BME PhD Prospectus Defense: Kunyu Li

Title: "Metabolic biomaterials for fuel delivery to improve astrocyte proliferative responses and wound healing after spinal cord injury"

Advisory Committee: Timothy O’Shea, PhD – BU BME (Research Advisor) Mark Grinstaff, PhD – BU BME (Chair) Brianne Connizzo, PhD – BU BME Zhigang He, PhD – Harvard Neurology

Abstract: Spinal cord injury (SCI) causes permanent neurological deficits and major long-term medical complications. Reduced mortality after SCI has resulted in several hundred thousand individuals living with chronic SCI who suffer from recurrent medical problems related to cardiovascular, respiratory, bladder, bowel and sexual function as well as complications from skin and urinary infections. In adult mammals, the SCI do not spontaneously regenerate but instead trigger a wound response that forms fibrotic scars. By contrast, scar-free and glia-based parenchymal repair is observed in neonates and can support neural circuit regeneration and functional recovery into adulthood. While there is adaptive reprogramming in adult astrocytes after SCI that involves neonate-like proliferative responses, it is transient, spatially constrained, and inadequate for astroglia frameworks within the lesion. Metabolism is a critical driver of healthy astrocyte functions and injury-induced adaptive transcriptional reprogramming. Astrocytes induced into a proliferative state after SCI have altered metabolic demands and require metabolic reprogramming involving aerobic glycolysis to support biosynthesis needed for generating daughter cells. Maintaining proliferative capacity in adult astrocytes after SCI likely requires sustaining aerobic glycolysis, while delayed angiogenesis at SCI lesions leads to dysfunctional delivery of fuels, potentially limiting astrocyte proliferation during this critical period of wound repair. Current metabolic therapies after SCI such as ketogenic treatments, lactate-related signaling, and strategies to restore mitochondrial bioenergetics have primarily focused on systemic interventions. However, the localized biomaterial-based delivery of metabolic substrates to fuel astrocytes proliferation post injury remains unexplored. Therefore, there is a need to develop and test approaches that can locally deliver and prolong metabolic fuel availability at SCI lesions. I have screened the metabolites required to sustain astrocytes proliferation in vitro, and synthesized a copolymer which can release those essential fuels under serum environment. I proposed to (1) screen and characterize both individual and synergistic effect of fuels on astrocytes and fibroblasts in vitro; (2) synthesize a copolymer platform composing a labile version of the most critical fuel for astrocytes, and evaluate how formulation as an injectable biomaterial affects control delivery of these fuels and impact on astrocytes proliferation in vitro; (3) evaluate astrocyte wound response after SCI following coacervate-mediated co-delivery of fuel and pro-proliferative cues. This work will provide important insights into the metabolic reprogramming involved in proliferative astrocyte responses in SCI and how delivery of exogenous metabolic fuels can modulate this reprogramming to progress new mechanism-based therapeutic approaches for SCI.