Somponpun, Suwit Jack PhD

Research Overview

2010-2011 RMATRIX Collaboration Pilot Projects Program Awards

(Co-funded in Partnership with the RTRN Small Grant Awards Program)

Project Description

Abstract

Morphogenetic Mechanism of Embryonic six2 in Establishing Nephron Endowment

Suboptimal kidney development resulting in an in-born deficit in nephron number can have lifelong consequences and is associated with a significant risk of cardiovascular-renal disease in later life, compared to those born with a typical nephron endowment. The long-term goal of the current proposal is to identify cellular mechanisms that drive successful nephron differentiation to achieve optimal nephron endowment. Specifically, we will explore the roles of the homeobox gene sine oculis 2 (six2), and determine whether six2 is involved in the establishment of nephron number during kidney organogenesis. Using an RNAi methodology, experiments are designed to determine whether inactivation of six2 transcription early in nephrogenesis results in a significant decrease in ureteric bud growth and, therefore, nephron number in an organotypic kidney explant culture. Further, using a mouse model of heritable renal hypoplasia that lacks sufficient expression of six2 during development (the Brachyrrhine (Br) mutant mouse), we will take a systematic approach to re-introduce six2 to kidney explants that are prepared from Br mice and determine if exogenous six2 stimulates branching of the ureteric buds leading to an enhanced nephron production. This proposal will take advantage of the Br mouse strain that displays haploinsufficiency of six2 gene expression and is the only working colony in the world. Taken together, these experiments will provide the fundamental insights that constitute the genetic basis of six2 in renal morphogenesis and specifically establish whether six2 directly determines nephron endowment in the developing kidney. Results from this study will also underscore the importance of six2 in possible nephron restoration approaches in the adult diseased kidney. RELEVANCE: The proposed research is oriented toward a significant translational topic, namely the establishment of nephron number in the developing kidney that pertains specifically to cardiovascular disease and chronic renal failure. Specifically, the current study is aimed at identifying morphogenetic mechanisms that drive successful nephron differentiation to achieve optimal nephron number in the developing kidney.