Reduced endowment of the nephrons, the basic functional units of the kidney, is associated with future development of hypertension and even chronic kidney disease (CKD), ultimately leading to end stage renal disease (ESRD), a significant, growing economic health burden in the US. The PI has previously identified that the cap mesenchyme is a multipotent self-renewing nephron progenitor population during mammalian kidney development. It is critical to understand how cap mesenchyme cells are regulated during kidney development in order to develop therapeutic approaches to increase nephron endowment in situations like prematurity or malnutrition. Renal-coloboma syndrome (RCS) is a congenital developmental disorder characterized by renal hypodysplasia with reduced nephron numbers caused by PAX2 mutations. Although Pax2 has been widely recognized as an important factor for kidney development over the past two decades, Pax2 function in the developing kidney has not been investigated in vivo. Our central hypothesis supported by extensive preliminary data is that Pax2 function maintains the nephron lineage by repressing trans-differentiation into interstitial cell fates in the cap mesenchyme. In the Aim 1, we will determine cellular mechanisms for the trans-differentiation by molecular characterization of intermediate and terminally trans-differentiated cell states. We will also test whether Pax2 is sufficient to specify cap mesenchyme. In the Aim 2, we will distinguish Pax2 functions in the cap mesenchyme and differentiating nephron cells by comparing stage-specific Pax2 mutants before and after the onset of nephron differentiation. In the Aim 3, we will test our hypothesis that integrin ?8 activity for maintenance of the nephron lineage, acting downstream of Pax2 in cap mesenchyme cells. Results from our proposed studies will initiate to uncover the genetic networks in nephron progenitor cells regulating the lineage boundary to maintain the nephron compartment during formation of the functional kidney with the full complement of nephrons.

Public Health Relevance

Dialysis and renal transplantation are huge burdens for patients with kidney diseases and their families. Multipotent self-renewing nephron progenitor cells have great potential for regenerative medicine approaches for the treatment of kidney diseases because these cells could be expanded in vitro and provide a cellular resource for disease modeling, toxicity testing and ultimately cellular therapies. Our proposed studies to understand the genetic regulatory mechanisms for nephron progenitor cells are crucial to establish regenerative protocols of cell replacement therapy for kidney abnormalities, which will ultimately eliminate the need of dialysis and renal transplantation for patients with kidney diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094933-01A1
Application #
8506855
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Hoshizaki, Deborah K
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$364,458
Indirect Cost
$146,958
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Kobayashi, Akio; Mugford, Joshua W; Krautzberger, A Michaela et al. (2014) Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis. Stem Cell Reports 3:650-62
Kusaba, Tetsuro; Lalli, Matthew; Kramann, Rafael et al. (2014) Differentiated kidney epithelial cells repair injured proximal tubule. Proc Natl Acad Sci U S A 111:1527-32
Hung, Chi; Linn, Geoffrey; Chow, Yu-Hua et al. (2013) Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188:820-30