Serum amyloid P and chronic noncommunicable diseases

描述（由申请人提供）：本申请涉及广泛的挑战领域（06）启用技术和特定挑战主题，06- hl -105：开发转基因动物模型，为理解人类慢性炎症提供信息。慢性非传染性疾病（CNCDs），包括心血管疾病和2型糖尿病，约占全世界死亡总数的60%。越来越多的证据表明，低级别的慢性炎症有助于动脉粥样硬化和胰岛素抵抗的发展。血清淀粉样蛋白P （SAP）是戊烷素家族的一个原型成员，参与先天免疫和低级别慢性炎症。我们最近的研究表明，编码SAP的Apcs是影响空腹血糖水平和体重的小鼠1号染色体位点的一个有希望的候选基因。我们发现

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.