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，大脑连接到各种场合的破坏以及在损伤部位周围形成致密的疤痕，最终导致永久性移动性丧失。没有可靠的临床解决方案或药物干预措施来逆转科学疾病。为了为SCI开发成功的治疗选择，重要的是要首先了解受伤的时机随着时间的流逝而发生的物理，化学和生物学变化。此信息反过来将有助于发展这种受伤的组织的模仿（结合重要的结构，机械和炎症方面），以测试各种细胞居民对脊髓的反应，并评估药物在促进组织再生中的有效性，以最终改善下游临床应用的成功。这些目标的成功实施将导致与物理相关的集成系统的开发和验证，从而提高我们对SCI的基本理解，同时还可以启用新的测试平台。这项工作的更广泛影响将包括对神经细胞生长和靶向抑制在炎症性SCI组织中如何抑制的新见解，并可能在SCI的背景下克服修复益处。除了将研究传播给科学界的机会外，该项目还将导致对潜水员的本科生和研究生的培训。通过开发研究/教育模块的发展，以及通过研究人员的相对机构既定的夏季实习/外展计划的主持。中枢神经系统（CNS）由于组织的先天性低下能力和围绕受伤部位的glial毛的形成而产生了深远的长期生理后果。该疤痕具有较大的软区域，对轴突/神经突生长具有抑制作用，赋予了抗再生环境，并以神经胶质症和抑制性软骨素硫酸盐蛋白聚糖的产生为特征。损伤部位这种改变特征的基本机制尚不清楚。这项研究的目标是（1）阐明并将CNS损伤后关键阶段处的脊髓组织尺度的机械性能，结构和机械信号传导，以及（2）确定CNS细胞对疤痕样物理性能的机械响应，可通过定义的信号通路，改变的膜张力和紧张张力和紧张张力和紧张的行为来测量疤痕样物理性能。这种多学科的综合策略建立了隐藏的不确定的多尺度关系，在神经胶质疤痕结构，微力特性，ECM组成和CNS细胞机械化学响应之间。新确定的神经胶质疤痕特性将用于开发可调的仿生水凝胶，用于分离中枢神经系统细胞功能，机械化学轮廓，膜张力和调节行为，以模仿人性化的体外平台中的急性损伤阶段。该项目的更广泛的研究影响包括对细胞功能在炎症环境中如何失调的新机械见解产生，同时提供了新的再生目标。通过强调神经胶质疤痕生物象征脚手架的机械知识驱动的公式，该项目代表了中枢神经系统维修和再生策略的范式转移。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛的影响审查标准来通过评估来通过评估来支持的。