This proposal aims to establish a novel transgenic mouse line, referred to as D2D that can serve as a model for the study of diabetes and obesity. Our laboratory has been studying the transcriptional regulation of a glucose regulated protein GRP78 that is a major molecular chaperone localized in the endoplasmic reticulum (ER). To understand how physiological stress activates the Grp78 promoter in vivo, we have created a series of transgenic mouse lines. One of these lines, D2D, contains a genetically modified version of the Grp78 promoter driving the expression of the bacterial lacZ gene encoding for beta-galactosidase. In this line, the lacZ transgene activity is strongly expressed in all pancreatic beta-cells, and some expression is also detected in the liver and brain including the hypothalamus controlling glucose sensing. To our surprise, we discovered that the D2D founder mouse became increasingly obese with age. Further analysis of the founder and its F1 and F2 offspring reveals that the D2D line exhibits properties of type II diabetes and age dependent onset of obesity. Examination of the D2D pancreatic sections showed normal range of beta-cell mass, proliferation and apoptosis. Taken together, our preliminary results suggest that D2D could offer a novel model for type II diabetes and obesity, and provide a new experimental system for the study of beta-cell defect with possible connection to liver and brain problems.
In Specific Aim 1, we propose to perform comprehensive analyses of glucose metabolism and phenotypic tests for the D2D mice and two other independently derived lines that exhibit similar but distinct lacZ expression profile.
In Specific Aim 2, we will determine the various mechanism(s) that could account for the diabetic phenotype observed in D2D. This pilot project has the potential to identify a new gene critical for glucose homeostasis through integration site analysis of D2D and it will provide the foundation for future studies to decipher the detail mechanism and preclinical applications of the D2D model towards therapy of diabetes and obesity.
| Ye, Risheng; Ni, Min; Wang, Miao et al. (2011) Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes. J Endocrinol 210:209-17 |
| Ye, Risheng; Mareninova, Olga A; Barron, Ernesto et al. (2010) Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. Am J Pathol 177:2827-36 |
| Ye, Risheng; Jung, Dae Young; Jun, John Y et al. (2010) Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes 59:6-16 |
