Chronic kidney disease is becoming more prevalent as the epidemic of type II diabetes spreads. Dialysis and transplantation can compensate for deteriorating kidney function, but each of these therapies has limitations: dialysis cannot replace all kidney functions, and the availability of matched organs for transplantation is restricted. Progress in regenerative medicine offers hope that individually matched kidney tissue may be generated de novo for afflicted patients. The adult kidney lacks the capacity for organogenesis, and therapies based on de novo nephrogenesis must recapitulate embryonic nephrogenesis. Our long term goal is to understand mechanisms by which renewal and differentiation of nephron progenitor cells is balanced by the immediate cellular environment or niche in the embryonic kidney, so that this process can be recreated in the adult. In the first project period we defined signaling pathways that control renewal of nephron progenitors, and in this application we propose to extend these studies to the important question of how niche signals control the balance between renewal and differentiation. Conceptual and technical advances made in the ongoing project allow us to approach this question from three complementary angles. The following aims are proposed: 1. Elucidate the mechanism by which BMP7 controls renewal of nephron progenitor cells through MAPK activation. 2. Define mechanisms by which the proteoglycan decorin controls nephron progenitor differentiation. 3. Model self renewal versus differentiation of progenitor cells in kidney organoids. Scientifically, we propose novel developments of the model for progenitor cell turnover in the nephron progenitor niche. In terms of technological innovation, we propose to develop a system for in vitro organogenesis from defined single cell suspensions of nephron progenitor cells in which the balance between renewal and differentiation can be studied. A potential medical innovation based directly on these studies would be the development of an organoid-based model of human genetic kidney disease such as polycystic kidney disease.

Public Health Relevance

Our studies to date have defined the signaling environment governing self-renewal of embryonic nephron progenitors, a cell-type of great potential in cell-based therapy for renal disease. In this proposal we will elucidate mechanisms by which the adjacent cellular environment regulates nephron progenitor cell renewal, and test the potential of kidney organoids to model these processes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK078161-07
Application #
8640926
Study Section
(KMBD)
Program Officer
Hoshizaki, Deborah K
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Maine Medical Center
Department
Type
DUNS #
City
Portland
State
ME
Country
United States
Zip Code
04102
Muthukrishnan, Sree Deepthi; Yang, Xuehui; Friesel, Robert et al. (2015) Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nat Commun 6:10027
Yang, Xuehui; Liaw, Lucy; Prudovsky, Igor et al. (2015) Fibroblast growth factor signaling in the vasculature. Curr Atheroscler Rep 17:509
Brown, Aaron C; Muthukrishnan, Sree Deepthi; Oxburgh, Leif (2015) A synthetic niche for nephron progenitor cells. Dev Cell 34:229-41
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
Guay, Justin A; Wojchowski, Don M; Fang, Jing et al. (2014) Death associated protein kinase 2 is expressed in cortical interstitial cells of the mouse kidney. BMC Res Notes 7:345
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
Kirov, Aleksandr; Duarte, Maria; Guay, Justin et al. (2012) Transgenic expression of nonclassically secreted FGF suppresses kidney repair. PLoS One 7:e36485
Moskowitz, Ivan P; Wang, Jun; Peterson, Michael A et al. (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected] Proc Natl Acad Sci U S A 108:4006-11
Brown, Aaron C; Adams, Derek; de Caestecker, Mark et al. (2011) FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development. Development 138:5099-112

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