The 14 members of Eph kinases constitute the largest subfamily of receptor tyrosine kinases in mammalian system and bind membrane-anchored ligands called ephrins. The pivotal role of Eph/ephrin interactions in regulating development of nervous and cardiovascular systems is well substantiated. However, whether they also epithelial development remains largely unexplored. The published and preliminary results by the applicant show that Eph kinases are novel regulators of epithelial branching morphogenesis. In MDCK renal epithelial cells, ligand activation of endogenous EphA2 potently inhibited HGF/SF-induced branching morphogenesis in 3-D collagen gels. In embryonic kidneys in vivo, EphA2 was selectively expressed in ureteric bud (UB), while ephrin-A1 was preferentially expressed in surrounding metanephric mesenchyme (MM). We hypothesize that the localized Eph/ephrin interactions UB/MM boundary allows contact-dependent guidance of renal branching morphogenesis. Supporting this hypothesis, kidneys from EphA2 knockout mice showed abnormal branching morphogenesis. The goal of this proposal is to take advantage of the unique model systems that we have established to determine the cellular and molecular bases underlying Eph kinase regulation of kidney development.
In Aim 1, we will establish spatiotemporal expression profiles of all major EphA kinases and ephrin-As during metanephric kidney development.
In Aim 2, we will focus on how perturbations of EphA/ephrin-A interactions will affect renal morphogenesis in vivo, by creating EphA1/EphA2 compound knockout.
Specific Aim 3, we will use renal epithelial cell in vitro to gain insights on how EphA kinases regulate E-cadherin-mediated cell-cell adhesion and signaling. Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development metanephric kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases.Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development of the kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension and end stage renal disease. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases.
Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development of the kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension and end stage renal disease. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases. ? ? ?
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