Grant: CIHR Fellowship

The regulation of protein production is critical to maintain cellular homeostasis. When disrupted, this can result in devastating human disease. The cellular machinery used to produce proteins, termed ribosomes, has traditionally been viewed as a universal machine that is similar between organisms and cell types. Interestingly, mutations in core ribosome proteins lead to devastating congenital birth defects (e.g. neural crest defects) and stem cell defects (e.g. Diamond Blackfan Anemia), suggesting that specific proteins are required for proper development and cellular maintenance. Indeed, specialized ribosomes have been found to drive synthesis of specific proteins in key pathways of tissue development. As well, this level of specialization has recently been found to be augmented by auxiliary proteins that bind to the ribosome to effect its function; however, the role of these ribosome-associated proteins in human health and disease remains largely unknown. Here, we aim to fill this gap in knowledge by characterizing ribosome-associated proteins and their functions during stem cell differentiation. Specifically, we hypothesize that proteins bound to the ribosome are crucial in directing cell fate decisions of human embryonic stem cells down cardiac cell lineages. To study this, we will combine state-of-the-art methodologies including high-throughput ribosome profiling and mass spectrometry to fully understand the repertoire of ribosome-associated proteins during cardiac cell development and their cognate regulatory targets. Moreover, we will use gene editing technology to further understand their specific functional roles in cellular protein synthesis and eventually use animal models to assess their impacts on disease.