This application is a continuation of the applicant's long-term efforts to elucidate the cellular and molecular pathways in the pathogenesis of chronic kidney diseases (CKD), most of which originates from glomerular lesions. Proteinuria, resulting from defective glomerular filtration, is an early hallmark and principal pathologic feature of a large number of CKD. Although podocyte dysfunction is known to play a critical role in the onset of proteinuria, the underlying mediators, signaling pathways and mechanisms remain poorly defined. Recent studies from the applicant's laboratory have linked the aberrant b-catenin signaling to podocyte injury and proteinuria. The central hypotheses of this application are that: b-catenin activation plays an imperative role in mediating podocyte dysfunction and proteinuria;and therefore inhibition of this signaling by small molecule inhibitor (ICG-001) provides a novel approach for therapeutic intervention of proteinuric kidney diseases. The overall goal of this application is to delineate the role of 2- catenin and its downstream target MMP-7 in the pathogenesis of podocyte injury and proteinuria and to explore the feasibility of targeting 2-catenin signaling for therapeutic intervention.
In Aim 1, we will evaluate the feasibility and efficacy of targeted inhibition of 2-catenin by a novel small molecule in three models of proteinuric kidney diseases.
In Aim 2, we will investigate the mechanism underlying the pathogenic actions of 2-catenin and explore how inhibition of 2-catenin leading to protection of podocyte integrity in vitro. Finally, we will focus on one major target of 2-catenin, MMP-7, and investigate its role in the pathogenesis of proteinuria in Aim 3. These studies will likely offer fundamental and important insights into understanding of the patho-mechanism of proteinuria, and could provide a foundation for the exploitation of b-catenin signaling as therapeutic target. The proposed studies may potentially have wide implications in designing future therapeutic regimens for the treatments of proteinuric kidney diseases.

Public Health Relevance

It is estimated that up to 13% of the US adult population has some degree of chronic kidney disease (CKD), and the leaks of protein to urine (proteinuria) is an early hallmark and principal pathologic feature of a large number of CKD. The studies proposed in this application promise to provide important insights into understanding the mechanism of proteinuria, and may offer unique opportunities for designing rational strategies for the treatment of human proteinuric CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091239-02
Application #
8467710
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-05-10
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$217,805
Indirect Cost
$73,055
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tan, Roderick J; Chartoumpekis, Dionysios V; Rush, Brittney M et al. (2016) Keap1 hypomorphism protects against ischemic and obstructive kidney disease. Sci Rep 6:36185
Zhou, Lili; Liu, Youhua (2016) Wnt/β-catenin signaling and renin-angiotensin system in chronic kidney disease. Curr Opin Nephrol Hypertens 25:100-6
Zhou, Dong; Tan, Roderick J; Fu, Haiyan et al. (2016) Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword. Lab Invest 96:156-67
Zhou, Dong; Liu, Youhua (2016) Renal fibrosis in 2015: Understanding the mechanisms of kidney fibrosis. Nat Rev Nephrol 12:68-70
Zhou, Dong; Liu, Youhua (2016) Therapy for kidney fibrosis: is the Src kinase a potential target? Kidney Int 89:12-4
Tan, Roderick J; Zhou, Dong; Liu, Youhua (2016) Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury. Kidney Dis (Basel) 2:136-144
Zhou, Lili; Liu, Youhua (2015) Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease. Nat Rev Nephrol 11:535-45
Fu, Haiyan; Liu, Youhua (2015) Loss of Klotho in CKD Breaks One's Heart. J Am Soc Nephrol 26:2305-7
Tan, Roderick J; Zhou, Dong; Xiao, Liangxiang et al. (2015) Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease. J Am Soc Nephrol 26:2447-59
Zhou, Lili; Li, Yingjian; He, Weichun et al. (2015) Mutual antagonism of Wilms' tumor 1 and β-catenin dictates podocyte health and disease. J Am Soc Nephrol 26:677-91

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