Astrocyte Mechanobiology Following Central Nervous System Injury Revealed By Magnetically Active Hydrogels

这一奖项将支持我们提高对胶质细胞瘢痕形成机制的理解。中枢神经系统的损伤通常会导致终生残疾。脊髓损伤或创伤性脑损伤患者可能会遭受严重的功能丧失。像身体的其他区域一样，中枢神经组织的机械硬度在受伤后会发生变化。这既会影响传递信号的神经元，也会影响大脑和脊髓中的支持细胞类型，这些细胞被称为神经胶质细胞。一种叫做星形胶质细胞的胶质细胞促成了胶质疤痕的形成。疤痕抑制了损伤后功能恢复所需的神经元的再生。目前，组织的动态变化对星形胶质细胞功能的影响尚不清楚。利用这笔赠款所做的工作将改变星形胶质细胞周围环境的硬度，利用磁性来了解细胞如何促进神经胶质疤痕的形成。最终，这些结果可能会导致脊髓损伤后恢复功能的新疗法。此外，这项研究还将辅以一个名为“科学与运动”的幼儿教育项目，该项目将向孩子们介绍科学家和工程师如何使用磁力。磁性活性水凝胶提供了一种新的手段，可以在三维微环境中询问时间和空间变化的机械特性。这些变化是快速和可逆的，研究表明，细胞对改变的机械特性做出快速反应(在几秒钟内)。本实验将利用体外切片模型来表征脊髓挫伤后力学性能的动态变化，然后使用磁性水凝胶在体外模拟这些变化，以询问星形胶质细胞的机械生物学。为了更好地了解胶质瘢痕形成的机制，实验将重点放在星形胶质细胞的转录变化上。这些研究将涉及粘弹性力学的时间和空间梯度，以体外脊髓损伤模型的力学测试结果为依据。总体而言，这项工作将提高我们对星形胶质细胞机制生物学的理解，并可能导致修复脊髓损伤的新疗法。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award will support work to improve our understanding of the mechanisms underlying scar formation in glial cells. Injury to the central nervous system often results in life-long disability. Patients with spinal cord injury or traumatic brain injury may suffer severe loss of function. Like other regions in the body, the mechanical stiffness of central nervous tissue changes after an injury. This affects both the neurons that transmit signals as well as supporting cell types in the brain and spinal cord, which are called glial cells. One type of glial cell, called an astrocyte, contributes to the formation of a glial scar. The scar inhibits the regeneration of neurons needed for functional recovery following an injury. Currently, the effects of the dynamically changing stiffness of the tissue on the function of the astrocytes is unknown. The work done with this grant will alter the stiffness of astrocytes’ surroundings using magnetism to understand how the cells contribute to glial scar formation. Eventually, these results can lead to new treatments for restoring function following spinal cord injury. Additionally, the research will be supplemented with an early childhood education program called “Science and Movement” that will introduce children to the ways in which scientists and engineers use magnetism.Magnetically active hydrogels provide a new means to interrogate time and spatial varying mechanical properties in three-dimensional microenvironments. The changes are fast and reversible, and studies indicate that cells respond to the altered mechanical properties rapidly (within seconds). The experiments will characterize the dynamic changes to the mechanical properties of the spinal cord following contusion injury using an ex vivo slice model, and then use magnetically active hydrogels to mimic these changes in vitro to interrogate astrocyte mechanobiology. Experiments will focus on the transcriptomic changes of the astrocytes in order to better understand the mechanisms underlying the formation of a glial scar. These studies will involve both temporal and spatial gradients of viscoelastic mechanics, informed by the results of the mechanical testing of the ex vivo spinal cord injury model. Overall, this work will improve our understanding of astrocyte mechanobiology and potentially lead to new treatments to repair spinal cord injury.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.