Emerging evidence indicates that bone marrow derived cells (BMDC) can participate in renal repair. The current consensus finding is that donor BM derived renal epithelial cells appear at low frequency. On the other hand, there are other sources of stem cells that may contribute effectively in renal regeneration, e.g., the renal papilla is considered the niche for renal resident stem cells, metanephric mesenchyme contains embryonic renal stem cells and resident renal tubular epithelial cells can participate in tubular repair after acute injury. Based on these data, this proposal hypothesized that (a), dramatic reduction or complete ablation of podocytes will enhance BMDC becoming podocytes;(b). metanephric mesenchyme can participate in nephron regeneration after transplantation into recipients with acute glomerular injury and (c). renal resident cells may participate in podocyte regeneration. The long-term objective of this proposal and beyond is to optimize conditions to improve podocyte repair/regeneration by stem cells to prevent or attenuate the progression of acute or chronic glomerular disease into end stage renal disease (ESRD). The immediate goal of this proposed work is to establish new mouse models with inducible, modifiable glomerular injuries to serve as model system to study plasticity of stem cells, compare the efficiency and capacity of different sources of (stem) cells in renal repair. The proposed project will shed fresh lights on the robustness of plasticity of different stem cells in renal repair under proposed experimental settings. The findings of this project will help to further understand the underlying cellular and molecular mechanism of glomerular repair and to pave the way for stem cell based therapy for various glomerular diseases that progress inevitablly toward end stage renal failure without a sound cure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK075464-03
Application #
7656818
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$134,990
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Guo, Jian-Kan; Shi, Hongmei; Koraishy, Farrukh et al. (2013) The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages. Kidney Int 84:1041-6
Weiss, Robert M; Guo, Songshan; Shan, Alan et al. (2013) Brg1 determines urothelial cell fate during ureter development. J Am Soc Nephrol 24:618-26
Liu, Na; Guo, Jian-Kan; Pang, Maoyin et al. (2012) Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol 23:854-67
Guo, Jian-Kan; Marlier, Arnaud; Shi, Hongmei et al. (2012) Increased tubular proliferation as an adaptive response to glomerular albuminuria. J Am Soc Nephrol 23:429-37
Guo, Jian-Kan; Cantley, Lloyd G (2010) Cellular maintenance and repair of the kidney. Annu Rev Physiol 72:357-76