Injury, to the terminally differentiated glomerular podocyte causes proteinuria in diabetic and non-diabetic renal disease. The inability of podocytes to proliferate adequately and replace those lost following injury underlies the decline in renal function due to glomerulosclerosis. In this grant proposal, we will test the central hypothesis that a novel mechanism limiting podocyte proliferation is DNA damage, with a focus on immune-mediated injury. Studies will be performed in cultured immortalized mouse podocytes, and in experimental models of podocyte injury in mice. In the first specific aim, we will show that DNA damage occurs in podocytes following sublytic C5b-9 (membrane attack complex) injury, and examine which signaling pathways mediate this effect. In the second aim, we will test the hypothesis that C5b-9 increases p53, which limits podocyte proliferation. In the final aim, we will test the hypothesis that the CDK-inhibitor, p21, regulates p53. The ultimate goal of this grant is to identify new targets for potential therapies in order to reduce the heavy burden of disease in patients with glomerular disease. ? ? ?
| Hauser, Peter V; Pippin, Jeffrey W; Kaiser, Cora et al. (2010) Novel siRNA delivery system to target podocytes in vivo. PLoS One 5:e9463 |
| Vaughan, Michael R; Quaggin, Susan E (2008) How do mesangial and endothelial cells form the glomerular tuft? J Am Soc Nephrol 19:24-33 |
| Ohse, Takamoto; Pippin, Jeffrey W; Vaughan, Michael R et al. (2008) Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture. J Am Soc Nephrol 19:1879-90 |
