The genetics and pathophysiology of impaired Wnt signaling in metabolic syndrome

代谢综合征中 Wnt 信号传导受损的遗传学和病理生理学

基本信息

批准号：
7565423
负责人：
Arya Mani
金额：
$ 41.38万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-16 至 2013-02-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7565423
关键词：
1-Phosphatidylinositol 3-Kinase Amino Acids Arginine Beta Cell Blood Glucose Cause of Death Clinical Research Collaborations Complex Coronary Arteriosclerosis Cysteine Defect Development Diabetes Mellitus Diet Disease EGF-Like Domain Embryo Environment Enzymes Epidemiologic Studies Euglycemic Clamping Family Fatty acid glycerol esters Functional disorder Future Gene Targeting General Population Genes Genetic Genetic Transcription Genotype Glucose Glucose Clamp Glucose Intolerance Glucose tolerance test Glycogen Glycogen (Starch) Synthase Glycolysis Goals Hepatic Heterozygote High Density Lipoproteins High Prevalence Human Hyperglycemia Hyperlipidemia Hypertension Hypertriglyceridemia Impairment In Vitro Inherited Insulin Insulin Receptor Insulin Resistance Investigation Islets of Langerhans Knock-out Knockout Mice Knowledge Lead Link Liver Liver Glycogen Low Density Lipoprotein Receptor Measures Mediating Metabolic Metabolic syndrome Metabolism Modeling Molecular Morbidity - disease rate Mus Muscle Mutation Nodal Non-Insulin-Dependent Diabetes Mellitus Nuclear Family OGTT Osteoporosis Pathway interactions Patients Peptide Signal Sequences Peroxisome Proliferator-Activated Receptors Phenotype Phosphorylation Physiological Prevalence Proteins Receptor Activation Recruitment Activity Risk Factors Role Serine Serine/Threonine Phosphorylation Serum Signal Pathway Signal Transduction Site Skeletal Muscle Syndrome TCF7L2 gene Time Tissues Tyrosine Western World base bone metabolism collagenase disease-causing mutation early onset genetic linkage analysis glucagon-like peptide 1 glucose disposal glucose output impaired glucose tolerance in vivo insulin secretion insulin sensitivity intrahepatic islet kindred mRNA Expression mortality mouse model mutation carrier non-diabetic novel overexpression premature public health relevance receptor segregation skeletal trait

项目摘要

DESCRIPTION (provided by applicant): Metabolic syndrome is a major risk factor for development of diabetes and coronary artery disease (CAD), two most common causes of morbidity and mortality worldwide. By genetic linkage analysis in large kindreds with autosomal dominant premature coronary artery disease (CAD), diabetes hyperlipidemia, hypertension, and osteoporosis we have identified the disease causing mutations that substitute evolutionarily highly conservative amino acids in the LDL receptor like protein (LRP6), a co-receptor in the Wnt signaling pathway. Further studies have revealed that the mutations impair the Wnt signaling and impact many component of the metabolic syndrome that is present in these kindreds. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and metabolic syndrome and raises the possibility of complex downstream effects of the mutation which warrant further investigation. Oral glucose tolerance tests and studies of intrahepatic fat content in LRP6 mutation carriers have indicated that the underlying cause of impaired glucose tolerance caused by LRP6 mutation is impaired insulin sensitivity. We have created a LRP6 knockout mouse to investigate physiological and cellular mechanisms of metabolic syndrome caused by LRP6 mutation in vivo. Preliminary results from IPGTT in heterozygote knockout mice on Western diet has demonstrated increased glucose stimulated insulin levels and reduced hepatic glycogen content. Reduced glycogen synthesis in the skeletal is a common heritable disorder in patients with familial type 2 diabetes. The molecular basis for inherited impaired glycogen synthesis is not well understood. GSK32 is a signal peptide that is inversely regulated by the Wnt signaling pathway. Our studies have shown that GSK32 is excessively expressed and activated in LRP6 mice tissues. GSK3 inhibits glycogen synthase activity by phosphorylation of its serine/tyrosine residues. Our goal is to study the effect of LRP6 mutation on glycogen synthase activity and glycogen synthesis in LRP6 mice and to identify the primary site of insulin resistance in this model. In additional, clinical studies in LRP6 mutation carriers suggest that the mutation may cause beta cell defect. In separate studies we will examine the insulin secretory capacity of the pancreatic islets in LRP6 mice. In addition, we will screen 60 recruited kindreds with familial early CAD, metabolic syndrome and osteoporosis for mutations in LRP6, in order to identify the spectrum and prevalence of LRP6 mutation and establish genotype-phenotype correlations. PUBLIC HEALTH RELEVANCE: Coronary artery disease (CAD) and the metabolic syndrome are two most common causes of morbidity and mortality in the Western world. What links the risk factors of the metabolic syndrome to each other and to coronary artery disease remains vastly unknown. We have identified the disease causing gene in several families with early coronary artery disease and metabolic syndrome. The identified disease gene (LRP6) is a co-receptor that in normal condition activates a signaling pathway known as Wnt signaling pathway. This pathway is impaired in patients who carry one of these mutations. Our finding is the first evidence for relationship between impairment of this pathway and development of CAD and metabolic syndrome in humans. The current study goals are to investigate the disease mechanisms in a mouse model of this mutation that we have created in the lab. Moreover, we plan to screen number of families with inherited CAD, metabolic syndrome, and osteoporosis for mutations within this gene to identify novel mutations and to investigate their disease causing mechanisms.

描述（由申请人提供）：代谢综合征是糖尿病和冠状动脉疾病（CAD）发展的主要危险因素，这是全球发病率和死亡率的两个最常见原因。通过与常染色体显性过早的冠状动脉疾病（CAD），糖尿病高脂血症，高血压和骨质疏松症的大型遗传连接分析，我们已经鉴定出疾病在LDL受体（LRP6）中替代了进化上高度保守的氨基酸（LRP6）的疾病（LRP6），一个co-Receptor co-Receptor co-Receptor。进一步的研究表明，该突变会损害Wnt信号传导，并影响这些属性中存在的代谢综合征的许多成分。这些发现建立了由LRP6突变引起的Wnt信号传导障碍与代谢综合征之间的因果关系，并提高了突变的复杂下游效应的可能性，这需要进一步研究。口服葡萄糖耐量测试和LRP6突变载体中肝内脂肪含量的研究表明，由LRP6突变引起的葡萄糖耐受性受损的根本原因是胰岛素敏感性受损。我们创建了一个LRP6敲除小鼠，以研究由LRP6突变在体内引起的代谢综合征的生理和细胞机制。 IPGTT在杂合子敲除小鼠中的初步结果表明，葡萄糖刺激的胰岛素水平增加并降低了肝糖原含量。骨骼中糖原合成的降低是家庭2型糖尿病患者的常见遗传疾病。遗传受损的糖原合成的分子基础尚不清楚。 GSK32是一种信号肽，由Wnt信号通路成反比。我们的研究表明，GSK32在LRP6小鼠组织中过度表达和激活。 GSK3通过其丝氨酸/酪氨酸残基的磷酸化抑制糖原合酶活性。我们的目标是研究LRP6突变对LRP6小鼠中糖原合酶活性和糖原合成的影响，并在该模型中鉴定胰岛素抵抗的主要位点。在另外，LRP6突变载体中的临床研究表明该突变可能导致β细胞缺陷。在单独的研究中，我们将检查LRP6小鼠胰岛的胰岛素分泌能力。此外，我们还将筛选60种招募的Kindred，其中包括家族性早期CAD，代谢综合征和骨质疏松症，以鉴定LRP6中的突变，以鉴定LRP6突变的频谱和流行率并建立基因型 - 表型相关性。公共卫生相关性：冠状动脉疾病（CAD）和代谢综合征是西方世界中发病和死亡的两个最常见原因。是什么将代谢综合征的危险因素与彼此与冠状动脉疾病联系起来仍然鲜为人知。我们已经确定了几个早期冠状动脉疾病和代谢综合征的家庭中引起基因的疾病。鉴定出的疾病基因（LRP6）是一种共受体，在正常情况下，它激活了称为Wnt信号通路的信号通路。携带这些突变之一的患者中这种途径受损。我们的发现是这种途径损害与人类中CAD的发展与代谢综合症之间关系的第一个证据。当前的研究目标是研究我们在实验室中创建的该突变的小鼠模型中的疾病机制。此外，我们计划在该基因内筛选具有遗传CAD，代谢综合征和骨质疏松症的家庭数量，以鉴定新的突变并研究其疾病，从而导致机制。