Wayne Isaac Lencer, M.D.
|Title||Professor of Pediatrics|
|Institution||Children's Hospital Boston|
GI Cell Biology, Enders 720
300 Longwood Ave
Boston MA 02115
Available: 09/04/13, Expires: 09/03/14
The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense.
We have recently found that Inositol-REquiring-1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by cholera and Shiga toxins as they co-opt the ER to cause disease. Other known UPR transducers, including the IRE1α effector XBP1 are dispensable for signaling. The inflammatory response depends instead on the RNase activity of IRE1 and RIG-I, a cytosolic sensor of RNA fragments. These observations implicate Regulated IRE1α-Dependent Decay of mRNA (RIDD) in a novel innate immune mechanism of host defense originating from within the ER lumen.
We propose IRE1 may represent one way intestinal cells sense the 100-trillion microbes colonizing the GI tract.
The short project would be to test this idea by examining the IRE1beta isoform (which is restricted in expression to intestinal cells) and by searching for microbial products that bind the cholera toxin receptor, GM1, which carries the toxin into the ER of host cells. The student would express IRE1beat isoforms for in vitro binding studies, and prepare affinity columns to screen intestinal contents (from normal and diseased mice) for binding ligands by LC-MS-MS (mass spectroscopy).
Cholera Toxin Endocytosis Via Ganglioside GM1 Enriched Detergent-Insoluble Membrane Microdomains: Molecular Mechanisms
Part Time/Continuation, 09/01/98 - 04/01/99
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