The application's broad, long-term objectives are to determine how fibroblast growth factor receptor (FGFR) signaling is crucial for the patterning and interactions between developing renal lineages at early and later stages.
The Specific Aims are: 1.To fully characterize the temporal and lineage specific expression patterns of fgfr1 and fgfr2 in the developing kidney. 2. To fully characterize the temporal and lineage specific patterning defects resulting from deleting fgfr1 and/or fgfr2 in the ureteric bud or the metanephric mesenchyme. 3. To determine the functional consequences of blocking FGFR1 and/or FGFR2 signaling in the kidney using a combination of in vitro and in vitro strategies. Elucidating the roles of FGFR signaling in kidney development may impact on a range of devastating congenital kidney disorders, which are the most frequent causes of end stage renal failure in children. ? The expression patterns of fgfr1 and fgfr2 in the kidney will be characterized at early and later stages of kidney development by in situ hybridization and immunohistochemistry. ? The temporal and lineage-specific patterning defects resulting from conditional targeting of individual and combinations of fgfr1 and fgfr2 will be assessed first by examining histological markers for each of the lineages. Assays for abnormalities in apoptosis and/or proliferation will also be assessed in each of the conditional knockouts. ? The functional consequences of deleting the receptors will be addressed first by whether the fgfrs are truly functionally equivalent in the kidney, with a combination of in vitro and in vitro approaches. The mechanisms responsible for the phenotypic abnormalities described in Aim 2 will be investigated in each conditional knockout. Expression of other genes that control renal development will be assessed to place FGFR signaling in molecular pathways. In vitro explant approaches will be used to knockdown FGFR signaling to uncover additional developmental roles of the FGFRs in the kidney. Finally, complementary in vitro and in vitro assays will be performed to determine the FGFR downstream signaling pathways relevant to kidney development. ? ? ?
| Walker, Kenneth A; Sims-Lucas, Sunder; Bates, Carlton M (2016) Fibroblast growth factor receptor signaling in kidney and lower urinary tract development. Pediatr Nephrol 31:885-95 |
| Walker, K A; Ikeda, Y; Zabbarova, I et al. (2015) Fgfr2 is integral for bladder mesenchyme patterning and function. Am J Physiol Renal Physiol 308:F888-98 |
| Sims-Lucas, Sunder; Di Giovanni, Valeria; Schaefer, Caitlin et al. (2012) Ureteric morphogenesis requires Fgfr1 and Fgfr2/Frs2? signaling in the metanephric mesenchyme. J Am Soc Nephrol 23:607-17 |
| Bates, Carlton M (2011) Role of fibroblast growth factor receptor signaling in kidney development. Pediatr Nephrol 26:1373-9 |
| Sims-Lucas, Sunder; Cusack, Brian; Baust, Jeffrey et al. (2011) Fgfr1 and the IIIc isoform of Fgfr2 play critical roles in the metanephric mesenchyme mediating early inductive events in kidney development. Dev Dyn 240:240-9 |
| Bates, Carlton M (2011) Role of fibroblast growth factor receptor signaling in kidney development. Am J Physiol Renal Physiol 301:F245-51 |
| Sims-Lucas, Sunder; Cusack, Brian; Eswarakumar, Veraragavan P et al. (2011) Independent roles of Fgfr2 and Frs2alpha in ureteric epithelium. Development 138:1275-80 |
| Sims-Lucas, Sunder; Cullen-McEwen, Luise; Eswarakumar, Veraragavan P et al. (2009) Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia. Am J Physiol Renal Physiol 297:F1208-19 |
| Liu, Yingjie; Chattopadhyay, Nibedita; Qin, Shan et al. (2009) Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis. Development 136:843-53 |
| Sims-Lucas, Sunder; Argyropoulos, Christos; Kish, Kayle et al. (2009) Three-dimensional imaging reveals ureteric and mesenchymal defects in Fgfr2-mutant kidneys. J Am Soc Nephrol 20:2525-33 |
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