Wednesday, March 22, 2023
3/22/2023
Traumatic neural injury causes debilitating and permanent paralysis, in part because chronic inflammation prevents the wound from healing. Our over-arching goal is to design biomaterial strategies for neural repair that instruct remodeling of glial cells – important neural cells capable of regulating inflammation and tissue regeneration. Glial cells become reactive after injury, propagating and maintaining the pro-inflammatory environment leading to chronic inflammation. Recent studies have shown that these glial cells, namely astrocytes and microglia, can adapt phenotypes for neuroprotection and repair given the right stimuli. In our own work using a patient-designed model of brain cancer, we found introduction of glial cells to cancer cells significantly alters glial cell reactivity. Cancer cells are known to express matrix proteins and cell-surface glycans that train local cells, including glial cells, to adopt anti-inflammatory phenotypes. We hypothesize that factors produced by cancer cells may inform design of new materials to retrain reactive glial cells to suppress inflammation and promote repair after injury. To addressing these hypotheses, we will in this proposal 1) characterize expression of extracellular matrix proteins and cell-surface glycans from several patient-derived brain cancer cells, 2) from this characterization identify potential candidate molecules regulating glial cell phenotype, and 3) screen for ligand combinations inducing anti-inflammatory glial phenotypes under normal and inflamed conditions. This approach will leverage patient-derived glioblastoma cancer cells, two high throughput biomaterial platforms, and programmable ligands for ‘click’ chemistry to establish the therapeutic potential of using cancer to inform strategies for tissue regeneration. Ultimately, understanding how brain cancer dictates behavior of neural cells, biasing them toward anti-inflammatory phenotypes, will enable development of materials to instruct remodeling of the injury environment and promote repair, with possibly widespread applications in a number of tissues and pathologies.
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