The mesangial cell of the renal glomerulus occupies a central role in physiological regulation as it governs both systemic blood pressure and blood flow through the nephron. Although it is proposed that debilitating mesangial disease secondary to conditions such as diabetes may occur through reactivation of developmental mechanisms or dedifferentiation, the normal development of mesangium remains poorly understood. One recent breakthrough in developmental nephrology was the finding that mesangial cells along with the kidney capsule and medullary interstitium arise from the cortical interstitial cells of the developing kidney. The purpose of this study is to investigate mechanisms by which renal cortical interstitial cells maintain their cortical identity, preserving a pool of cells that can adopt any one of these three fates. The cortical interstitium expresses high levels of the forkhead domain transcription factor Foxd1, which decrease as the cells mature. To test the hypothesis that FOXD1 may be repressing genes required for mesangial differentiation, a microarray was conducted, comparing E14.5 Foxd1 null kidneys with wild-type. These results lead to the hypothesis that FOXD1 acts in the cortical stroma as a transcriptional repressor, maintaining a cortical state in part by inhibiting the ability of cells to transcribe genes characteristic of a more differentiated state.
Specific aims are to i) define the role of FOXD1 in repressing target genes to maintain the identity of cortical interstitial cells and ii) test the requirement for FOXD1 down regulation in mesangial differentiation by transgenically maintaining FOXD1 expression in differentiating cells in vivo. The work proposed herein is the first to take a mechanistic approach to understand FOXD1 function, by identifying transcriptional targets and potential co-repressors. Furthermore, this work will provide the first in vivo evidence of the necessity of turning off Foxd1 expression to permit the differentiation of mesangium and medullary stroma during embryonic kidney development. A full understanding of the development of mesangial cells is essential to clarifying the pathogeneses of common diseases in which these processes are reactivated, resulting in expansion and sclerosis of the glomerulus. These studies and the proposed training plan will prepare the applicant for a career as a nationally competitive, independent investigator in developmental nephrology and organogenesis through mentoring and support for focused major scientific investigations, continual academic advancement, focused training in the construction of major publications, career development via regional and national scientific interactions and opportunities, teaching and instructional experience, and training in ethics, compliance and responsible conduct of research.
Appropriate regulation of blood flow to the kidney is essential for normal functioning of the organ, and damage to blood vessels is a common consequence of kidney disease. The processes by which blood vessels develop in the kidney during the embryonic period are not well characterized, but they are key to understanding: i) the pathological processes that result from aberrant vascular repair following kidney injury, and ii) the potential to regenerate fully vascularized kidney tissue for transplantation purposes.
The aim of this study is to understand basic mechanisms governing blood vessel assembly in the developing kidney.
|Fetting, Jennifer L; Guay, Justin A; Karolak, Michele J et al. (2014) FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney. Development 141:17-27|
|Oxburgh, Leif; Brown, Aaron C; Muthukrishnan, Sree Deepthi et al. (2014) Bone morphogenetic protein signaling in nephron progenitor cells. Pediatr Nephrol 29:531-6|
|Brown, Aaron C; Muthukrishnan, Sree Deepthi; Guay, Justin A et al. (2013) Role for compartmentalization in nephron progenitor differentiation. Proc Natl Acad Sci U S A 110:4640-5|