? During kidney development, ureteric bud (UB) cells undergo branching morphogenesis to form the distal collecting system. Aberrant branching may lead to developmental anomalies and regulate nephron number variation that contributes to hypertension and end-stage renal disease. A full understanding of the signals that regulate UB branching morphogenesis will therefore lead to the identification of regulators of these pathologic processes. ? The protein tyrosine phosphatase Shp2 is required to generate signals that drive branching morphogenesis, but its precise biochemical and developmental roles are unclear. In preliminary studies, I validated the importance of Shp2 in epithelial cell signaling, and also uncovered a novel, Shp2-independent pathway that may regulate additional aspects of UB development. I will use biochemical and cell biological approaches to define the components of these Shp2-dependent and ? -independent signaling pathways. I will also directly define the in vivo role of Shp2 in UB branching morphogenesis, and use ex vivo organ culture methods to further determine the roles of the signaling pathway components I identify in this developmental process. These studies will substantially advance our understanding of renal development and more fully define pathways that may apply to other pathologic conditions related to epithelial plasticity. ? The candidate for this K08 award, Frank David, is a pathologist who will receive advanced training in biochemistry and renal developmental biology through this work. His mentor, Benjamin Neel, is an expert in Shp2 and transgenic mouse studies. His consultants -- Joseph Bonventre, Lewis Cantley, Jordan Kreidberg, Andrew McMahon and Helmut Rennke -- are experts in phosphorylation-dependent signaling and renal pathophysiology and development, who will contribute substantially to his training during the course of this award. ? LAY SUMMARY: This work will define mechanisms in kidney development that may underlie several kidney-related birth defects and the development of high blood pressure. They will also advance our understanding of other pathologic processes, including metastasis and wound heaing, that share common signals and cellular behaviors with those defined here. ? ?
| David, Frank S; Cullen-McEwen, Luise; Wu, Xue Sue et al. (2010) Regulation of kidney development by Shp2: an unbiased stereological analysis. Anat Rec (Hoboken) 293:2147-53 |
