Project Summary/Abstract (From the original application) Coordinated regulation of protein synthesis, trafficking, post-translational modification and degradation is a basic requirement for cellular function. Targeted protein degradation in eukaryotic cells is largely carried out by the proteasome. The proteasome allows dynamic regulation of protein stability and enforces protein quality control by removing defective proteins. Importantly, demand for protein degradation by the proteasome within individual cells can vary due to endogenous signals or exogenous stressors. Thus, condition-specific regulation of proteasome capacity to maintain adequate, but avoid excessive, protein degradation is needed to ensure normal development and physiology. Failure to appropriately regulate the proteasome is implicated in disease. For example, deficient proteasome capacity is associated with neurodegenerative conditions, whereas proteasome levels and activity are often elevated in cancerous cells. We do not understand how cells dynamically maintain appropriate proteasome capacity to meet changing cellular needs. Critically, we do not understand how the failure or hyperactivity of these mechanisms contributes to disease. Here I propose a forward genetic approach in C. elegans to discover the factors that control proteasome capacity, understand how they work at the molecular level, uncover their roles in normal development, and begin to identify how they may mitigate or contribute to disease. We will (1) use simple GFP-based reporter assays to perform large-scale genetic screens that will comprehensively identify proteasome capacity regulators and (2) characterize novel proteasome regulators we have discovered through these screens. (3) We will uncover how alterations to specific proteasome subunits differentially alter protein degradation capacity, development, and proteasome inhibitor resistance. This work will improve our understanding of the fundamental cellular mechanisms that regulate proteasome capacity in a whole animal context. In the long-term, these insights will form the conceptual basis for pharmacological interventions that improve human health via modulation of cellular protein degradation capacity.