The Chen lab aims to understand how physical and chemical signals embedded in the microenvironment instruct aberrant behavior of resident cells to drive the progression of diseases and disorders within the central nervous system (CNS).
Current research projects include (1) investigating the mechanobiology of mesenchymal transitions in glioblastoma, (2) quantifying the micromechanical damage of traumatic CNS injury and (3) examining the mechanistic drivers of neurodegneration in an injured CNS microenvironment.
How do mesenchymal transitions influence mechanosensing and cellular invasion?
The rapid infiltration of GBM cells through the surrounding healthy tissue represents a characteristic barrier to complete resection and treatment of GBM. Heightened cell invasiveness is thought to be due to a loss of mechanosensing and alterations to cytoskeletal dynamics, a mechanism tightly regulated by RhoGTPase activity. Mesenchymal transitions are key events that worsen prognosis in GBM and can alter cell mechanosensing and invasion. Identifying mesenchymal transition targets regulating cytoskeletal control may restrict tumor cell spread and improve prognosis. Mesenchymal cadherin-11 is novel marker of mesenchymal transition and controls a p120-Rac axis that stimulates invasion and presumably affects mechanosensing; however, the downstream regulation of cadherin-11 and its interactions with RhoGTPase activity remains unclear. We are interrogating the pathways involved in this axis using genetic knockdowns, molecular biological assays, and engineered platforms.
What are the mechanical changes that occur after CNS injury?
Injury in the CNS is accompanied with dramatic molecular and cellular changes that develop into glial scars. Although tremendous efforts have been placed on describing the molecular changes that occur during glial scar formation, the mechanical changes are much less understood. Notably, neuronal and glial cell growth and function has been shown to respond to mechanical changes in the microenvironment. We aim to characterize the spatial-temporal mechanical changes of traumatic injury to the CNS at defined zones of injuries to uncover new insight regarding the micromechanical changes of traumatic injury of the CNS and the subsequent impact these cues can have on the resident cells.
Can we tune astrocyte activation to preserve the CNS post injury?
A major impediment to CNS repair is the formation of a glial scar after injury or neurodegeneration, which is primarily driven by the existence of reactive astrocytes. The transition of astrocytes to this reactive phenotype resembles mesenchymal activation and is a viable therapeutic target; however, mechanisms that regulate this transition are not completely understood. Interestingly, recent work reported that mechanical softening occurs at the scar interface, suggesting mechanical cues as a regulator of astrocyte transitions. Therefore, investigations into the role of mechanical inputs on astrocyte activation may lead to the discovery of novel mechano-dependent pharmacological targets.