RESEARCH OVERVIEW       

The cells of our bodies are surrounded by a membrane that separates the molecules inside the cell from those on the outside.  This membrane barrier provides cellular identity, and is essential for life as we know it, but it also represents a problem.  How are large molecules that the cell needs to survive internalized?  Likewise, how can the composition of the membrane be controlled to optimize the interaction of the cell with its environment?  These fundamental issues of cellular function are solved in part by membrane traffic, the regulated movement of regions of membrane and their associated macromolecules using small carriers called vesicles.

Research in the Grant lab focuses on the molecular mechanisms controlling uptake from the cell surface (endocytosis), and endocytic recycling, the return of internalized macromolecules to the cell surface from internal structures called endosomes. Understanding endocytic recycling is of fundamental importance to cell biology and has broad relevance to many areas of biomedicine. For instance, endocytic recycling is a key control point in the insulin-stimulated movement of glucose transporters (Glut4) from endosomes to the plasma membrane of adipose and muscle cells. Failure in this recycling event is linked to type II diabetes, a disease that has recently reached epidemic proportions in the United States. In addition, endocytic recycling controls many aspects of cellular behavior that run amok in cancer. For example endocytic recycling contributes critically to growth factor receptor signal transduction, the completion of cytokinesis, and the regulation of cell migration (metastasis). A better understanding of how endocytic recycling functions will be profoundly important in identifying therapeutic targets to combat these diseases. The recycling process appears to have greatly increased in complexity with the advent of multicellularity, and is highly conserved among metazoans.

To gain new insight into the mechanisms that drive this pathway, we are taking advantage of the unique experimental features of the microscopic nematode C. elegans that have made it a leading model organism in nearly all areas of modern biological research. Chief among these features are highly advanced genetics, including extremely facile gene knockdown, knockout, and transgenic technology, coupled with a transparent body that allows visualization of fluorescently tagged molecules in living animals, in the physiologically relevant context of an intact organism. While C. elegans is relatively simple, it possesses many of the important features of higher animals, such as multiple tissue types (muscles, nerves, epithelia), that are unique to metazoan animals. The phylogenetic conservation of basic cell and molecular biological pathways between worms and humans has allowed C. elegans research to provide many important insights into the underlying mechanisms that operate in human cells and tissues. Much of our current research focuses on trafficking mechanisms in the worm intestine, a simple polarized epithelium, the component cells of which must maintain two distinct plasma membrane domains to perform their specialized functions. Recent studies indicate that epithelia must sort membrane-bound cargo in both the secretory and endocytic recycling pathways to maintain the distinct features of apical and basolateral membranes..