Allosteric Small Molecule Inhibitor Of Nerve Growth Factor Signaling in Low Back Pain

腰痛神经生长因子信号传导的变构小分子抑制剂

• 批准号: 9146276
• 负责人: DI CHEN
• 金额: $ 17.05万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146276
• 关键词: Abbreviations; Address; Adult; Adverse event; Affect; Afferent Neurons; Animal Model; Arthralgia; Back; Back Pain; Behavioral; Beryllium; Binding; Brain-Derived Neurotrophic Factor; Chronic; Chronic inflammatory pain; Chronic low back pain; Clinical; Clinical Research; Collaborations; Data; Degenerative Disorder; Degenerative polyarthritis; Development; Disease; Elderly; Etiology; Evaluation; Facet joint structure; Female; Future; Goals; Health; Human; Incidence; Inflammation; Intervertebral disc structure; Iodoacetates; Knee joint; Knowledge; Life; Ligands; Link; Low Back Pain; MAP Kinase Gene; Mediator of activation protein; Mitogen-Activated Protein Kinases; NGFR Protein; Nerve Growth Factor Pathway; Nerve Growth Factors; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Nociception; Outcome; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Play; Positioning Attribute; Prevalence; Production; Publishing; Quality of life; Reagent; Reporting; Research; Rodent Model; Role; Safety; Sensory; Signal Transduction; Specificity; Spinal Ganglia; Staging; Structure; System; Techniques; Testing; Therapeutic; Time; Tissues; Tropomyosin; United States; base; burden of illness; chronic back pain; clinical effect; cost; design; disability; drug efficacy; economic impact; gender difference; inhibitor/antagonist; joint destruction; kinase inhibitor; male; nanomolar; novel therapeutics; pain inhibition; receptor; relating to nervous system; research study; skeletal; skills; small molecule; small molecule inhibitor; socioeconomics; success; translational study; tropomyosin kinase; years lived with disability

 DESCRIPTION (provided by applicant): There has been a dramatic increase in the world-wide incidence of chronic low back pain, which compromises the quality of life for millions of people and has a formidable socio-economic impact. A recent study published by the US Burden of Disease Collaborators showed that, in 2010, low back pain was the disease with the highest number of years lived with disability, and was responsible for the third largest disability-adjuste life- years in the US. Despite its prevalence and societal impact, the etiology of chronic back pain is poorly understood; as a result, many patients are not achieving optimal pain control through existing treatments. Nerve growth factor (NGF) and its cognate receptor tropomyosin-receptor-kinase (TrkA) system play a crucial role in the development and function of the nociceptive reception in humans. The dramatic clinical effects of targeting NGF among the myriad pain mediators in chronic conditions suggest that NGF has a special role in pain, including knee joint osteoarthritic pain. Our current knowledge, however, does not permit a conclusion on the potential efficacy of anti-NGFs for chronic back pain treatment, and also there is no documented record regarding the safety of this class of drug. Given the existing potential for anti-NGF treatment and a need for novel therapies for chronic back pain, the evaluation of pharmacological efficacy and safety of anti-NGF in low back pain is urgently needed to fill the gaps in current knowledge. Successful completion of the proposed studies will highlight the pharmacological efficacy and safety of a selective inhibitor of TrkA on alleviation of chronic back pain that is evoked by facet joint degeneration. Our results will also emphasize that a TrkA- selective inhibitor will reduce neural distribution in the facet joint tissues and alterations of neurotransmitter production through inhibition of sensory neuronal plasticity in the innervating dorsal root ganglion (DRG). Abbreviations used in the application: LBP, low back pain; NGF, nerve growth factor; TrkA, tropomyosin-receptor-kinase; FJD, facet joint degeneration; OA, osteoarthritis; IVD, intervertebral disc; BDNF, brain-derived neurotrophic factor; DRG, dorsal root ganglion; ERK/MAPK, extracellular signal-regulated kinase/mitogen-activated protein kinase; MIA, monosodium iodoacetate; BID, bis in die, twice a day.

 描述(申请人提供)：慢性下腰痛在全球范围内的发病率急剧增加，这损害了数百万人的生活质量，并产生了巨大的社会经济影响。美国疾病负担合作者最近发表的一项研究表明，2010年，下腰痛是残疾寿命最长的疾病，是美国第三大残疾调整寿命年。尽管慢性背痛的发病率和社会影响很大，但人们对其病因知之甚少；因此，许多患者无法通过现有的治疗方法实现最佳的疼痛控制。神经生长因子(NGF)及其同源受体原肌球蛋白受体-激酶(TrkA)系统在人类伤害性感受的发育和功能中起着至关重要的作用。在众多慢性疼痛介质中靶向NGF的显著临床效果表明，NGF在包括膝关节骨关节炎疼痛在内的疼痛中具有特殊的作用。然而，我们目前的知识不允许就抗神经生长因子治疗慢性腰痛的潜在疗效得出结论，也没有关于这类药物安全性的书面记录。鉴于抗NGF治疗的现有潜力和对慢性腰痛新疗法的需求，迫切需要评估抗NGF在下腰痛中的药理疗效和安全性，以填补现有知识的空白。成功完成拟议的研究将突出TrkA选择性抑制剂在缓解慢性背部疾病方面的药理疗效和安全性 小关节退变引起的疼痛。我们的结果还强调，TrkA选择性抑制剂将通过抑制支配背根神经节(DRG)的感觉神经元可塑性而减少小关节组织中的神经分布和神经递质产生的改变。应用中使用的缩写：LBP，下腰痛；NGF，神经生长因子；TrkA，原肌球蛋白受体-激酶；FJD，小关节退行性变；OA，骨关节炎；IVD，椎间盘；BDNF，脑源性神经营养因子；DRG，背根节；ERK/MAPK，细胞外信号调节激酶/丝裂原活化蛋白激酶；MIA，碘乙酸单钠；BID，BIS，一天两次。