Hepatocyte growth factor (HGF), via its c-met receptor, is an important regulator of kidney development, growth, and function and plays a central role in regulating the renal repair processes following injury. Studies from this and other laboratories indicate that renal c-met induction is a crucial event increasing HGF action and targeting it specifically to renal epithelial cells. Since c-met induction occurs primarily at the transcriptional level, induced c-met transcription is an important mechanism leading to tubular repair and regeneration. Therefore, the overall goals of this proposal are to examine the molecular mechanism(s) governing c-met regulation and to investigate the biological effects of c-met/HGF in kidney cells. This will be accomplished by applying molecular and cellular biologic techniques in three Specific Aims.
In Aim 1, the c-met gene will be cloned and its structural organization and promoter region will be fully characterized.
In Aim 2, the molecular mechanism(s) underlying ligand induced c-met expression will be characterized by transfecting promoter-CAT reporter gene constructs into renal epithelial cells and exposing them to HGF. Novel elements dictating c-met expression will also be identified and further analyzed by DNA-protein interaction and site-directed mutagenesis studies.
In Aim 3, the biological effects of HGF/c-met on renal epithelial cell injury and repair will be investigated by examining the role of HGF in protecting renal epithelial cell from apoptosis. These studies will provide novel information on the gene structure of this unique receptor as well as important insights into the transcriptional regulation of c-met expression and its function in normal and diseased kidneys. Ultimately, these studies may suggest novel strategies to alter the course of human renal disease by regulating the HGF/c-met axis, and thereby, modifying cell repair and growth.
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