Renal dysplasia/hypoplasia is a leading cause of renal failure in children, leading to significant morbidity and mortality associated with transplan and dialysis. The risk of chronic kidney disease is linked to decreased renal reserve as a result of the formation of fewer and/or abnormal nephrons during kidney development. While much is known about the genetic control of nephron development, very little is known about the role of microRNAs (miRNAs), small, non-coding RNA molecules that negatively regulate gene expression. Our laboratory has data demonstrating that the miR-17~92 miRNA cluster is crucial to regulating nephron number and formation. Conditional loss of miR-17~92 in nephron progenitors results in renal hypodysplasia, glomerular injury and renal dysfunction in adult mice. Moreover, we observe an intermediate phenotype in animals with heterozygous loss of miR-17~92 in nephron progenitors, suggesting that the gene dosage of miR- 17~92 is key. Heterozygous mutations in the orthologous human gene (MIR17HG) results in the first known developmental defects associated with a miRNA mutation in humans, including renal anomalies. We hypothesize that loss of the miR-17~92 cluster in nephron progenitors results in an intrinsic nephron progenitor defect, and therefore abnormal nephron number and pattern during kidney development.
Aim 1. Define the role of miR-17~92 gene dosage in establishing nephron number and pattern.
Aim 2. Characterize the intrinsic defect in miR-17~92 null nephron progenitors.
Aim 3. Validate downstream miR-17~92 targets to elucidate mechanism(s) by which the miR-17~92 cluster regulates nephron number and patterning.

Public Health Relevance

Together, these studies seek to define how the miR-17~92 cluster regulates nephron number and patterning during kidney development. To our knowledge, this represents the first known mutation in a miRNA cluster associated with a renal developmental defect. This raises the possibility that regulation of gene expression via miRNAs may be a more general mechanism in the determination of congenital nephron endowment, an important risk factor for chronic kidney disease and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK103776-01
Application #
8798885
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Hoshizaki, Deborah K
Project Start
2014-09-19
Project End
2019-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$339,210
Indirect Cost
$114,210
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213