Research Project
10490484
ABSTRACT All cells within our bodies are surrounded by the extracellular matrix (ECM), which consists of a network of proteins and polysaccharides secreted by cells. The ECM is not only critical for physically supporting cell and tissue structures, but is also mediates a large number of receptor signaling on the cell surface that enables proper cellular functions and tissue homeostasis. For example, recent work from our lab have shown that TMEM2, which breaks down a major ECM polysaccharide, hyaluronic acid (HA), can modulate ER stress resistance and immune response in both human cell culture and the C. elegans model system. This highlights the importance of ECM- derived signals in maintaining cell and organismal health. However, the underlying signaling pathways and specific changes of ECM that regulates ER stress and immunity remain unclear. To understand how ECM changes can signal to alter ER stress and immune response, we propose to first use TMEM2 as a model for ECM alteration and elucidate how TMEM2 activity influences ER function and morphology. Next, we will determine whether such ER changes influence immune signaling and identify genetic regulators downstream of TMEM2 that mediates immune signaling in both C. elegans and human cell culture systems. Finally, to uncover how other alterations in ECM regulates ER stress and immune response, we will characterize how expression of TMEM2 along with other known human and C. elegans ECM-modifying proteins alter the ECM network, and determine whether these changes can also modulate ER proteostasis and immune signaling. Taken together, our proposal will reveal ECM changes regulate ER stress and immune signaling, providing insight into how cells and tissues might sense extracellular signals to promote organismal homeostasis.
