模型，用于研究慢性的分子和表观遗传机制 疼痛，这可以使人们对SCD中的疼痛机制有更彻底的了解，并且可能 指导有效疗法的开发。该R35程序将提高分子知识 SCD中慢性疼痛的基础机制，并将新知识应用于设计和检查实验 SCD小鼠模型中的治疗。该程序旨在具有扩展或新的灵活性 当新发现或新兴技术可用时，可以迅速采取研究方向。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， 有针对性的交付和其他尖端工具，我们拥有现有的研究，专业知识和研究机构 用于在分子，细胞和系统水平上研究镰状疼痛问题。该程序将在方法论上 使用几项新开发的创新研究SCD中的慢性疼痛，并开始填补我们的空白 了解SCD的慢性疼痛。已经确定了CAMKIIα的SC疼痛靶标，并最近移动了 CAMKIIα抑制剂从长凳上到I期研究的SCD患者，我们的团队非常适合进行 该R35计划中的研究。鉴于我们的出色轨道，我们的创新很有可能成功 记录，充满活力的正在进行的研究计划以及追求新研究方向的设计灵活性。