Type 2 diabetes mellitus involves insulin resistance combined with a failure of pancreatic beta-cells to compensate for the increased insulin demand. Although insulin resistance is a feature of type 2 diabetes, a person can be severely insulin resistant without ever developing diabetes. Therefore, beta-cell failure, or beta-cell decompensation, is an essential feature of type 2 diabetes. The objective of this project is to identify genetic modifiers of diabetes susceptibility that are associated with beta-cell decompensation in type 2 diabetes. The approach is to combine genetics with gene array technology. We shall map mRNA abundance as a quantitative trait in a population of animals segregating for type 2 diabetes mellitus alleles. We have shown that BTBR-ob/ob mice, in stark contrast to C57BLI6-ob/ob mice, develop severe diabetes. We have shown that F2 mice generated from these two strains segregate diabetes susceptibility alleles. In the present studies, we propose to generate a (C57BL/6 x BTBR)-ob/ob F2 population. We will isolate RNA from their pancreatic islets and quantitate mRNA abundance using microarray technology. The mRNA values (gene expression traits) will be used as phenotypes for gene mapping. Using dimension reduction approaches (clustering and principal components), the gene expression traits will be transformed into superphenotypes in order to genetically map networks that are dysfunctional in type 2 diabetes mellitus and result in beta-cell decompensation.
| Ye, Shuyun; Bacher, Rhonda; Keller, Mark P et al. (2017) Statistical Methods for Latent Class Quantitative Trait Loci Mapping. Genetics 206:1309-1317 |
| Attie, Alan D; Churchill, Gary A; Nadeau, Joseph H (2017) How mice are indispensable for understanding obesity and diabetes genetics. Curr Opin Endocrinol Diabetes Obes 24:83-91 |
| Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj et al. (2016) Genetic Architectures of Quantitative Variation in RNA Editing Pathways. Genetics 202:787-98 |
| Tian, Jianan; Keller, Mark P; Broman, Aimee Teo et al. (2016) The Dissection of Expression Quantitative Trait Locus Hotspots. Genetics 202:1563-74 |
| Baughman, Joshua M; Rose, Christopher M; Kolumam, Ganesh et al. (2016) NeuCode Proteomics Reveals Bap1 Regulation of Metabolism. Cell Rep 16:583-595 |
| Tian, Jianan; Keller, Mark P; Oler, Angie T et al. (2015) Identification of the Bile Acid Transporter Slco1a6 as a Candidate Gene That Broadly Affects Gene Expression in Mouse Pancreatic Islets. Genetics 201:1253-62 |
| Broman, Karl W; Keller, Mark P; Broman, Aimee Teo et al. (2015) Identification and Correction of Sample Mix-Ups in Expression Genetic Data: A Case Study. G3 (Bethesda) 5:2177-86 |
| Shang, Jin; Li, Jing; Keller, Mark P et al. (2015) Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic ?-Cells. Mol Endocrinol 29:1243-53 |
| Shortreed, Michael R; Wenger, Craig D; Frey, Brian L et al. (2015) Global Identification of Protein Post-translational Modifications in a Single-Pass Database Search. J Proteome Res 14:4714-20 |
| Bhatnagar, Sushant; Soni, Mufaddal S; Wrighton, Lindsay S et al. (2014) Phosphorylation and degradation of tomosyn-2 de-represses insulin secretion. J Biol Chem 289:25276-86 |
Showing the most recent 10 out of 49 publications
