Mechanisms of lipid-laden astrocyte formation after spinal cord injury

Abstract Spinal cord injury (SCI) results in a persistently debris-ridden and scarred lesion site. This environment results in a scar that is non-permissive to wound repair, axon regeneration, and full functional recovery. Astrocytes are a main component of the injury site border that begin to rapidly proliferate 3 days after injury and slow by 7 days. By 28 days post-injury, a prominent gliotic region is present where reactive astrocytes densely surround the lesion. It has been previously shown that macrophages become oversaturated by up taking excessive lipid debris and become inflammatory “foamy” cells that fill the injury site – possibly blocking regeneration across the injury. After injury, reactive astrocytes also observably become lipid laden cells that chronically border the injury site. It is unknown if reactive astrocytes become foamy and if reducing this lipid accumulation will yield a more growth permissive gliotic region and promote recovery after SCI. The first aim of this proposal is to identify the time course of lipid accumulation in astrocytes after SCI in vivo and characterize the unique genetic signatures of foamy astrocytes by developing an in vitro model. The mechanism of lipid accumulation in astrocytes has not been previously identified. However, the PI3K pathway has been shown in macrophages as a regulator of lipid accumulation and the pro inflammatory phenotype. Therefore, the second aim of this proposal is to identify pathways, including PI3K, for foamy astrocyte formation using compound and lentiviral knockdowns in an in vitro model of the SCI environment. Together, these studies aim to address the hypothesis that reducing lipid-laden or foamy astrocytes is beneficial for functional recovery and regeneration after SCI. The proposed research will take place at the University of Miami Miller School of Medicine with the Miami Project to Cure Paralysis, where I will be in close contact with peers and mentors with specialized knowledge on my project. Along with my research, my training will consist of attending multiple seminar series within the neuroscience program and university, presenting at conferences and symposiums, participating in responsible conduct of research lessons, and broadening my scientific perspective in translational research with extracurriculars.