Deciphering Mechanisms of Mechanotransduction in Astrocyte Reactivity

该奖项将支持更好地了解创伤性脑损伤的长期影响的研究。创伤性脑损伤在美国是一个沉重的负担。虽然有许多治疗方法可用，但还没有经过验证的治疗方法来减轻这些损伤的长期影响。这项工作的结果最终将导致新的治疗方法。这项工作将专门研究星形胶质细胞，这是大脑和脊髓中的一种特殊细胞类型。星形胶质细胞负责许多关键的支持功能。星形胶质细胞功能障碍会发生在阿尔茨海默病和癌症等疾病中。星形胶质细胞在机械损伤反应中的作用尚不清楚。该项目将使用工程化的三维模型脑组织，以更好地了解特定细胞类型对脑损伤反应的贡献。这些模型提供了脑细胞如何对冲击伤等损伤做出反应的真实视角。这项工作将使星形胶质细胞对机械创伤的感知和反应变得非常有趣。这一结果可能会导致新的方法来确定患者对损伤的敏感性，或改善患者在脑损伤后的预后。该项目的跨学科性质还将包括为弗吉尼亚州西南部农村地区的不同学生群体提供教育推广机会。星形胶质细胞通过调节代谢物、炎症和细胞外微环境在脑组织动态平衡中发挥重要作用。它们也是延长和解决脑创伤后病理过程的主要效应细胞。对大脑发育和功能的机械生物学研究一直局限于分析机械转导如何调节神经元信号和可塑性。少数研究星形胶质细胞机制生物学的研究还没有集中在创伤性脑损伤后的细胞效应。该项目将结合组织工程和细胞机械生物学的各个方面，以了解通过细胞-基质相互作用进行的力传导如何可能导致与脑创伤继发性损伤级联相关的高比率侮辱后发生的复杂后遗症。这项工作最终可能揭示新的治疗途径，以中断细胞-微环境机械相互作用反馈回路，放大二次损伤机制。该奖项反映了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 research to better understand the long-term effects of traumatic brain injury. Traumatic brain injury represents a significant burden in the United States. While there are many treatments available, there are no proven therapies to mitigate the long-term effects of these injuries. The results of this work will ultimately lead to new treatments. This work will look specifically at astrocytes, which are a specific cell type in the brain and spinal cord. Astrocytes are responsible for many critical supportive functions. Astrocyte dysfunction occurs in conditions as Alzheimer’s disease and cancer. The role of astrocytes in responding to mechanical injury is not well understood. This project will use engineered three-dimensional model brain tissues to better understand the contribution of specific cell types to brain injury response. These models provide a realistic view of how the brain cells respond to injuries such as blast trauma. This work will revel how astrocytes sense and respond to mechanical trauma. The results may lead to new ways to determine patient susceptibility to damage, or improve patient outcomes following injury to the brain. The interdisciplinary nature of the project will also include educational outreach opportunities for a diverse group of students in rural southwestern Virginia. Astrocytes play a vital role in brain tissue homeostasis through modulation of metabolites, inflammation, and the extracellular microenvironment. They are also the major effector cells in both prolonging and resolving pathologic processes following brain trauma. Mechanobiology studies of brain development and function have been limited to analysis of how mechanotransduction mediates neuronal signaling and plasticity. The few studies that have examined astrocyte mechanobiology have not focused on the cellular effects following traumatic brain injury. This project will incorporate aspects of tissue engineering and cellular mechanobiology to understand how force transduction via cell-matrix interactions may contribute to complex sequelae that occur after high-rate insults associated with brain trauma secondary injury cascades. This work may ultimately reveal novel therapeutic avenues to interrupt the cell-microenvironment mechanical interaction feedback loops that amplify secondary damage mechanisms.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.