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.
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.
|Cerqueira, Débora 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|
|Liu, Xiaoning; Edinger, Robert S; Klemens, Christine A et al. (2017) A MicroRNA Cluster miR-23-24-27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where it Alters Sodium Transport. J Cell Physiol 232:1306-1317|
|Phua, Yu L; Ho, Jacqueline (2016) Renal dysplasia in the neonate. Curr Opin Pediatr 28:209-15|
|Hemker, Shelby L; Sims-Lucas, Sunder; Ho, Jacqueline (2016) Role of hypoxia during nephrogenesis. Pediatr Nephrol 31:1571-7|
|Phua, Yu Leng; Ho, Jacqueline (2015) MicroRNAs in the pathogenesis of cystic kidney disease. Curr Opin Pediatr 27:219-26|
|Ho, Jacqueline (2014) The regulation of apoptosis in kidney development: implications for nephron number and pattern? Front Pediatr 2:128|
|Edinger, Robert S; Coronnello, Claudia; Bodnar, Andrew J et al. (2014) Aldosterone regulates microRNAs in the cortical collecting duct to alter sodium transport. J Am Soc Nephrol 25:2445-57|
|Chu, Jessica Y S; Sims-Lucas, Sunder; Bushnell, Daniel S et al. (2014) Dicer function is required in the metanephric mesenchyme for early kidney development. Am J Physiol Renal Physiol 306:F764-72|
|Marrone, April K; Stolz, Donna B; Bastacky, Sheldon I et al. (2014) MicroRNA-17~92 is required for nephrogenesis and renal function. J Am Soc Nephrol 25:1440-52|
|Marrone, April K; Ho, Jacqueline (2014) MicroRNAs: potential regulators of renal development genes that contribute to CAKUT. Pediatr Nephrol 29:565-74|
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