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.

胰岛素通过降低血糖的能力作为代谢调节剂具有重要作用。但是，胰岛素也是强大的有丝分裂（生长）因子。因此，大多数单基因胰岛素抵抗综合征与短统计数据有关。我们的研究小组已经确定了一名患有极为罕见的胰岛素抵抗综合症的患者，与过度生长和高统计有关。该综合征，胰岛素介导的假性肿瘤（IMPA）的特征是胰岛素水平极高，高身，肢端肿瘤特征，肥胖和毛毛。外显子组测序表明，该问题在成纤维细胞生长因子受体1（FGFR1）和β-KLOTHO（KLB）中带有2种罕见的，潜在删除的变体，这两种变体都在成纤维细胞生长因子21（FGF21）信号途径中。 KLB是一种跨膜辅助因素，FGF21与FGFR1结合并激活FGFR1，从而激活了固有的酪氨酸激酶活性和随后的信号转导。 FGF21是一个主要衍生的循环马。 FGF21是对饥饿的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。 FGF21还通过下调Hepatitic Stat5和IGF-1以及IGF-1结合蛋白1的上调有助于生长马酮的耐药性。因此，对FGF21的耐药性可以解释该患者的严重胰岛素抵抗和高统计。 FGF21的水平增加与肥胖，脂肪肝，动脉粥样硬化脂质谱和骨矿物质密度降低有关。 FGF21的药理学给药具有对高脂肪饮食诱导的体重增加，提高葡萄糖耐受性，肝胰岛素敏感性（无需触发低血糖）的耐药性，并使高胰岛素抵抗，高统计量，高统计和HIRSUTISTIS和HIRSUTISM归一化。在此R21建议中，FGFR1和KLB中的这些变体具有致病性，导致FGF21抗性状态。我们将：1）确定IMPA相关的FGFR1和KLB变体是否会损害FGF21信号传导；和2）表征在FGFR1和KLB中携带IMPA突变的小鼠的生理和代谢。这些目的共同用作识别新型胰岛素耐药综合征机制的一种功能基因组方法。此外，这些研究将提高我们对人类FGF21生物学的理解。这与胰岛素抵抗的常见疾病（例如2型糖尿病和代谢综合征）具有附加相关性。