This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-HL-105: Develop transgenic animal models that are informative for understanding chronic inflammation in humans. Chronic noncommunicable diseases (CNCDs), including cardiovascular disease and type 2 diabetes, account for around 60% of all deaths worldwide. Emerging evidence suggests that low-grade, chronic inflammation contributes to the development of atherosclerosis and insulin resistance. Serum amyloid P (SAP) is a prototypic member of the pentraxin family, which is involved in innate immunity and low grade chronic inflammation. Our recent studies have suggested that Apcs, which encodes SAP, is a promising candidate gene for a mouse chromosome 1 locus affecting fasting blood glucose levels and body weight. We have found that apolipoprotein E-deficient (apoE-/-) mice develop significant hyperglycemia and severe dyslipidemia when fed a western diet. Linkage analysis of an intercross derived from C57BL/6J (B6) and C3H/HeJ (C3H) apoE-/-mice has revealed one significant locus, named Bglu3, on distal chromosome 1 (156-189 Mb) that accounts for major variation in blood glucose levels. Bglu3 coincides with loci that have major effects on plasma SAP levels and body weight. Significant associations of SAP with plasma glucose and body weight were observed in the intercross. Sequence analysis of the Apcs gene has revealed multiple SNPs between the B6 and C3H strains. Allelic variation of Apcs is associated with variation in plasma SAP and glucose levels and body weight in the intercross. Therefore, the hypothesis to be tested is that Apcs or a closely linked gene in the distal chromosome 1 region contributes to hyperglycemia. To test this hypothesis, we will dissect the role of Apcs in hyperglycemia by making transgenic strains. Transgenic mice overexpressing C3H Apcs will be constructed and the resulting mice will be analyzed for the development of hyperglycemia and related traits. SAP has been detected in atherosclerotic lesions with a concentration approximately 50 times higher than plasma, where it colocalizes with apolipoproteins, including apoA-I, apoB, apoC-II, and apoE. However, the functional implications of this SAP accumulation in atherosclerotic lesions remain to be defined. The transgenic mice generated will be used to evaluate the role of SAP in atherosclerosis.
Chronic noncommunicable diseases, including cardiovascular disease and type 2 diabetes, account for around 60% of all deaths worldwide. Fundamental to the development of strategies to combat the diseases is an understanding of the mechanisms by which they develops. The proposed research offers an opportunity to assess the contribution of serum amyloid P to the development of chronic noncommunicable diseases.
| Zhang, Zhimin; Rowlan, Jessica S; Wang, Qian et al. (2012) Genetic analysis of atherosclerosis and glucose homeostasis in an intercross between C57BL/6 and BALB/cJ apolipoprotein E-deficient mice. Circ Cardiovasc Genet 5:190-201 |
