PROJECT SUMMARY Autophagy is a homeostatic mechanism that cells utilize to clear waste. Autophagy is especially important for neurons because they cannot dilute waste through cell division. However, the rate of neuronal autophagy decreases during aging, and the misregulation of autophagy has been implicated in many age-related neurodegenerative diseases (NDDs) including Alzheimer’s Disease and Related Dementias (ADRD). We previously found that the decrease in autophagy seen in aged primary neurons can be rescued through the overexpression of WIPI2B, a key autophagy component. Moreover, the phosphorylation state of WIPI2B dictates its ability to restore autophagy in aged neurons. Based on these data, I hypothesize that the phosphorylation state of WIPI2B regulates its function in neuronal autophagy and that increasing levels of dephosphorylated WIPI2B upregulates neuronal autophagy. Overall, this proposal aims to investigate the mechanisms of neuronal autophagy regulation in vivo (Aims 1 and 2) and apply this in a NDD context using a C. elegans model of AD (Aim 3). A better understanding of how neurons utilize and regulate autophagy will uncover novel therapeutic targets for treating NDDs. The Stavoe lab at UTHealth Houston is the ideal environment for me to conduct this research and complete my graduate training. In addition to performing the experiments outlined in the research plan, I will develop my technical, critical thinking, and communication skills through in-class instruction, mentorship in the lab, and attendance of seminars and conferences. As my graduate institution is located in the largest medical center in the world, I have access to classes, workshops, and seminars held by the different institutions, and I have the opportunity to network and discuss science with experts across a broad range of topics. Altogether, the proposed project and my training plan will impact our understanding of neuronal autophagy regulation and prepare me for my future research career in neurobiology.