CAREER: Alternative Non-Opioid Therapies for Low Back Pain

职业：治疗腰痛的替代非阿片类药物疗法

• 批准号: 1846857
• 负责人: Rebecca Wachs
• 金额: $ 51.04万
• 依托单位: University of Nebraska-Lincoln
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1846857&HistoricalAwards=false
• 关键词: CAREER; Alternative; Non; Opioid; Therapies

While the majority of the population will experience low back pain during their lifetime, over 25% of these people will go on to suffer from chronic unresolved low back pain. Pain medicine is a common treatment for chronic low back pain patients and often results in addiction, which is a huge problem in the United States. This problem can be reduced by creating treatments that target pain directly at its source and thus reduce the need for the systemic pain medicines. Chronic low back pain can arise from the discs in the spine. Nerves can grow into these discs and be a source of pain. The hypothesis of this project is that local delivery of treatments can reduce low back pain by causing existing nerves to retract and by preventing re-growth of new nerves. As such, the research goal of this project is to understand undesired nerve growth and to engineer treatments for local delivery to prevent and reverse nerve growth. The project will identify and test compounds that cause retraction of and prevent regrowth of nerve fibers. In parallel with the research goal, the major education goal is to present this new back pain research to both scientific and public audiences and to train students to communicate with varied audiences. Therefore, this project will train students and peer faculty in the communication of science and educate the local community over the age of 50 about low back pain. Taken together, the completion of this project will provide the foundation for the principal investigator's career in low back pain research while preparing the next group of engineers and increasing knowledge among the general public about low back pain and treatments.The principal investigator's long-term career research goal is to develop novel biomaterial-based treatments for musculoskeletal pain. Toward this goal, this project will engineer targeted biomaterials that will prevent and reverse the sprouting of painful (nociceptive) sensory nerve fibers into the previously nerve-free nucleus pulposus (NP) core of intervertebral discs (IVD), which is one of the major causes of chronic low back pain (LBP). The project's overarching hypothesis is that local delivery of therapeutic biomaterials and compounds can alleviate pain and prevent chronicity by causing existing nerves to retract or dieback and prevent re-growth of painful nerve fibers. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to identify and test compounds that cause dieback of undesired sensory nerve fibers and characterize mechanisms of dieback. Studies will be performed in 3D cell cultures in which neurite extensions have been grown from trimmed dorsal root ganglion (DRG) harvested from rat pups. Myelin associated glycoprotein (MAG) and Resiniferatoxin (RTX), two compounds associated with dieback after spinal cord injury and in cell culture studies, will be added to the culture medium and dieback of neurite extensions will be assessed. Studies are designed to determine ideal concentrations of MAG and RTX to cause dieback of sensory neurons in vitro, to assess cell health of DRGs and NP cells with dieback compounds and to differentially assess how MAG and/or RTX impact gene expression of pain-associated ion channels in sensory neurite subsets, and therefore downstream pain. The SECOND OBJECTIVE is to develop novel materials to prevent undesired nerve growth. Studies will be performed in 3D gel cocultures consisting of a human derived NP core surrounded by a gel containing rat derived DRGs and matrix support for the NP core. Various compositions of microparticles containing methacrylated chondroitin sulfate A and C (MA-CS-A and MA-CS-C), which are known to be neuro-inhibitory, will be incorporated into the NP core and their ability to prevent nerve ingrowth will be assessed. Studies are designed to develop a neurological 3D in vitro mimic of NP with tunable composition for long term culture of NP cells and DRGs, to determine CS concentration and type effects on DRG growth in vitro, to verify mechanism of inhibition and to fabricate microparticles for injectable delivery of neuro-inhibitors, enabling in vivo delivery. The THIRD OBJECTIVE is to test efficacy of identified materials and compounds to prevent and reverse LBP in an animal model. Studies will be performed in a rat lumber disc puncture model that has been used extensively as a model of disc degeneration. Ten weeks after puncture, animals will be divided into 5 treatment groups depending on results obtained in objectives 1 and 2: MAG or RTX dieback compounds, MA-CS-A or MA-CS-C microparticles, dieback compound and microparticles, type I collagen control or sham surgical control. The degree and resolution of pain will be assessed using a novel rodent gait analysis. Studies are designed to identify novel biomaterial and compound combinations that alleviate pain and stabilize the disc in an animal model of LBP and to increase understanding of the effects of biomaterials/compounds on neurites in the NP. Determining the effectiveness of these therapeutics to directly treat LBP without the use of addictive pain medications has the potential to lead to new treatments that will greatly benefit patients and society.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

虽然大多数人在有生之年都会经历下腰痛，但其中超过25%的人将继续遭受慢性未解决的下腰痛的痛苦。止痛药是慢性下腰痛患者的常见治疗方法，经常会导致成瘾，这在美国是一个巨大的问题。这个问题可以通过创造直接针对疼痛根源的治疗来减少，从而减少对全身止痛药的需求。慢性下腰痛可由脊柱内的椎间盘引起。神经可以生长到这些椎间盘中，成为疼痛的来源。该项目的假设是，局部治疗可以通过使现有神经收缩和防止新神经重新生长来减少下腰痛。因此，这个项目的研究目标是了解不受欢迎的神经生长，并设计局部给药的治疗方法，以防止和逆转神经生长。该项目将识别和测试导致神经纤维回缩和防止神经纤维再生的化合物。在研究目标的同时，主要的教育目标是向科学和公众受众展示这一新的背痛研究，并培养学生与不同受众交流。因此，该项目将培训学生和同行教职员工进行科学交流，并对50岁以上的当地社区进行关于腰痛的教育。总而言之，该项目的完成将为首席研究员在下一批工程师和公众中增加关于下一批腰痛和治疗的知识的同时，为其在下一代腰痛研究领域的职业生涯奠定基础。首席研究员的长期职业研究目标是开发基于生物材料的新型肌肉骨骼疼痛治疗方法。为了实现这一目标，该项目将设计有针对性的生物材料，以防止和逆转疼痛(伤害性)感觉神经纤维发芽进入以前无神经的髓核(NP)的椎间盘核心(IVD)，这是慢性下腰痛(LBP)的主要原因之一。该项目的总体假设是，局部输送治疗性生物材料和化合物可以通过导致现有神经收缩或萎缩并防止疼痛神经纤维的重新生长来缓解疼痛和防止慢性化。研究计划是按照三个目标组织的。第一个目标是鉴定和测试导致不受欢迎的感觉神经纤维死亡的化合物，并表征死亡的机制。研究将在3D细胞培养中进行，在3D细胞培养中，从大鼠幼鼠的修剪后的背根节(DRG)中生长出轴突延伸。髓鞘相关糖蛋白(MAG)和树脂毒素(RTX)是与脊髓损伤后死亡相关的两种化合物，在细胞培养研究中，这两种化合物将被添加到培养液中，并将评估轴突延伸的死亡。研究的目的是确定MAG和RTX在体外引起感觉神经元死亡的理想浓度，评估含有死背化合物的DRG和NP细胞的细胞健康状况，并差异地评估MAG和/或RTX如何影响感觉轴突亚群中疼痛相关离子通道的基因表达，从而影响下游疼痛。第二个目标是开发新材料来防止不受欢迎的神经生长。研究将在3D凝胶共培养中进行，包括人来源的NP核心和包含大鼠来源的DRGs的凝胶和对NP核心的基质支持。含有甲基丙烯酸软骨素硫酸盐A和C(MA-CS-A和MA-CS-C)的不同成分的微粒将被纳入NP核心，并将评估它们防止神经内陷的能力。本研究旨在开发一种用于长期培养NP细胞和DRG的可调节成分的神经学3D体外模拟NP，以确定CS浓度和类型对体外DRG生长的影响，验证其抑制机制，并制备可注射递送神经抑制剂的微球，使其能够在体内释放。第三个目标是在动物模型中测试已识别的材料和化合物预防和逆转LBP的有效性。研究将在大鼠腰椎间盘穿刺术模型中进行，该模型已被广泛用作椎间盘退变的模型。穿刺术10周后，根据实验1和实验2的结果分为5组：MAG或RTX组、MA-CS-A或MA-CS-C微粒组、DI型胶原组和假手术对照组。疼痛的程度和解决方案将使用一种新的啮齿动物步态分析来评估。研究旨在确定新型生物材料和化合物组合，在LBP动物模型中缓解疼痛和稳定椎间盘，并增加对生物材料/化合物对神经节突起影响的了解。确定这些疗法在不使用令人上瘾的止痛药的情况下直接治疗LBP的有效性，有可能导致极大地造福患者和社会的新疗法。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。