The ASPIRE Path in Molecular Medicine

My thesis project focuses on modeling the impact of disrupting peroxisomal biogenesis and fission in neurodevelopment. Peroxisomes are single membrane bound organelles containing more than 50 enzymes involved in a range of metabolic pathways. An area where peroxisomes are particularly important is in the brain. Here, they are involved in critical functions including myelin production, reactive oxygen species (ROS) homeostasis, and microglial response to inflammation. These peroxisomal-mediated functions have not been studied in any detail in neurodevelopment, and a family of diseases marked by the consequences of dysfunction in these processes are Zellweger spectrum disorders (ZSDs). To elucidate the role of peroxisomes in early human neurogenesis and ZSDs, we will generate forebrain organoids to explore the effects of dysregulating peroxisomal maturation and peroxisomal biogenesis on the maintenance of the neural progenitor pool, the formation of cortical layers, and the electrophysiological activity of neuronal cells. This project fits in with the goals of APMM because it will help elucidate the potential mechanisms of ZSDs and provide a closer look at the morphological and biochemical changes that may occur in patient brains. Additionally, the systems proposed in this project can be paired with techniques like drug screens to evaluate therapeutic options.