Jonathan P. Stoehr
| Years in MSTP | 1995-2004 |
| PhD |
Cellular and Molecular Biology, 2002 |
| Mentor | Alan D. Attie |
| Thesis |
A Genetic Dissection of Obesity and Type 2 Diabetes Mellitus in the Mouse |
| Residency |
Medicine, Yale University |
| Fellowship |
Endocrinology, University of Oregon |
Thesis Abstract
The American population is witnessing an unprecedented and disturbing trend toward adiposity. According to the current medical definition, one third of the US adult population is obese.
The negative health implications of this trend toward adiposity are well established. They include increased risk of hypertension and coronary vascular disease, stroke, insulin resistance and type 2 diabetes mellitus. My colleagues and I have previously used the obese allele of the leptin gene to unmask the latent effects of other diabetes-susceptibility alleles present within the genomes of two mouse strains, C57BL/6J and BTBR. I mapped three quantitative trait loci to regions of mouse chromosomes 2, 16 and 19, and characterized a specific non-linear interaction between two loci that enhanced the diabetes-promoting effects of one locus in certain genetic backgrounds.
In that study, I was also surprised to find that the strong obesity-promoting effects of the ob allele could be modified extensively by strain background. Within the same population, I detected and mapped two different loci that segregate strongly with body weight gain.
Although an initial detection of linkage is an important step in the identification of the relevant disease genes, positional cloning requires localization of the genes with far greater precision than that afforded by studies of F2 mice, such as my own. Therefore, I have endeavored to generate a large panel of Interval Specific Congenic mouse lines to dissect each of the five gene loci with sub-centimorgan resolution. Two loci have successfully been mapped to small regions of chromosomes 2 and 19, respectively.
This manuscript discusses my efforts to support positional cloning of the genes, and to characterize the pathophysiological role of each of the loci in their respective disease syndromes. It also discusses my efforts to understand how loss of function of one gene, Stearoyl CoA Desaturase 1 (SCD1), promotes leanness in SCD1 knockout mice.
Thesis Publications
Clee SM, Yandell BS, Schueler KM, Rabaglia ME, Richards OC, Raines SM, Kabara EA, Klass DM, Mui ET, Stapleton DS, Gray-Keller MP, Young MB, Stoehr JP, Lan H, Boronenkov I, Raess PW, Flowers MT, Attie AD. 2006. Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38:688-93.
Stoehr JP, Byers JE, Clee SM, Lan H, Boronenkov IV, Schueler KL, Yandell BS, Attie AD. 2004. Identification of major quantitative trait loci controlling body weight variation in ob/ob mice. Diabetes 53:245-
Lan H, Stoehr JP, Nadler ST, Schueler KL, Yandell BS, Attie AD. 2003. Dimension reduction for mapping mRNA abundance as quantitative traits. Genetics 164:1607-14. PMCID: 1462655
Lan H, Rabaglia ME, Stoehr JP, Nadler ST, Schueler KL, Zou F, Yandell BS, Attie AD. 2003. Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility. Diabetes 52:688-700. PMCID: 1462655
Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, Lusis AJ, Stalenhoef AF, Stoehr JP, Hayden MR, Ntambi JM. 2002. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. Lipid Res 43:1899-907.
Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Chohen P, Friedman JM, Attie AD. 2002. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA 99:11482-6. PMCID: 123282
Nadler ST, Stoehr J, Rabaglia ME, Schueler KL, Birnbaum MJ, Attie AD. 2001. Normal Akt/PKB with reduced P13K activation in insulin-resistant mice. Am J Physiol Endocrinol Metab 281:E1249-54.
Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD. 2000. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc Natl Acad Sci USA 97:11371-6.
Stoehr JP, Nadler ST, Schueler KL, Rabaglia ME, Yandell BS, Metz SA, Attie AD. 2000. Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes 49:1946-54.