Bcl-2 protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Mice deficient in bcl-2 (bcl-2 -/-) develop renal hypoplastic/cystic dysplasia, a condition that leads to significant morbidity and mortality in children. The precise mechanism of action of bcl-2 has not been elucidated. Our hypothesis is that early embryonic expression of bcl-2 facilitates morphogenesis by supporting survival of precursor cells allowing them to be less adherent and migratory without the threat of apoptosis. Bcl-2 may facilitate survival of precursor cells and/or play a more """"""""active"""""""" role during morphogenesis by interacting with other proteins such as paxillin. Our data demonstrate that paxillin interacts with the bcl-2 BH4 domain in embryonic kidneys. The bcl-2 BH4 domain is sufficient and necessary for its cell survival activity. Bcl-2 with the BH4 domain deleted lacks the survival function but still avidly binds to other bcl-2 family members. We will determine the domain(s) of paxillin that interact with bcl-2 and their influence on cell adhesive mechanisms during kidney development. Our preliminary data indicate that ureteric bud (UB) branching morphogenesis is adversely affected in bcl-2 -/- mice. Metanephroi from bcl-2 -/- mice undergo decreased UB branching in organ culture and bcl-2 -/- UB cells fail to undergo branching morphogenesis in collagen gels. Furthermore, wild-type embryonic kidneys incubated with bcl-2 BH4 domain peptide exhibit defective UB branching morphogenesis. We will investigate the role bcl-2 plays during UB branching and whether aberrant UB branching contributes to excessive apoptosis of the metanephric blastema in bcl-2 -/- mice. We will determine whether the abnormalities of renal development in bcl-2 -/- mice is primarily or exclusively the result of the absence of bcl-2 in the UB or metanephric mesenchyme. Therefore, understanding the normal functions of bcl-2 during nephrogenesis and the consequences of its interaction with paxillin will give us important insight into kidney morphogenesis and pathogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067120-02
Application #
7020758
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Wilder, Elizabeth L
Project Start
2005-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$281,320
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Grutzmacher, Cathy; Park, SunYoung; Zhao, Yun et al. (2013) Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes. Am J Physiol Renal Physiol 304:F19-30
Sheibani, Nader; Morrison, Margaret E; Gurel, Zafer et al. (2012) BIM deficiency differentially impacts the function of kidney endothelial and epithelial cells through modulation of their local microenvironment. Am J Physiol Renal Physiol 302:F809-19
Maleki, Sepideh; Sepehr, Reyhaneh; Staniszewski, Kevin et al. (2012) Mitochondrial redox studies of oxidative stress in kidneys from diabetic mice. Biomed Opt Express 3:273-81
Wang, Shoujian; Park, SunYoung; Fei, Ping et al. (2011) Bim is responsible for the inherent sensitivity of the developing retinal vasculature to hyperoxia. Dev Biol 349:296-309
Grutzmacher, Cathy; Park, SunYoung; Elmergreen, Tammy L et al. (2010) Opposing effects of bim and bcl-2 on lung endothelial cell migration. Am J Physiol Lung Cell Mol Physiol 299:L607-20
Tang, Yixin; Scheef, Elizabeth A; Gurel, Zafer et al. (2010) CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress. Am J Physiol Cell Physiol 298:C665-78
Scheef, Elizabeth A; Sorenson, Christine M; Sheibani, Nader (2009) Attenuation of proliferation and migration of retinal pericytes in the absence of thrombospondin-1. Am J Physiol Cell Physiol 296:C724-34
Tang, Yixin; Scheef, Elizabeth A; Wang, Shoujian et al. (2009) CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression. Blood 113:744-54
Wang, Shoujian; Gottlieb, Justin L; Sorenson, Christine M et al. (2009) Modulation of thrombospondin 1 and pigment epithelium-derived factor levels in vitreous fluid of patients with diabetes. Arch Ophthalmol 127:507-13
Huang, Qiong; Wang, Shoujian; Sorenson, Christine M et al. (2008) PEDF-deficient mice exhibit an enhanced rate of retinal vascular expansion and are more sensitive to hyperoxia-mediated vessel obliteration. Exp Eye Res 87:226-41

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