Our laboratory's staff studies the intracellular signals that mediate fibrosis in progressive kidney disease. We use as our model cultured human mesangial cells. These cells occupy a central location in the filters of the kidney, where they provide a support structure for the blood vessels entering the filter (also known as the glomerulus). In addition, mesangial cells may play a role in regulating the local production of soluble mediators that regulate many aspects of local cell function.

Normally, there is a small amount of connective tissue called the extracellular matrix (ECM)--including collagen, laminin and other structural proteins--around the mesangial cells and the blood vessels. In a disease called focal segmental glomerulosclerosis (FSGS), the ECM accumulates, starting in the region around the mesangial cells.

Our central question is: how does a fibrogenic hormone called transforming growth factor TGF-beta stimulate excessive ECM production by the mesangial cell? The immediate intracellular mediating molecules are members of the Smad signal transduction family. TGF-beta binds to its cognate receptor, which then activates the Smads to aggregate. The Smad complex is transported to the nucleus where it participates in the transcriptional activation of genes that encode for ECM and other proteins. Although the Smads are the only signaling molecules that the TGF-beta receptors are known to activate directly, we and other researchers have identified many signaling pathways that are activated in mesangial cells after TGF-beta stimulation.

We have determined that some of these other pathways play a significant role in TGF-beta -activated collagen production. Currently, we are investigating the mechanism by which these other pathways are activated, and how cross-talk among the pathways influences ECM gene expression.

By understanding these interactions, we hope to identify ways to interrupt the signals that mediate ECM accumulation, and slow the scarring process in kidney disease.
 

Contact

Pediatrics W-140
303 E. Chicago Ave Ward 12-191
Chicago, IL 60611-3008
Phone: 312-503-1476