Grant: Operating Grant-PA: INMD Start Up Funds (bridge funding) - New Investigators

Clinically evident kidney failure eventually develops in patients with type 1 and continues to progress despite receiving intensified glycemic control. The mechanisms underlying this metabolic memory phenomenon on progression of kidney damage are not completely understood. Toxic metabolites induced by elevated glucose levels for several months may cause local factor changes affecting podocyte survival, an important vascular cell in kidney, which are not easily reversed. I made a very interesting finding on a potential target called SHP-1 that is elevated with high glucose concentrations in diabetic kidneys of rodent animals and remained elevated despite glucose level correction after poor glycemic control. SHP-1 is a member of the protein tyrosine phosphatase family that downregulates the activity of important growth factors, such as insulin, which is crucial for podocyte survival and function. Thus, activation of SHP-1 may contribute to unwanted abnormalities of renal podocyte function causing insulin unresponsiveness and diabetic nephropathy in type 1 patients. The aim of the present proposal will characterize and explore the role of persistent activation of SHP-1 triggering biological abnormalities such as podocyte death and insulin resistance. To accomplish this aim, we will use several methods to specifically manipulate the protein expression level of SHP-1 in podocyte cell line and evaluate its impact on insulin action. Moreover, I will use genetically modified tissue specific mice of SHP-1 to characterize its cellular mechanisms implicated in diabetic nephropathy using a type 1 diabetic mouse model that have been poor control for 3 months and well controlled for 2 addition months. We believe that this proposal will help us better understand the mechanisms underlying glomerular cell dysfunction related to the glycemic memory, and will provide a tremendous impact on developing new strategies to prevent and reverse kidney failure in type 1 diabetes.