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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077876-02
Application #
7588914
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2008-06-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$328,312
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lee, Hyeong J; Hota, Prasanta K; Chugha, Preeti et al. (2012) NMR structure of a heterodimeric SAM:SAM complex: characterization and manipulation of EphA2 binding reveal new cellular functions of SHIP2. Structure 20:41-55
Petty, Aaron; Myshkin, Eugene; Qin, Haina et al. (2012) A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo. PLoS One 7:e42120
Lin, Samantha; Wang, Bingcheng; Getsios, Spiro (2012) Eph/ephrin signaling in epidermal differentiation and disease. Semin Cell Dev Biol 23:92-101
Miao, Hui; Wang, Bingcheng (2012) EphA receptor signaling--complexity and emerging themes. Semin Cell Dev Biol 23:16-25
Tian, Haibin; Lu, Xincheng; Guo, Hong et al. (2012) Radio-deoxynucleoside Analogs used for Imaging tk Expression in a Transgenic Mouse Model of Induced Hepatocellular Carcinoma. Theranostics 2:597-606
Lu, Xincheng; Guo, Hong; Molter, Joseph et al. (2011) Alpha-fetoprotein-thymidine kinase-luciferase knockin mice: a novel model for dual modality longitudinal imaging of tumorigenesis in liver. J Hepatol 55:96-102
Khan, Shenaz; Lakhe-Reddy, Sujata; McCarty, Joseph H et al. (2011) Mesangial cell integrin ?v?8 provides glomerular endothelial cell cytoprotection by sequestering TGF-? and regulating PECAM-1. Am J Pathol 178:609-20
Wang, Bingcheng (2011) Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners. Sci Signal 4:pe28
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2010) DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24:2019-29
Miao, Hui; Li, Da-Qiang; Mukherjee, Amitava et al. (2009) EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16:9-20

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