How Do Astrocytes Participate in Demyelination and Myelin Repair

项目总结

PROJECT SUMMARY Stroke and traumatic brain injury (TBI) cause alterations to the vasculature, disrupting the neurovascular unit (NVU) and causing neuroinflammation and neuronal death. In response to vascular damage, glial cells of the central nervous system (CNS), astrocytes and microglia, produce pro-inflammatory cytokines that can contribute to neuronal death. However, the specific signaling that connects the damaged neurovasculature to the glial response after injury remains to be understood. The eye, as CNS tissue, allow us to study the interactions between the vasculature and glial cells. Similar to human pathology, Retinal Vein Occlusion (RVO) in mice causes retinal edema, inflammation, and neuronal death; providing a model to study these interactions. Using this model, previous studies in our lab identified non-apoptotic activation of the protease caspase-9, that is usually associated with cell death, in the endothelium. Inhibiting caspase-9 or genetically deleting it from the endothelium, protects the retina from edema and neuronal death. These results indicated that expression of endothelial caspase-9 (EC Casp9) leads to neurodegeneration after vascular injury. Furthermore, we discovered that inhibiting caspase-9 significantly reduces the activity of caspase-6 (executioner caspase that can be activated by caspase-9) in astrocytes, but not microglia. Activation of caspase-6 in astrocytes is associated with increased cleavage and hyper-aggregation of GFAP and production of pro-inflammatory cytokines. I hypothesize that non-apoptotic activation of EC Casp9 increases astroglial caspase-6 which will result in the cleavage of GFAP, production of inflammatory cytokines, and neurodegeneration P-RVO. The long-term objective of this proposal is to study the role of caspase-9 signaling in vascular-glial communication and its contribution to increased pro-inflammatory cytokine and neurodegeneration. Studies in EC Casp9 KO mice revealed that EC Casp9 activates astroglial caspase-6. To further test the role of caspase-9 signaling on vascular-astroglial communication, we will determine if astroglial caspase-9 (1) is upstream of astroglial caspase-6 and mediates GFAP cleavage in RVO, (2) increases the production of pro-inflammatory cytokines, and (3) leads to retinal neuronal death and visual pathway dysfunction. Understanding vascular-glial signaling in neurovascular injury can help in the discovery of novel therapeutic targets for neuroprotection. The focus of the postdoctoral phase will be to study caspase signaling in glial cells and its contribution to retinal ganglion loss in Optic Neuritis associated with Multiple Sclerosis (MS). The ultimate goal of this F99/K00 proposal is to prepare me to be a principal investigator and study how neuroinflammation is regulated in neurodegenerative diseases of the brain that also affect the eye. To accomplish these goals, I developed a plan with mentors and collaborators to guide my specific research and professional activities. With the opportunities for scientific and career development available at Columbia, the objectives of this proposal are expected to be achieved.