Serum amyloid P and chronic noncommunicable diseases

血清淀粉样蛋白 P 与慢性非传染性疾病

• 批准号: 7833108
• 负责人: WEIBIN SHI
• 金额: $ 36.27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7833108
• 关键词: Accounting; Address; Affect; Amyloid; Animal Model; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Apolipoproteins C; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Glucose; Body Weight; Candidate Disease Gene; Cardiovascular Diseases; Cessation of life; Characteristics; Chromosomes, Human, Pair 1; Chronic; Chronic Disease; Development; Diet; Disease; Distal; Dyslipidemias; Exhibits; Family; Fatty acid glycerol esters; Foam Cells; Genes; Glucose; Hand; Human; Hyperglycemia; Inflammation; Insulin Resistance; Level of Evidence; Link; Mus; Names; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Plasma; Quantitative Trait Loci; Research; Role; Sequence Analysis; Serum; Technology; Testing; Time; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Variant; atherogenesis; combat; fasting blood glucose level; fasting plasma glucose; feeding; genetic linkage analysis; interest; macrophage; member; overexpression; oxidized low density lipoprotein; public health relevance; trait; uptake

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.

描述（由申请人提供）：此申请介绍了广泛的挑战领域（06）启用技术和特定挑战主题，06-HL-105：开发转基因动物模型，这些模型非常有用，以了解人类的慢性炎症。 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％。新兴的证据表明，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）是五生型蛋白家族的原型成员，它参与先天免疫和低级慢性炎症。我们最近的研究表明，编码SAP的APC是一个有前途的候选基因，用于小鼠1染色体的基因座，影响空腹血糖水平和体重。我们找到了 喂食西方饮食时，那只载脂蛋白E缺陷型（APOE - / - ）小鼠会出现明显的高血糖和严重的血脂异常。对C57BL/6J（B6）和C3H/HEJ（C3H）APOE - / - 小鼠的链接分析显示，在远端染色体1（156-189 MB）上，一个具有重大变化的重要位置，称为BGLU3。 BGLU3与对等离子体SAP水平和体重有重大影响的基因座一致。在间交叉中观察到SAP与血浆葡萄糖和体重的显着关联。 APCS基因的序列分析揭示了B6和C3H菌株之间的多个SNP。 APC的等位基因变化与间跨等离子体SAP和葡萄糖水平以及体重的变化有关。因此，要检验的假设是远端染色体区域中的APC或紧密连接的基因有助于高血糖。为了检验这一假设，我们将通过产生转基因菌株来剖析APC在高血糖中的作用。将构建过表达C3H APC的转基因小鼠，并将分析产生的小鼠以开发高血糖和相关性状。在动脉粥样硬化病变中检测到SAP，其浓度比血浆高约50倍，在该病变中，它与载脂蛋白（包括ApoA-I，ApoB，ApoB，ApoC-II和ApoE）共定位。但是，该SAP积累在动脉粥样硬化病变中的功能含义仍有待定义。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，约占全球所有死亡人数的60％。制定打击疾病战略的基础是对它们发展的机制的理解。拟议的研究提供了一个机会，可以评估血清淀粉样蛋白P对慢性非传染性疾病的发展的贡献。