The process of receptor-mediated transcytosis is a critical, yet highly selective, mechanism for the transport of proteins from the intestinal lumen into systemic circulation. Despite the fundamental importance of this transport mechanism and the potential to exploit it to revolutionize oral delivery of protein therapeutics, our understanding of intestinal transcytosis has been limited by both the lack of a more accurate, scalable in vitro model of the human intestinal epithelium and the difficulty in identifying the full repertoire of receptors that can actively and selectively transport cargo from the luminal side to the basolateral side of this physical barrier. In this R01 proposal, we will synergistically integrate stem cell engineering, directed protein evolution, and synthetic biology approaches to first uncover new mechanisms of receptor-mediated transcytosis and to then apply these findings to create a novel platform for oral delivery of insulin. More generally, our approaches and results should have broad utility in understanding the formation of epithelial barriers and in efficiently delivering drugs across them in a highly selective manner.
The transport of molecules from the digestive tract into circulation is tightly controlled by the cells lining the intestine and is critical to human health. A better understanding of the mechanisms by which this process occurs will not only improve our understanding of diseases arising from dysregulation of this transport, but may also be exploited to non-invasively deliver protein drugs such as insulin via oral administration.
| Ye, Zi; Sarkar, Casim A (2018) Towards a Quantitative Understanding of Cell Identity. Trends Cell Biol 28:1030-1048 |
