Deciphering Mechanisms of Mechanotransduction in Astrocyte Reactivity

Virginia Polytechnic Institute And State University, Blacksburg VA

Investigators

Abstract

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.