The origin of activated stromal cells in the diseased kidney and the role that these cells play in precipitating end stage renal disease remains elusive, This recalcitrant clinical problem is difficult to address since the origin, differentiation and function of renal stroma in the healthy kidney remains poorly understood. We show that the Winged Helix transcription factor, BF-2, is selectively expressed by renal stromal progenitors and that BF-2 expressing stromal progenitors are essential for renal epithelial growth and differentiation. In this proposal we will use BF-2 mRNA as a molecular marker to identify renal stromal progenitors and test hypotheses describing the origin, differentiation, and fate of this cell population.
In Specific Aim 1, the origin of renal stromal cells will be analyzed by retroviral mediated gene transfer lineage tracing techniques. The differentiated fate of lineage tagged, BF-2 expressing cells present in the early chick embryo will be characterized by morphological and molecular marker analyses.
Specific Aim 2 will probe BF-2 function and the cellular processes perturbed by BF2 deletion. We show BF-2 null stromal cells undergo precocious differentiation while control cells down-regulate BF-2 expression coincident with differentiation. We will determine if adenovirus mediated constitutive, high level BF-2 expression delays stromal differentiation in vitro. We will test the hypothesis that precocious differentiation caused by BF-2 deletion perturbs the temporal expression patterns of stromal factors regulating ureteric bud growth. Data generated will provide the basis for future studies on the origin of activated stromal cells in the diseased kidney and their role in nephron degeneration and/or repair.
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