MicroRNAs (miRNAs) are a group of novel small RNAs that regulate gene expression via the post- transcriptional repression of specific target mRNAs. As a group, miRNAs play a key role in diverse developmental processes, and are required for the differentiation of embryonic stem cells;however the function of miRNAs during kidney development remains largely undefined. Our preliminary work indicates that the loss of miRNAs within the nephron progenitor compartment of the developing kidney results in a premature depletion of this population, and as a consequence, a marked decrease in nephron number. Furthermore, this is accompanied by elevated expression of the pro-apoptotic protein Bim (also known as Bcl-2L11) specifically in nephron progenitors, and an increase in apoptosis in this cell population. We propose that specific miRNAs promote the survival of nephron progenitors by regulating the expression of Bim, and that this mechanism represents a means of determining congenital nephron endowment during normal kidney development.
Specific aim 1 : To characterize the role of Bim (Bcl-2L11) in the survival of nephron progenitors during kidney development.
Specific aim 2 : To define the function of the miRNA clusters, mmu-miR-106b~25 and mmu- miR-17~92, in regulating Bim expression and nephron progenitors.
Specific aim 3 : To determine the functional role of mmu-miR-10a during kidney development. The work proposed in this grant will serve as the foundation for the PI's transition into an independent career as a physician-scientist in an academic pediatric renal division over the next two years. The mentored phase (K99) will occur at Children's Hospital Boston and Harvard Medical School under the guidance of Dr. Jordan Kreidberg.

Public Health Relevance

Together, these studies will further our understanding of the molecular and cellular processes that regulate nephron progenitors in establishing the full complement of nephrons during kidney development. This will ultimately inform the pathophysiology underlying congenital renal anomalies, the leading cause of renal failure in young children, and the mechanisms that determine congenital nephron number, which has important implications for long-term kidney health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK087922-02
Application #
8142096
Study Section
Special Emphasis Panel (ZDK1-GRB-G (J2))
Program Officer
Rankin, Tracy L
Project Start
2010-09-15
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$90,000
Indirect Cost
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cerqueira, D├ębora M; Bodnar, Andrew J; Phua, Yu Leng et al. (2017) Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development. FASEB J 31:3540-3554
Ho, Jacqueline; Kreidberg, Jordan A (2013) MicroRNAs in renal development. Pediatr Nephrol 28:219-25
Ho, Jacqueline; Kreidberg, Jordan A (2012) The long and short of microRNAs in the kidney. J Am Soc Nephrol 23:400-4
Ho, Jacqueline; Bates, Carlton M (2011) ?-Catenin: too much of a good thing is not always good. J Am Soc Nephrol 22:592-3
Ho, Jacqueline; Pandey, Priyanka; Schatton, Tobias et al. (2011) The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. J Am Soc Nephrol 22:1053-63
Pandey, Priyanka; Qin, Shan; Ho, Jacqueline et al. (2011) Systems biology approach to identify transcriptome reprogramming and candidate microRNA targets during the progression of polycystic kidney disease. BMC Syst Biol 5:56
Hartwig, Sunny; Ho, Jacqueline; Pandey, Priyanka et al. (2010) Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development. Development 137:1189-203