Intervertebral Disc Degeneration and Cross-Talk with the Nervous System

椎间盘退变和与神经系统的交互作用

• 批准号: 10412615
• 负责人: Lori A. Setton
• 金额: $ 5.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412615
• 关键词: Alginates; Attenuated; Azides; Biocompatible Materials; Biomedical Engineering; Cardiovascular system; Cell Culture Techniques; Chemistry; Coupling; Development; Development Plans; Disease model; Drug Delivery Systems; Education; Educational workshop; Engineering; Environment; Gel; Goals; Hydrogels; Individual; Injectable; Intervertebral disc structure; Kinetics; Knowledge; Low Back Pain; Mentors; Mentorship; Modification; Musculoskeletal; Nerve Growth Factors; Nervous system structure; Neurons; Pain; Pharmaceutical Preparations; Plant Roots; Post Graduate Year; Pre-Clinical Model; Regenerative Medicine; Research; Research Activity; Research Project Grants; Resources; Schools; Scientist; Spinal Ganglia; Training Activity; Universities; Washington; Work; afferent nerve; calcium indicator; design; experience; graduate student; intervertebral disk degeneration; medical schools; mouse model; novel; pain relief; parent grant; perineural; skills; spinal nerve posterior root; success; symposium; transmission process

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.

腰椎间盘退变是导致下腰痛的最大因素之一，然而，腰椎间盘退变如何 产生疼痛的原因仍然知之甚少。家长助学金将追求特定的目标来研究发展 神经功能的时间和空间变化及其与退行性IVD变化的“串扰” 在腰椎IVD变性的小鼠模型中。在这里，我们提出了一个补充项目，名为“新型可注射性 用于背根节(DRG)局部止痛的水凝胶“将支持西德尼·尼尔女士 设计一种新型的可注射药库，以减轻腰椎IVD变性的神经元敏感性。 总体目标是让生物医学工程专业的研究生尼尔女士开发一种新的 将神经生长因子(NGF)拮抗剂Tanuzemab偶联到可注射的凝胶海藻酸盐上的化学 目的是在伴有IVD变性的腰背根节局部释放NGF拮抗剂。在增刊中 目的1，Neal女士将对海藻酸盐的二元混合物进行修饰，并评估凝胶动力学和对 模拟神经周分娩后的DRGs。在补充目标2中，尼尔女士将制定一项战略，以 使用叠氮修饰将Tanezumab偶联到海藻酸盐上，并评估偶联效率。在……里面 补充目标3，Neal女士将评估药物偶联海藻酸水凝胶在体外的生物活性 背根神经节神经元与神经生长因子共同孵育。尼尔女士将由Nate Huebsch博士共同赞助 谁给团队带来了生物材料和药物输送方面的经验，以及洛里·塞顿博士带来了经验 有IVD变性和神经周围药物输送到团队。 在这个项目期间，尼尔女士将在神经细胞培养方面获得新的宝贵技能， 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知识。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，参加国家会议介绍她的工作，并有机会参加国家 指导黑人科学家会议。华盛顿大学为学生提供了良好的学习环境 完成这一研究项目，并继续发展西德尼·尼尔女士的职业生涯。尼尔女士将 在麦凯维工程学院和医学院内工作，并参与 肌肉骨骼研究中心、心血管研究中心和再生中心 医学。总而言之，这些联合研究和培训活动的目的是让尼尔女士为继续 她在研究生时期从事学术研究。