Mouse Models to Characterize the Role of Lrp6 in Metabolic Syndrome

表征 Lrp6 在代谢综合征中作用的小鼠模型

• 批准号: 7878600
• 负责人: Bart O Williams
• 金额: $ 22.52万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878600
• 关键词: Accounting; Adipocytes; Adult; Affect; Age; Age-Years; Albumins; Alleles; Animal Model; Atherosclerosis; Birth; Blood; Budgets; Cardiovascular Diseases; Cause of Death; Cells; Defect; Deposition; Development; Diabetes Mellitus; Diet; Disease; Epidemic; FABP4 gene; Fatty acid glycerol esters; Genes; Healthcare; Healthcare Systems; Hepatocyte; Histocompatibility Testing; Hypertension; Hypertriglyceridemia; Incidence; Inherited; Knowledge; LDL-Receptor Related Protein 1; Laboratories; Lead; Left; Link; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Managed Care; Metabolic; Metabolic syndrome; Methods; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Penetrance; Physiological; Prevalence; Proteins; Regulation; Reporting; Role; Serum; Signal Transduction; Source; Structure; Symptoms; Syndrome; Testing; Therapeutic Intervention; Tissues; United States; Work; cardiovascular disorder risk; cell type; feeding; human FABP4 protein; human disease; hypercholesterolemia; improved; insight; interest; lipoprotein receptor-related protein 6; liver function; low density lipoprotein triglyceride; mouse model; novel; prevent; promoter; public health relevance; recombinase

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the United States. Patients who inherit a mutation in the low density lipoprotein receptor related protein 6 (LRP6) developed CVD at a very early age due to metabolic syndrome (a constellation of symptoms which includes high serum levels of LDL and triglycerides, hypertension, and diabetes). This knowledge increases opportunities to better understand the factors that lead to the development of metabolic syndrome. Using novel mouse models, we seek to identify which cell type(s) are affected by reduced LRP6 function to cause metabolic syndrome. Two potential sources for the primary cell type affected by this mutation are the adipocytes and hepatocytes. To examine Lrp6 function in these cells, we will create and characterize mice carrying hepatocyte- or adipocyte-specific deletions of Lrp6. In Specific Aim 1, Lrp6-flox mice will be crossed to a strain expressing cre recombinase under the control of the albumin promoter (Albumin-cre). This will direct expression specifically and with high penetrance to the liver. Albumin-cre; Lrp6-flox/flox mice and littermate controls maintained on low- and high-fat diets will be evaluated for changes in liver function, as well as alterations in serum levels of components relevant to metabolic syndrome (with an emphasis on serum levels of LDL and triglycerides). We hypothesize that these mice will develop elevated levels of serum LDL and triglycerides when fed a high fat diet. We further predict that this will predispose these mice to the development of atherosclerosis. In Specific Aim 2, Lrp6-flox mice will be crossed to a strain expressing cre recombinase under the control of the 5.4 kb promoter fragment of the Fatty acid binding protein 4 gene (FABP4-cre). FABP4-cre mice express cre exclusively in adipocytes with virtually full penetrance. FABP4-cre; Lrp6-flox/flox mice and littermate controls maintained on low- and high-fat diets will be evaluated for changes in fat deposition and alterations in serum levels of components relevant to metabolic syndrome. We hypothesize that these mice with adipocyte-specific deletion of Lrp6 will display defects in adipocyte function which will eventually induce systemic changes in the mice, including the development of diabetes. PUBLIC HEALTH RELEVANCE: People who inherit a mutation in the low-density lipoprotein receptor 6 (LRP6) genes are dramatically predisposed to metabolic syndrome (a constellation of symptoms including high serum LDL and triglyceride levels, hypertension, and diabetes that dramatically increases the risk of cardiovascular disease). We will create mice carrying liver- or adipocyte-specific inactivating mutations in Lrp6 to gain insight into the tissue type(s) affected and to develop a mouse model of metabolic syndrome that can be used to test therapeutic interventions. Given that cardiovascular disease is the leading killer in the United States, this work will be very significant in gaining a better understanding of the underlying causes of this disease.

描述（由申请人提供）：心血管疾病（CVD）是美国的主要死亡原因。遗传低密度脂蛋白受体相关蛋白6（LRP 6）突变的患者在很小的年龄时由于代谢综合征（一系列症状，包括高血清LDL和甘油三酯水平、高血压和糖尿病）而发展为CVD。这些知识增加了更好地了解导致代谢综合征发展的因素的机会。使用新的小鼠模型，我们试图鉴定哪些细胞类型受到LRP 6功能降低的影响而导致代谢综合征。受这种突变影响的原代细胞类型的两个潜在来源是脂肪细胞和肝细胞。为了检查Lrp 6在这些细胞中的功能，我们将创建和表征携带肝细胞或脂肪细胞特异性Lrp 6缺失的小鼠。在特定目标1中，将Lrp 6-flox小鼠与在白蛋白启动子（白蛋白-cre）控制下表达cre重组酶的品系杂交。这将直接表达特异性和高转移率的肝脏。白蛋白-肌酐;将评价维持低脂肪和高脂肪饮食的Lrp 6-flox/flox小鼠和同窝对照小鼠的肝功能变化以及与代谢综合征相关的组分的血清水平的变化（重点是LDL和甘油三酯的血清水平）。我们假设这些小鼠在喂食高脂饮食时会出现血清LDL和甘油三酯水平升高。我们进一步预测，这将使这些小鼠易患动脉粥样硬化。在特定目标2中，将Lrp 6-flox小鼠与在脂肪酸结合蛋白4基因（FABP 4-cre）的5.4 kb启动子片段控制下表达cre重组酶的品系杂交。FABP 4-cre小鼠仅在脂肪细胞中表达cre，几乎完全不表达。FABP4-cre;将评价维持低脂肪和高脂肪饮食的Lrp 6-flox/flox小鼠和同窝对照小鼠的脂肪沉积变化和与代谢综合征相关的组分的血清水平变化。我们假设这些具有脂肪细胞特异性Lrp 6缺失的小鼠将表现出脂肪细胞功能的缺陷，这将最终诱导小鼠的全身变化，包括糖尿病的发展。公共卫生相关性：遗传低密度脂蛋白受体6（LRP 6）基因突变的人明显易患代谢综合征（一系列症状，包括高血清LDL和甘油三酯水平，高血压和糖尿病，大大增加了心血管疾病的风险）。我们将创建携带Lrp 6中肝脏或脂肪细胞特异性失活突变的小鼠，以深入了解受影响的组织类型，并开发可用于测试治疗干预措施的代谢综合征小鼠模型。鉴于心血管疾病是美国的头号杀手，这项工作将对更好地了解这种疾病的根本原因非常重要。