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SubContract(s)

Humanized Mouse Models of Diabetic Nephropathy

Small immunodeficient animal models of diabetic nephropathy are needed to assess the impact of human cell populations on diabetic kidney complications. Immunocompetent mice bearing a mutated leptin receptor gene, leprdb-5J/db-5J (abbreviated db/db), develop obesity, insulin resistance, and chronic hyperglycemia as they age. However, they fail to develop robust nephropathy. It has been reported that endothelial nitric oxide synthase deficiency caused by introduction of a mutated Nos3 gene leads to accelerated and robust nephropathy in immunocompetent diabetic mice. However, these immuncomponent mice will reject human cells and cannot be used to test the potential of human cell-based therapies to impact diabetic complications. We have recently developed immunodeficient NOD-scid IL2r?null (NSG) mice that readily engraft with human cells and tissues, including hematopoietic stem cells, mesenchymal stem cells, and embryonic stem cells - cell populations under consideration as treatment for diabetic complications. We propose to develop three new immunodeficient stocks of mice that represent type 2 diabetes, nephropathy, and diabetic nephropathy, and can be readily engrafted with human cells: 1) NSG mice bearing a mutation in the leptin receptor (leprdb/db, abbreviated db/db, type 2 diabetes model), and 2) NSG mice bearing a mutated Nos3 gene (NOS3null, nephropathy model). We will then intercross these two NSG stocks of mice to 3) generate NSG-Nos3null db/db (diabetic nephropathy model) mice. We have recently generated NSG-db/db mice that are now available and propose to generate NSG-Nos3null mice using a speed congenic marker assisted backcrossing approach. At the end of the first year of this P&F, we will have 1) characterized the development of obesity, diabetes, and nephropathy (or lack thereof) in NSG-db/db/ mice, validating this new model of type 2 diabetes, 2) be at the n3 backcross generation of NSG-Nos3null mice. In year 2, we will finish the backcross, and intercross with NSG-db/db mice to generate the stock of most interest, the NSG-Nos3null db/db mouse. This mouse will be available to the AMDCC for screening for the development of diabetic nephropathy and for its ability to support human cell engraftment and cell-based therapy.

Progress Reports


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Application	Complete Date	Report	Options
Humanized Mouse Models of Diabetic Nephropathy (Shultz, Leonard)	5/16/2011	View Progress Report Document

Annual Reports

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Publication	Submitted By	PubMed ID	Status
Year: 2013; Items: 1
Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2r?(null) mice treated with alogliptin. Jurczyk A, Diiorio P, Brostowin D, Leehy L, Yang C, Urano F, Harlan DM, Shultz LD, Greiner DL, Bortell R Diabetes, metabolic syndrome and obesity : targets and therapy, 2013 (6), 493 - 499	Submitted Externally	24376359	Published
Year: 2012; Items: 2
Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice. Brehm MA, Powers AC, Shultz LD, Greiner DL Cold Spring Harbor perspectives in medicine, 2012 (2), a007757	Submitted Externally	22553498	Published
Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice. Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR, der Kracht SM, Kester MG, Serreze DV, Shultz LD, Griffioen M, Drijfhout JW, Greiner DL, Roep BO PLoS ONE, 2012 (7), e49213	Submitted Externally	23155466	Published
Year: 2011; Items: 3
HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/?c(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. Whitfield-Larry F, Young EF, Talmage G, Fudge E, Azam A, Patel S, Largay J, Byrd W, Buse J, Calikoglu AS, Shultz LD, Frelinger JA Diabetes, 2011 (60), 1726 - 1733	Shultz, Leonard	21521873	Published
Hyperglycemia-induced proliferation of adult human beta cells engrafted into spontaneously diabetic immunodeficient NOD-Rag1null IL2r?null Ins2Akita mice. Diiorio P, Jurczyk A, Yang C, Racki WJ, Brehm MA, Atkinson MA, Powers AC, Shultz LD, Greiner DL, Bortell R Pancreas, 2011 (40), 1147 - 1149	Shultz, Leonard	21926555	Published
Humanized mice for the study of type 1 and type 2 diabetes. Greiner DL, Brehm MA, Hosur V, Harlan DM, Powers AC, Shultz LD Annals of the New York Academy of Sciences, 2011 (1245), 55 - 8	Shultz, Leonard	22211980	Published

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Name	Description
Nephropathy	The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.

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