Renal (e.g., glomerular mesangial) cell adhesion, growth and extracellular matrix deposition are crucially involved in the progression of end-stage renal failure. The long-term goal of this competing continuation application is to elucidate the molecular mechanism by which renal cells control these processes. The studies proposed in this competing continuation application focus on the role of integrin-linked kinase (ILK), a key component of cell-matrix contact sites, in the regulation of glomerular mesangial cell behavior.
Aim 1 is to test the hypothesis that a PINCH/ILKICH-ILKBP complex provides a key connection between integrins and the actin cytoskeleton at glomerular mesangial cell-matrix contact sites and thereby regulates mesangial cell adhesion, growth and fibronectin matrix deposition. Dominant negative inhibitors that disrupt the formation of the PINCH/ILKICH-ILKBP complex will be introduced into primary mesangial cells by adenoviral infection and their effects on mesangial cell adhesion, proliferation and fibronectin matrix deposition will be determined.
Aim 2 is to test the hypothesis that PINCH-RP, a newly identified PiNCH-related protein whose expression in glomerular mesangial cells is regulated by glucose, is a naturally occurring negative regulator of the assembly and functions of the P1INCH/ILKICH-ILKBP complex in mesangial cells. A combination of molecular and cellular approaches will be used to determine the functions of P1NCH-RP in mesangial cells.
Aim 3 is to molecularly characterize Mig-2, a newly identified protein that co-localizes and physically associates with the PINCH/ILKICH-ILKBP complex, and to determine whether it functions as a positive regulator facilitating the localization and functions of the ILK complex in mesangial cells. These studies will advance our knowledge on the molecular mechanisms that govern glomerular mesangial cell adhesion, growth and extracellular matrix deposition. They could potentially lead to development of novel therapeutic approaches to control end-stage renal failure that is intimately associated with abnormal renal cell adhesion, proliferation and extracellular matrix deposition.
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