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）使能技术和特定的挑战主题，06-HL-105：开发可为理解人类慢性炎症提供信息的转基因动物模型。 慢性非传染性疾病（CNCD），包括心血管疾病和2型糖尿病，约占全球所有死亡人数的60%。新出现的证据表明，低度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）是五聚蛋白家族的原型成员，其参与天然免疫和低度慢性炎症。我们最近的研究表明，Apcs，编码SAP，是一个有前途的候选基因的小鼠1号染色体基因座影响空腹血糖水平和体重。我们发现 当喂食西方饮食时，载脂蛋白E缺陷（apoE-/-）小鼠发生显著的高血糖症和严重的血脂异常。来自C57 BL/6 J（B6）和C3 H/HeJ（C3 H）apoE-/-小鼠的互交的连锁分析揭示了在远端1号染色体（156-189 Mb）上的一个显著位点，称为Bglu 3，其解释了血糖水平的主要变化。Bglu 3与对血浆SAP水平和体重具有主要影响的位点一致。在交叉试验中观察到SAP与血糖和体重显著相关。Apcs基因的序列分析揭示了B6和C3 H菌株之间的多个SNP。 Apcs的等位基因变异与交叉中血浆SAP和葡萄糖水平以及体重的变异相关。因此，有待检验的假设是Apcs或1号染色体远端区域的紧密连锁基因导致高血糖症。为了验证这一假设，我们将通过制备转基因菌株来剖析Apcs在高血糖中的作用。将构建过表达C3 H Apcs的转基因小鼠，并分析所得小鼠的高血糖症和相关性状的发展。在动脉粥样硬化病变中检测到SAP，其浓度约为血浆的50倍，在血浆中与载脂蛋白（包括apoA-I、apoB、apoC-II和apoE）共定位。然而，SAP在动脉粥样硬化病变中蓄积的功能意义仍有待确定。所产生的转基因小鼠将用于评估SAP在动脉粥样硬化中的作用。 公共卫生相关性：慢性非传染性疾病，包括心血管疾病和2型糖尿病，占全球所有死亡人数的60%左右。制定防治这些疾病的战略的根本是了解这些疾病的发展机制。这项研究提供了一个机会来评估血清淀粉样蛋白P对慢性非传染性疾病发展的贡献。

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.