Member Profile
Matthew Breyer
Generating Mouse Mutants with Diabetic Nephropathy
Grant Number: 1U01DK061018-01
Abstract: Diabetic nephropathy (DN) is a disease of monumental proportions both in terms of human suffering and public health expenditures. Approximately six percent of the U.S. population has diabetes mellitus, 10-20% of which develop DN, ultimately progressing to end stage renal disease (ESRD). The factors contributing to DN remain obscure. While hyperglycemia is a necessary trigger, alone, it is insufficient to cause DN. Sibling studies suggest a strong genetic component, however defining the specific genetic loci contributing to DN in man has been confounded by the heterogeneous causes of diabetes, and by the diversity of human genetic background. In contrast, the wide availability of genetically homogenous mouse strains, coupled with advances in transgenic technology, make mice uniquely amenable to dissection of the molecular mechanisms of disease. As in man, most mice do not develop diabetic nephropathy, and the array of genes that confer susceptibility to DN to this minority, have not been characterized. This proposal is to generate a robust murine model of DN that closely parallels the human disease; that is genetically defined; and can be easily transferred between mouse strains. To achieve these goals we propose to identify specific genes that convert the "nephropathy resistant" C57BL/6 strain to one that develops DN. We will take two approaches. The first will use a "candidate gene" approach. In man, patients susceptible to DN exhibit worse hypertension and dyslipidemia than those resistant to nephropathy. Treatment of these conditions slows the progression of nephropathy. Polymorphisms in Angiotensinogen (Atg) eNOS and ApoE alleles have been described in susceptible patients. The first specific aim will examine the effect of superimposing the hypertensive human Atg transgenic, eNOS-/- or hyperlipidemic ApoE-/- alleles on two different models of diabetes, insulin deficient HN6 transgenic mice and insulin resistant db/db mice. The second approach will attempt to identify novel dominant modifiers that predispose to DN. Diabetic HNF6 or db/db C57BL/6 mice will be mutagenized with ethylnitrosourea (ENU) and G 1 offspring screened for DN (renal insufficiency and/or proteinuria). These studies should not only yield a well-defined mouse model of DN, but also provide important new information regarding genes that contribute to the development of DN.
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Johnson & Johnson
One Johnson & Johnson Plaza
New Brunswick, NJ |
Fiscal Year: | 2001 |
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| Diabetic Nephropathy: A National Dialogue.Breyer MD, Coffman TM, Flessner MF, Fried LF, Harris RC, Ketchum CJ, Kretzler M, Nelson RG, Sedor JR, Susztak K, on behalf of the Kidney Research National Dialogue (KRND) Clinical journal of the American Society of Nephrology : CJASN, 2013 |
| | 23788618 | Published |
| Generation of a conditional allele for the mouse endothelial nitric oxide synthase gene.Jiang R, Wang S, Takahashi K, Fujita H, Fruci CR, Breyer MD, Harris RC, Takahashi T Genesis (New York, N.Y. : 2000), 2012 (50), 685 - 692 |
| | 22467476 | Published |
| SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice.Fujita H, Fujishima H, Takahashi K, Sato T, Shimizu T, Morii T, Shimizu T, Shirasawa T, Qi Z, Breyer MD, Harris RC, Yamada Y, Takahashi T Metabolism: clinical and experimental, 2012 (61), 1714 - 1724 |
| | 22632894 | Published |
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| | 23062985 | Published |
| Reduction of renal superoxide dismutase in progressive diabetic nephropathy.Fujita H, Fujishima H, Chida S, Takahashi K, Qi Z, Kanetsuna Y, Breyer MD, Harris RC, Yamada Y, Takahashi T Journal of the American Society of Nephrology : JASN, 2009 (20(6)), 1303 - 1313 |
| | 19470681 | Published |
| Mouse Models of Diabetic Nephropathy: A Midstream Analysis from the Diabetic Complications ConsortiumFrank C. Brosius IIIa, Charles E. Alpersb, Erwin P. Bottingerc, Matthew D. Breyerd, ThomasM. Coffmane, Susan B. Gurleye, Raymond C. Harrisf, Masao Kakokig, Matthias Kretzler, Edward H. Leiterh, Moshe Levii, Richard A. McIndoej, Kumar Sharmak, Oliver Smithiesg, Katalin Susztakl, Nobuyuki Takahashig, Takamune Takahashif Journal of the American Society of Nephrology : JASN, 2009 (20(12)), 2503 - 2512 |
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| Single amino acid substitution in aquaporin 11 causes renal failure.Tchekneva EE, Khuchua Z, Davis LS, Kadkina V, Dunn SR, Bachman S, Ishibashi K, Rinchik EM, Harris RC, Dikov MM, Breyer MD Journal of the American Society of Nephrology : JASN, 2008 (19(10)), 1955 - 1964 |
| | 18701606 | Published |
| A sensitized screen of N-ethyl-N-nitrosourea-mutagenized mice identifies dominant mutants predisposed to diabetic nephropathy.Tchekneva EE, Rinchik EM, Polosukhina D, Davis LS, Kadkina V, Mohamed Y, Dunn SR, Sharma K, Qi Z, Fogo AB, Breyer MD Journal of the American Society of Nephrology : JASN, 2007 (18), 103 - 112 |
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| Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator-Activated Receptor-alphaCheol Whee Park, M.D., Hyeong Wook Kim, M.D., Seung Hyun Ko, M.D., Hyun Wha Chung, M.D., Sun Woo Lim, Ph.D., Chul Woo Yang, M.D., Yoon Sik Chang, M.D., Akira Sugawara, M.D., YouFei Guan, M.D., Matthew D. Breyer Diabetes, 2006 (55), 885 - 893 |
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| Glomerular injury is exacerbated in diabetic integrin alpha1-null mice.Zent R, Yan X, Su Y, Hudson BG, Borza DB, Moeckel GW, Qi Z, Sado Y, Breyer MD, Voziyan P, Pozzi A Kidney international, 2006 (70) |
| | 16775606 | Published |
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| | 16971655 | Published |
| Mouse Models of Diabetic NephropathyMATTHEW D. BREYER, ERWIN BÖTTINGER, FRANK C. BROSIUS, III, THOMAS M. COFFMAN, RAYMOND C. HARRIS, CHARLES W. HEILIG, AND KUMAR SHARMA (FOR THE AMDCC) Journal of the American Society of Nephrology : JASN, 2005 (16), 27 - 45 |
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