Genetic Studies of Diabetes

糖尿病的遗传学研究

• 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
• 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

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.

除了被广泛研究的类型1和2型糖尿病外，还有许多单基因遗传形式 这种疾病，包括年轻人（Mody）的成熟度发作的糖尿病。第一个mody的遗传基础 亚型是20年前通过与HNF4A核接收器中的突变相关联发现的。 与转录因子集中精力定义HNF4A在关键组织中的主要作用的联系 它控制新陈代谢的地方：肝脏，肠道和胰腺。但是，小鼠模型中的遗传研究 没有概括与Mody1相关的全部症状 - 特别是持续的症状 诊所中可见的低胰岛素高血糖。我们发现HNF4A的表达模式是 通过进化，从苍蝇到哺乳动物保守，以及HNF4A果蝇直系同源物的突变体 （DHNF4）显示一系列类似于Mody1患者的表型。这些包括成人发病 高血糖，葡萄糖刺激的胰岛素分泌受损，葡萄糖肠道和外周还原 胰岛素信号传导。此外，我们的RNA-seq转录分析确定了几个功能组 DHNF4调节的基因在接收器以果蝇和人类表达的组织中作用。这 包括对炎症反应途径的宽度影响，类似于HNF4A在哺乳动物中的作用 肠以及参与葡萄糖刺激的胰岛素分泌的关键基因。出乎意料的是，我们也是 发现线粒体编码的基因表达在突变体中显着降低，并且DHNF4 蛋白质定位于线粒体，并特别结合线粒体基因组的对照区域。 DHNF4还直接调节编码线粒体蛋白的核基因，证明了核心作用 在线粒体生理学中。鉴于在 线粒体及其作用知之甚少，我们建议对 DHNF4的线粒体功能并将其链接到接收器的关键下游角色。此外，我们将 使用果蝇遗传学阐明线粒体功能障碍，注射和 糖尿病背景中的代谢缺陷。尽管这些途径通常与代谢有关 综合征，其因果关系尚不清楚。我们的总体假设是DHNF4在 多个时间安排维持线粒体功能并抑制注射和糖尿病。我们建议 （1）确定DHNF4的组织特异性功能的三个具体目的，（2）确定生理 DHNF4调节的途径和靶基因的功能，（3）表征进化保守 DHNF4功能，从苍蝇到哺乳动物。综上所述，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 Mody1的模型。反过来，我们的结果可用于指导鼠标模型的未来研究以及设计 预防和治疗人类糖尿病的新潜在治疗方法。