Intervertebral Disc Degeneration and Cross-Talk with the Nervous System

椎间盘（IVD）退变是下背痛的最大贡献者之一，但IVD如何能够 对疼痛的产生仍然知之甚少。家长补助金将用于研究发展的具体目标 神经元功能的时间和空间变化及其与退行性IVD变化的“串扰” 腰椎间盘退变小鼠模型。在这里，我们提出了一个补充项目，称为“新的注射剂 水凝胶用于背根神经节（DRG）局部疼痛缓解”，将支持悉尼·尼尔女士在 设计新型可注射药物贮库，以减弱腰椎IVD变性的神经元敏感性。 总体目标是让尼尔女士，一个生物医学工程的研究生，开发一种新的 将神经生长因子（NGF）拮抗剂Tanuzemab与可注射的凝胶藻酸盐结合的化学方法 以在IVD变性的腰椎DRG处提供NGF拮抗剂的局部释放。补充 目标1，Neal女士将修改海藻酸盐的二元混合物，并评估凝胶动力学和定位到 模拟神经周围分娩后的DRG。在补充目标2中，尼尔女士将制定一项战略， 使用叠氮化物修饰将他尼珠单抗偶联至藻酸盐，并评估偶联效率。在 补充目标3，Neal女士将评价药物缀合的藻酸盐水凝胶在分离的细胞中的生物活性。 DRG神经元经历与NGF孵育的时期。尼尔女士将与内特·休布什博士共同赞助 她为团队带来了生物材料和药物输送的经验，洛里塞顿博士带来了经验， 有椎间盘变性和神经周围给药的病人 在这个项目期间，Neal女士将获得神经细胞培养方面的新的和有价值的技能， 基因编码的钙指标，疾病发展的临床前模型，并与 临床医生增加她对工程生物材料治疗相关性的了解。尼尔女士将进一步 准备个人发展计划，参加华盛顿的研究成功研讨会 大学，参加全国会议，介绍她的工作，并有机会参加全国 会议指导黑人科学家。华盛顿大学提供了一个良好的环境， 完成这项研究项目，并继续悉尼尼尔女士的专业发展。尼尔女士会 在工程和医学院的麦凯维学校工作，并参与资源 肌肉骨骼研究中心、心血管研究中心和再生医学中心 药总之，这些研究和培训活动的目的是让尼尔女士做好准备， 研究生时期的学术研究。

Intervertebral disc (IVD) degeneration is one of the greatest contributors to low back pain, yet how the IVD can generate pain remains poorly understood. The parent grant will pursue Specific Aims to study the development of temporal and spatial changes in neuronal function and their “cross-talk” with changes in the degenerating IVD in a mouse model of lumbar IVD degeneration. Here, we propose a supplemental project called “Novel Injectable Hydrogels for Localized Pain Relief in the Dorsal Root Ganglion (DRG)” that will support Ms. Sydney Neal in the design of a novel injectable drug depot in order to attenuate neuronal sensitivity with lumbar IVD degeneration. The overall goal is for Ms. Neal, a graduate student in biomedical engineering, to develop a novel chemistry that will couple the nerve growth factor (NGF) antagonist, Tanuzemab, to an injectable, gelling alginate to provide for local release of an NGF antagonist at the lumbar DRGs with IVD degeneration. In Supplemental Aim 1, Ms. Neal will modify binary mixtures of alginate and evaluate gelation kinetics and localization to the DRGs following simulated perineural delivery. In Supplemental Aim 2, Ms. Neal will develop a strategy to couple Tanezumab to alginate using an azide modification and evaluate the efficiency of coupling. In Supplemental Aim 3, Ms. Neal will evaluate the bioactivity of the drug-conjugated alginate hydrogels in isolated DRG neurons subjected to periods of incubation with NGF. Ms. Neal will be co-sponsored by Dr. Nate Huebsch who brings experience with biomaterials and drug delivery to the team, and Dr. Lori Setton who brings experience with IVD degeneration and perineural drug delivery to the team. During the period of this project, Ms. Neal will gain new and valuable skills in neuronal cell culture, genetically-encoded calcium indicators, pre-clinical models of disease development, and work closely with clinicians to increase her knowledge of treatment relevance for engineered biomaterials. Ms. Neal will further prepare an Individual Development Plan, participate in workshops for research success at Washington University, attend national conferences to present her work, and have an opportunity to participate in a national conference to mentor Black scientists. Washington University provides an excellent environment for the completion of this research project and continued professional development of Ms. Sydney Neal. Ms. Neal will work within the McKelvey School of Engineering and the School of Medicine and participate in resources of the Musculoskeletal Research Center, the Cardiovascular Research Center, and the Center for Regenerative Medicine. In all, these combined research and training activities are designed to prepare Ms. Neal for continued academic research in her post-graduate years.