Genetic Studies of Diabetes

糖尿病的遗传学研究

基本信息

批准号：
9358416
负责人：
CARL S. THUMMEL
金额：
$ 37.9万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9358416
关键词：
Adult Affect Animal Model Animals Beta Cell Binding Biological Models Biology Cells Cellular biology ChIP-seq Clinic Defect Development Diabetes Mellitus Disease Drosophila genus Evolution Fat Body Foundations Functional disorder Future Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genetic study Glucose Glucose Intolerance Goals HNF4A gene Health Heart Diseases Homeostasis Human Hyperglycemia Impairment Incidence Inflammation Inflammatory Response Pathway Inherited Insulin Insulin-Dependent Diabetes Mellitus Intestines Kidney Failure Link Liver Mammals Messenger RNA Metabolic Metabolic syndrome Metabolism Mitochondria Mitochondrial Proteins Molecular Mutation Neurobiology Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Orthologous Gene Pancreas Pathway interactions Patients Pattern Peripheral Phenotype Physiological Physiology Protein Isoforms Proteins RNA Interference Research Research Design Risk Factors Role Signal Transduction Stroke Structure of beta Cell of islet System Testing Therapeutic Tissues Work associated symptom blood glucose regulation combat defined contribution design experimental study fly functional group gene function genome-wide improved insight insulin secretion insulin signaling liver metabolism mitochondrial dysfunction mitochondrial genome mouse model mutant novel strategies novel therapeutic intervention prevent receptor transcription factor transcriptome sequencing

项目摘要

In addition to the widely studied type 1 and type 2 diabetes, there are a number of monogenic inherited forms of this disorder, including Maturity-Onset Diabetes of the Young (MODY). The genetic basis for the first MODY subtype was discovered 20 years ago through its association with mutations in the HNF4A nuclear receptor. This link with a transcription factor focused efforts on defining the central roles of Hnf4A in the key tissues where it controls metabolism: the liver, intestine, and pancreas. Genetic studies in mouse models, however, did not recapitulate the full range of symptoms associated with MODY1 – in particular, the sustained hypoinsulinemic hyperglycemia seen in the clinic. We discovered that the expression pattern of HNF4A is conserved through evolution, from flies to mammals, and that mutants for the Drosophila ortholog of Hnf4A (dHNF4) display a range of phenotypes that resemble those of MODY1 patients. These include adult-onset hyperglycemia, impaired glucose-stimulated insulin secretion, glucose intolerance, and reduced peripheral insulin signaling. In addition, our RNA-seq transcriptional profiling identified several functional groups of dHNF4-regulated genes that act in the tissues where the receptor is expressed in flies and humans. This includes widespread effects on inflammatory response pathways, similar to the role of Hnf4A in the mammalian intestine, as well as key genes involved in glucose-stimulated insulin secretion. Unexpectedly, we also discovered that mitochondrial-encoded gene expression is significantly reduced in the mutant, and that dHNF4 protein localizes to mitochondria and binds specifically to the control region of the mitochondrial genome. dHNF4 also directly regulates nuclear genes that encode mitochondrial proteins, demonstrating a central role in mitochondrial physiology. Given that only a few nuclear transcription factors have been identified in mitochondria, and their roles are poorly understood, we propose to undertake a detailed analysis of the mitochondrial functions of dHNF4 and link these to key downstream roles of the receptor. In addition, we will use Drosophila genetics to elucidate the interactions between mitochondrial dysfunction, inflammation, and metabolic defects in the context of diabetes. Although these pathways are often associated in metabolic syndrome, their cause and effect relationships remain unclear. Our overall hypothesis is that dHNF4 acts in multiple tissues to maintain mitochondrial function and to suppress inflammation and diabetes. We propose three specific aims to (1) determine the tissue-specific functions of dHNF4, (2) determine the physiological functions of dHNF4-regulated pathways and target genes, and (3) characterize the evolutionary conservation of dHNF4 functions, from flies to mammals. Taken together, this research will provide a simple genetic system to dissect the interplay between mitochondrial dysfunction, inflammation, and diabetes, as well as an animal model for MODY1. Our results, in turn, can be used to guide future studies in mouse models as well as devise new potential therapeutic approaches for preventing and treating diabetes in humans.

除了广泛研究的 1 型和 2 型糖尿病外，还有许多单基因遗传形式这种疾病，包括青少年发病型糖尿病 (MODY) 第一个 MODY 的遗传基础。 20 年前通过其与 HNF4A 核受体突变的关联发现了亚型。这种与转录因子的联系集中于确定 Hnf4A 在关键组织中的核心作用然而，它控制新陈代谢的地方：肝脏、肠道和胰腺。没有概括与 MODY1 相关的全部症状——特别是持续的我们在临床上发现HNF4A的表达模式是低胰岛素高血糖。从果蝇到哺乳动物的进化过程中保守的，以及 Hnf4A 果蝇直系同源物的突变体 (dHNF4) 显示一系列与 MODY1 患者相似的表型。高血糖、葡萄糖刺激的胰岛素分泌受损、葡萄糖不耐受和外周血减少此外，我们的 RNA-seq 转录谱鉴定了胰岛素信号传导的几个功能组。 dHNF4 调节的基因在果蝇和人类表达受体的组织中发挥作用。包括对炎症反应途径的广泛影响，类似于 Hnf4A 在哺乳动物中的作用出乎意料的是，我们还发现了参与葡萄糖刺激胰岛素分泌的关键基因。发现突变体中线粒体编码的基因表达显着降低，并且 dHNF4 蛋白质定位于线粒体并特异性结合线粒体基因组的控制区域。 dHNF4 还直接调节编码线粒体蛋白的核基因，显示出核心作用鉴于线粒体生理学中仅发现了少数核转录因子。线粒体，并且人们对它们的作用知之甚少，我们建议对线粒体进行详细分析此外，我们还将研究 dHNF4 的线粒体功能并将其与受体的关键下游作用联系起来。使用果蝇遗传学来阐明线粒体功能障碍、炎症和线粒体功能之间的相互作用尽管这些途径通常与代谢相关，但糖尿病背景下的代谢缺陷。综合征，其因果关系仍不清楚，我们的总体假设是 dHNF4 作用于。我们建议维持线粒体功能并抑制炎症和糖尿病。三个具体目标是 (1) 确定 dHNF4 的组织特异性功能，(2) 确定生理学 dHNF4 调节途径和靶基因的功能，以及 (3) 表征进化保守性总而言之，这项研究将提供一个简单的遗传系统。剖析线粒体功能障碍、炎症和糖尿病之间的相互作用，以及动物反过来，我们的结果可用于指导小鼠模型的未来研究以及设计。预防和治疗人类糖尿病的新的潜在治疗方法。