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Signaling mechanisms and mouse models for insulin-mediated pseudoacromegaly

胰岛素介导的假性肢端肥大症的信号机制和小鼠模型

基本信息

批准号：
9764863
负责人：
David M Ornitz
金额：
$ 24.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764863
关键词：
Abbreviations Acromegaly Adipose tissue Asses Automobile Driving Biguanides Binding Biological Assay Biology Blood Glucose Body Composition Body Weight decreased Bone Density Brain Brown Fat CRISPR/Cas technology Cell Line Chronic Disease Complex Data Development Disease Disease model Dominant-Negative Mutation Down-Regulation Endocrine FGF2 gene Fatty Liver Fibroblast Growth Factor Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptors Functional disorder Future Genes Genetic Genetic study Genomic approach Glucose Growth Growth Factor Guide RNA Healthcare Systems Heparin Hepatic High Fat Diet Hirsutism Hormones Human Hyperglycemia Hyperinsulinism Hypertriglyceridemia Hypoglycemia Impairment In Vitro Individual Insulin Insulin Receptor Insulin Resistance Insulin-Like Growth Factor I Insulin-Like Growth-Factor Binding Protein 1 Insulin-Like-Growth Factor I Receptor Interleukin-3 Lead Length Leptin Ligands Lipids Liver MAP Kinase Gene Measures Mediating Metabolic Metabolic syndrome Metabolism Molecular Biology Mus Muscle Mutant Strains Mice Mutation Nerve Neuraxis Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Pathogenicity Patients Peripheral Pharmacologic Substance Pharmacology Phenotype Phosphorylation Physiology Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt RNA Recombinant Fibroblast Growth Factor Research Resistance SLC2A1 gene Signal Pathway Signal Transduction Skeletal Muscle Somatotropin Starvation Stat5 protein Syndrome Testing Thermogenesis Thiazolidinediones Tissues Unspecified or Sulfate Ion Sulfates Up-Regulation Variant Weight Weight Gain base bone cell growth exome sequencing experience fatty acid oxidation fibroblast growth factor 21 functional genomics genome editing glucose tolerance glucose uptake hormone resistance improved in vivo in vivo Model insulin sensitivity insulin sensitizing drugs insulin signaling insulin tolerance intraperitoneal mimetics mouse model mutant novel proband receptor response side effect

项目摘要

Insulin has important effects as a metabolic regulator via its ability to lower blood glucose. However, insulin is also a strong mitogenic (growth) factor. Therefore, the majority of monogenic insulin resistance syndromes are associated with short stature. Our research group has identified a patient with an extremely rare insulin resistance syndrome associated with overgrowth and tall stature. This syndrome, insulin-mediated pseudoacromegaly (IMPA), is characterized by extremely high levels of insulin, tall stature, acromegalic features, obesity, and hirsutism. Exome sequencing revealed that this proband carries 2 rare, potentially deleterious variants in Fibroblast Growth Factor Receptor 1 (FGFR1) and beta-Klotho (KLB), both of which are in the Fibroblast Growth Factor 21 (FGF21) signaling pathway. KLB is a transmembrane co-factor that is required for FGF21 to bind to and activate FGFR1, resulting in activation of intrinsic tyrosine kinase activity and subsequent signal transduction. FGF21 is a predominantly liver-derived circulating hormone. FGF21 is an important part of the metabolic response to starvation. It promotes insulin sensitivity in muscle and adipose tissue by permitting glucose uptake and fatty acid oxidation. FGF21 also contributes to growth hormone resistance via downregulation of hepatic STAT5 and IGF-1 and upregulation of IGF-1 binding protein 1. Therefore, resistance to FGF21 could explain this patient’s severe insulin resistance and tall stature. Increased levels of FGF21 is associated with obesity, fatty liver, atherogenic lipid profiles, and reduced bone mineral density. Pharmacologic administration of FGF21 imparts resistance to high fat diet-induced weight gain, improves glucose tolerance and hepatic and peripheral insulin sensitivity (without triggering hypoglycemia), and normalizes hyperinsulinemia and hypertriglyceridemia. Interestingly, resistance to FGF21 is similar to high circulating insulin and leptin concentrations in insulin- and leptin-resistant states, respectively. We posit that, together, these variants in FGFR1 and KLB are pathogenic, leading to a FGF21 resistant state. This could explain this proband’s severe insulin resistance, tall stature, and hirsutism. In this R21 proposal we will: 1) Determine whether IMPA associated FGFR1 and KLB variants together impair FGF21 signaling; and 2) Characterize the physiology and metabolism of mice carrying IMPA mutations in Fgfr1 and Klb. Together these aims serve as a functional genomic approach towards identifying the mechanism of a novel insulin resistance syndrome. Additionally, these studies will improve our understanding of FGF21 biology in humans. This has additional relevance for common disorders of insulin resistance such as type 2 diabetes and metabolic syndrome.

胰岛素通过其降低血糖的能力作为代谢调节剂具有重要作用。然而，胰岛素也是一种强促有丝分裂（生长）因子。因此，大多数单基因胰岛素抵抗综合征与身材矮小有关。我们的研究小组已经确定了一个非常罕见的胰岛素抵抗综合征与过度生长和高大身材的病人。这种综合征，胰岛素介导的假性肢端肥大症（IMPA），其特征是极高水平的胰岛素，身材高大，肢端肥大症特征，肥胖和多毛症。外显子组测序显示，该先证者携带成纤维细胞生长因子受体1（FGFR 1）和β-Klotho（KLB）中的2种罕见的潜在有害变体，这两种变体都在成纤维细胞生长因子21（FGF 21）信号通路中。KLB是FGF 21结合并激活FGFR 1所需的跨膜辅因子，导致内在酪氨酸激酶活性的激活和随后的信号转导。FGF 21是一种主要来源于肝脏的循环激素。FGF 21是饥饿代谢反应的重要组成部分。它通过允许葡萄糖摄取和脂肪酸氧化来促进肌肉和脂肪组织中的胰岛素敏感性。FGF 21还通过下调肝STAT 5和IGF-1以及上调IGF-1结合蛋白1而导致生长激素抵抗。因此，对FGF 21的抗性可以解释该患者的严重胰岛素抗性和高身材。 FGF 21水平升高与肥胖、脂肪肝、致动脉粥样硬化脂质谱和骨矿物质密度降低相关。FGF 21的药理学施用赋予对高脂肪饮食诱导的体重增加的抗性，改善葡萄糖耐量以及肝脏和外周胰岛素敏感性（不触发低血糖症），并使高胰岛素血症和高胰岛素血症正常化。有趣的是，在胰岛素抵抗和瘦素抵抗状态下，对FGF 21的抵抗分别类似于高循环胰岛素和瘦素浓度。我们认为，FGFR 1和KLB中的这些变体是致病性的，导致FGF 21耐药状态。这可以解释这个先证者的严重胰岛素抵抗、高身材和多毛症。在该R21提案中，我们将：1）确定IMPA相关的FGFR 1和KLB变体是否一起损害FGF 21信号传导;和2）表征在Fgfr 1和Klb中携带IMPA突变的小鼠的生理学和代谢。这些目标一起作为一个功能基因组学的方法对确定一种新的胰岛素抵抗综合征的机制。此外，这些研究将提高我们对人类FGF 21生物学的理解。这与胰岛素抵抗的常见疾病如2型糖尿病和代谢综合征有额外的相关性。