Glomerulosclerosis is the final common pathway of the many diverse etiologies of renal failure during childhood. In this grant we will focus on transgenic mouse models in which glomerular defects are observed, and we will propose how further studies of these models will elucidate the molecular basis for glomerular damage and dysfunction. The study of glomerular development in our laboratory was initiated when gene targeting experiments performed several years ago by the Principal Investigator showed that the Wtl and a3 integrin genes has a crucial role in kidney development [1, 2]. In the case of the alpha3 integrin gene it was immediately apparent that a3bl integrin was a key protein required to assemble podocyte foot processes. ? ? Loss of the Wtl gene led to a block in the earliest stages of kidney development, not allowing study of its role in glomerular development. However, studies of humans with either the Deny-Drash or Frasier Syndromes has demonstrated an important role for Wtl in glomerular function [3-5]. In this grant we present preliminary data demonstrating that a mouse model in which to study Wtl in glomerular function has been derived, and we propose ways to extend this model to further understand how Wtl acts to maintain normal glomerular function. ? ? The specific aims of this grant are to: (1) Establish a system to achieve inducible podocyte-specific expression of WT1 transgenes; (2) Conditionally mutate the Wtl gene in podocytes; and (3) Conditionally mutate the alpha3 integrin gene in podocytes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Wilder, Elizabeth L
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Children's Hospital Boston
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Qin, Shan; Taglienti, Mary; Cai, Lei et al. (2012) c-Met and NF-ýýB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol 23:1309-18
Qin, Shan; Taglienti, Mary; Nauli, Surya M et al. (2010) Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest 120:3617-28
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
Natoli, Thomas A; Alberta, Julia A; Bortvin, Alex et al. (2004) Wt1 functions in the development of germ cells in addition to somatic cell lineages of the testis. Dev Biol 268:429-40
Zhang, Hong; Palmer, Rachel; Gao, Xiaobo et al. (2003) Transcriptional activation of placental growth factor by the forkhead/winged helix transcription factor FoxD1. Curr Biol 13:1625-9
Natoli, Thomas A; McDonald, Alice; Alberta, Julia A et al. (2002) A mammal-specific exon of WT1 is not required for development or fertility. Mol Cell Biol 22:4433-8
Natoli, Thomas A; Liu, Jing; Eremina, Vera et al. (2002) A mutant form of the Wilms' tumor suppressor gene WT1 observed in Denys-Drash syndrome interferes with glomerular capillary development. J Am Soc Nephrol 13:2058-67