Identification of novel genes linking inflammation and insulin signaling

鉴定连接炎症和胰岛素信号传导的新基因

• 批准号: 8792845
• 负责人: Michelle L Bland
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792845
• 关键词: Adipocytes; Adipose tissue; Affect; American; Animal Model; Animals; Applications Grants; Categories; Communication; Data; Development; Diabetes Mellitus; Drosophila genus; Drosophila melanogaster; Epidemic; Fat Body; Fatty acid glycerol esters; Genes; Genetic; Genetic Screening; Goals; Grant; Growth; Health; Homologous Gene; Hormones; Human; Immune; Immune response; Immune system; Immunosuppression; Impairment; Individual; Infection; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Larva; Lead; Link; Lipids; Liver; Mammals; Mediating; Metabolic; Muscle; Mutation; Names; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Pathway interactions; Peripheral; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prevalence; Proteins; Regulation; Rest; Risk Factors; Role; Signal Transduction; Signal Transduction Pathway; Testing; Tissues; Transgenes; Transgenic Organisms; United States; United States National Institutes of Health; arm; base; cytokine; falls; fly; genetic approach; human disease; immune activation; immune function; insulin signaling; knock-down; macrophage; novel; novel strategies; nutrient metabolism; overexpression; receptor; transcription factor

DESCRIPTION (provided by applicant): The increasing prevalence of obesity worldwide has brought with it an epidemic of type 2 diabetes. How an increase in adiposity in obese individuals leads to diabetes is a fundamental, unanswered question. Considerable evidence supports the idea that inflammation of obese adipose tissue impairs insulin action in adipocytes, leading to insulin resistance in muscle and liver. However, it has been difficult to identify additional components that link innate immunity to insulin signaling in humans. In this grant proposal, we describe the use of the genetically-tractable model organism Drosophila melanogaster to employ classical genetics in the identification of such genes. The highly conserved insulin signaling pathway acts in the Drosophila fat body to promote nutrient storage and growth of the whole animal. This organ also serves as th director of the humoral arm of the innate immune response. Remarkably, the interactions between the innate immune and insulin signaling pathways are conserved in Drosophila. Activating innate immune signaling by infection or by transgenic expression of an activated Toll receptor in the fat body leads to decreased phosphorylation of the key downstream component of the insulin signaling pathway, dAkt, and also to decreased growth and viability of the whole animal. The growth impairment and reduced viability resulting frm innate immune suppression of insulin signaling forms the basis for the forward genetic screen proposed here. Already, when performed at a small scale, such an approach has yielded novel regulators of inflammatory and insulin signaling. By performing the proposed genetic screen at a large scale, we aim to identify genes that, when overexpressed or knocked down with the activated Toll receptor in the fat body, reverse the effects of inflammatory signaling on growth. Such genes may encode novel proteins that mediate interactions between the innate immune and insulin signaling pathways, or they may encode molecules that permit the fat body to communicate its nutrient status to the rest of the fly in a manner analogous to the communication between mammalian adipose tissue and peripheral organs. By focusing our studies on genes with clear human orthologues, we hope to identify novel genes that have relevance to human disease.

描述(申请人提供)：肥胖症在全球范围内的日益流行带来了2型糖尿病的流行。肥胖症的增加如何 肥胖导致糖尿病是一个根本性的、尚未回答的问题。相当多的证据支持这一观点，即肥胖脂肪组织的炎症损害了脂肪细胞的胰岛素作用，导致肌肉和肝脏的胰岛素抵抗。然而，很难确定将人类的先天免疫与胰岛素信号联系起来的其他成分。在这项拨款提案中，我们描述了使用遗传易驯化的模式生物黑腹果蝇来使用经典遗传学来鉴定这些基因。高度保守的胰岛素信号通路在果蝇脂肪体中作用于 促进整个动物的营养储存和生长发育。这个器官也是先天免疫反应体液臂的指挥。值得注意的是，果蝇的先天性免疫和胰岛素信号通路之间的相互作用是保守的。通过感染或通过在脂肪体中转基因表达激活的Toll受体来激活先天性免疫信号会导致胰岛素信号通路关键下游成分DAKT的磷酸化减少，并降低整个动物的生长和生存能力。胰岛素信号的先天免疫抑制导致的生长障碍和生存能力降低构成了正向遗传的基础。 这里建议使用屏幕。当小规模实施时，这种方法已经产生了炎症和胰岛素信号的新调节器。通过大规模进行拟议的基因筛查，我们的目标是识别当脂肪体内过度表达或被激活的Toll受体击倒时，逆转炎症信号对生长的影响的基因。这些基因可能编码新的蛋白质，介导先天免疫和胰岛素信号通路之间的相互作用，或者它们可能编码分子，允许脂肪体以类似于哺乳动物脂肪组织和外周器官之间的通讯的方式将其营养状态传达给苍蝇的其他部分。通过将我们的研究重点放在与人类有明确同源关系的基因上，我们希望找到与人类疾病相关的新基因。