Collaborative Research: Glial scar morphology informed tunable biomimetic platforms toward spinal cord injury repair

合作研究：胶质疤痕形态为脊髓损伤修复的可调仿生平台提供信息

• 批准号: 2042117
• 负责人: Nic Leipzig
• 金额: $ 30万
• 依托单位: University of Akron
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2042117&HistoricalAwards=false
• 关键词: Collaborative; Research; Glial; scar; morphology

Spinal cord injury (SCI) results in loss of cells and blood supply, disruption of brain connectivity to various tissues, and formation of a dense scar around the injury site, ultimately resulting in permanent loss of mobility. There are no proven clinical solutions or pharmaceutical interventions to reverse SCI. To develop successful treatment options for SCI, it is important to first understand the physical, chemical, and biological changes occurring over time in the injured tissues. This information would in turn help in developing improved mimics of such injured tissues (combining important structural, mechanical, and inflammatory aspects) to test the response of various cells resident to the spinal cord, as well as to evaluate the efficacy of pharmaceutical drugs in promoting tissue regeneration to ultimately improve the success of downstream clinical applications. Successful implementation of these objectives will lead to the development and validation of physiologically-relevant integrated systems that improve our fundamental understanding of SCI, while also enabling new testing platforms. The broader impact of this work will include the generation of new insights into how nerve cell outgrowth and targeting is inhibited in an inflammatory SCI tissue, and may be overcome for reparative benefit, specifically in the context of SCI. Besides opportunities for research dissemination to the scientific community, this project will lead to training of diverse undergraduate and graduate students through development of research/educational modules and through the auspices of established summer internship/outreach programs at the investigators’ respective institutions.Injury to the central nervous system (CNS) has profound, long-term physiological consequences due to the tissue’s low innate regenerative ability and formation of a glial scar around the injury site. This scar has large soft regions, is inhibitive to axonal/neurite outgrowth, confers an anti-regenerative environment, and is marked by gliosis and production of inhibitory chondroitin sulfate proteoglycans. The underlying mechanisms for such altered characteristics at the injury site are unclear. The goals of this study are to (1) elucidate and correlate spinal cord tissue-scale mechanical properties, architecture, and mechanochemical signaling at key phases following CNS injury, and (2) identify the mechanochemical response of CNS cells to scar-like physical properties measurable via defined signaling pathways, altered membrane tension, and tension-regulated behaviors. This multi-disciplinary, comprehensive strategy establishes hitherto undefined multi-scale relationships between glial scar structure, micromechanical properties, ECM composition, and CNS cell mechanochemical responses. The newly identified glial scar characteristics will be utilized to develop tunable biomimetic hydrogels for the isolation of CNS cell function, mechano-chemical profiles, membrane tension, and regulated behaviors, towards mimicking the acute injury phase in a humanized in vitro platform. The broader research impacts of this project include generation of new mechanistic insights into how cell functions are dysregulated in an inflammatory milieu, while offering new targets for regeneration. By emphasizing mechanobiological knowledge-driven formulation of glial scar-biomimetic scaffolds, this project represents a paradigm shift in CNS repair and regeneration strategies.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.

脊髓损伤（SCI）导致细胞损失和血液供应损伤部位，最终导致迁移率永久性损失。在受伤的组织中，此信息将有助于改善这种受伤的组织（结合重要结构和炎症方面）的模仿，以测试属于脊髓的各种细胞的反应这些目标的成功实施将导致与您的SCI基本地位相关的综合系统，同时还可以实现新的测试平台。在炎症的SCI组织中抑制神经细胞的ouu tgrowth和靶向，并且在SCI的情况下可能是过度的修复益处。研究人员对中心神经系统的伤害（CNS）具有深刻的长期生理惯例，这是由于组织的先天再生和形成的疤痕。抑制轴突/神经突的生长，赋予了抗再生环境，并以抑制性软骨素硫酸盐蛋白聚糖的形式出现了胶质性和生产。 1）阐明并与CNS损伤后的关键相位的脊髓组织尺度机械性能，d机械信号传导，以及（2）确定CNS细胞对可通过定义的信号通路测量的疤痕样物理特性的机械化学响应张力和张力的行为。细胞机械化学曲线，膜张力和常规行为，以模仿人性化的体外RM中逐步分阶段，该机制的更广泛的研究影响了细胞功能在炎症中如何疾病，同时为新目标提供了新的目标。再生。审查标准。