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.

椎间盘 (IVD) 退变是腰痛的最大诱因之一，但 IVD 如何 产生痛苦仍然知之甚少。家长拨款将追求特定目标来研究发展。 神经功能的时间和空间变化及其与退化 IVD 变化的“串扰” 在腰椎 IVD 退化的小鼠模型中，我们提出了一个名为“新型注射剂”的补充项目。 用于缓解背根神经节 (DRG) 局部疼痛的水凝胶”，将为 Sydney Neal 女士提供支持 设计一种新型注射药物储存库，以减弱腰椎 IVD 变性引起的神经元敏感性。 生物医学工程研究生 Neal 女士的总体目标是开发一种新颖的 将神经生长因子 (NGF) 拮抗剂 Tanuzemab 与可注射的胶凝藻酸盐偶联的化学物质 在补充的 IVD 变性中，在腰椎 DRG 处提供 NGF 拮抗剂的局部释放。 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 模拟神经周围递送后的 DRG 在补充目标 2 中，Neal 女士将制定一项策略 使用叠氮化物修饰将 Tanezumab 与藻酸盐偶联并评估偶联效率。 补充目标 3，Neal 女士将评估分离的药物结合藻酸盐水凝胶的生物活性 Neal 女士将与 Nate Huebsch 博士共同赞助 DRG 神经元与 NGF 的孵育期。 他为团队带来了生物材料和药物输送方面的经验，Lori Setton 博士为团队带来了经验 与 IVD 变性和神经周围药物输送到团队。 在这个项目期间，尼尔女士将获得神经细胞培养方面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 尼尔女士将进一步增加她对工程生物材料治疗相关性的了解。 制定个人发展计划，参加华盛顿研究成功研讨会 大学期间，参加全国性会议展示她的作品，并有机会参加全国性会议 华盛顿大学为黑人导师科学家提供了良好的环境。 悉尼尼尔女士将完成该研究项目并继续专业发展。 在麦凯尔维工程学院和医学院工作，并参与资源 肌肉骨骼研究中心、心血管研究中心、再生中心 总而言之，这些研究和培训活动相结合，旨在为尼尔女士的继续学习做好准备。 研究生期间的学术研究。