Ted Daniel Llera L&S Sciences
Establishing The Mechanisms of AGS MANF in Neuroprotection and Regulated Cell Death Using CRISPR-Engineered AGS and Mouse Neural Cells
My goal is to identify the mechanisms of innate metabolic resilience and discover targets with translational potential for neuroprotection by characterizing the function of protein variants that make Arctic ground squirrels (AGS) resistant to cerebral ischemia. Studies show that cellular resistance to metabolic stressors is an intrinsic property of neural cells generated from AGS. Through functional genomic screens and computational analysis, they identified novel cytoprotective protein variants with amino acid substitutions that are unique to AGS but otherwise conserved in mammals. Among the identified proteins with the most striking metabolic resilience phenotypes, mesencephalic astrocyte-derived neurotrophic factor (MANF) demonstrates enhanced cytoprotective effects specific to the AGS variant. I hypothesize that this key AGS MANF variant promotes ischemia resilience and neuronal survival by enhancing sulfatide binding, ER stress response, and mitochondrial function while reducing cell death under metabolic stress conditions. I will characterize the neuroprotective potential of this AGS cytoprotective variant, which can potentially create a cure or treatment for diseases like stroke.