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

基本信息

批准号：
7978297
负责人：
Morris Jay Birnbaum
金额：
$ 22.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7978297
关键词：
Address Adipocytes Adipose tissue Animal Model Animals Applications Grants Area Development Diabetes Mellitus Drosophila genus Drosophila melanogaster Epidemic Fat Body Fatty acid glycerol esters Funding Genes Genetic Genetic Models Genetic Screening Goals Growth Hormones Human Immune Immune response Immune system Individual Inflammation Insulin Insulin Resistance Insulin Signaling Pathway Intake Lead Link Mammals Mediating Metabolic Mutation Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organism Peripheral Phenotype Phosphorylation Phosphotransferases Prevalence Protein Biosynthesis Proteins Regulation Research Risk Factors Signal Transduction Signal Transduction Pathway Time Tissues Transgenes Whole Organism base fly immune activation insulin secretion insulin signaling macrophage novel public health relevance

项目摘要

DESCRIPTION (provided by applicant): In recent years, the increasing prevalence of obesity worldwide has brought with it an epidemic of type 2 diabetes. How increased fat mass in obese individuals leads to diabetes is a fundamental, unanswered question. There is considerable support for the idea that obesity initiates an innate immune response in adipose tissue that impairs insulin action in adipocytes, leading to insulin resistance in other tissues. Research in this area has been hampered by the difficulty in finding additional components that link innate immunity to insulin signaling in humans. In this grant proposal, we describe the use of a genetically tractable organism to employ classical genetics in the identification of such genes. The highly conserved insulin signaling pathway promotes growth and nutrient storage in animals ranging from fruit flies to humans. Remarkably, the interactions between the innate immune and insulin signaling pathways are also conserved in the genetic model organism Drosophila melanogaster. Activating innate immune signaling by expressing an activated Toll transgene in the Drosophila fat body leads not only to decreased phosphorylation of dAkt, a key downstream kinase of the insulin signaling pathway, but also to decreased growth of the whole organism. The decreased growth resulting from increased immune signaling and decreased insulin signaling in the fat body forms the basis for the forward genetic screen proposed here. We aim to identify genes that, when expressed with the activated Toll transgene, reverse the effects of Toll signaling in the fat body on growth. Such genes may encode novel molecules that mediate interactions between immune signaling and insulin signaling or they may encode molecules that permit the fat body to communicate its nutrient status to other parts of the fly. By focusing our studies on genes with clear human orthologues, we hope to identify novel genes that have relevance to human diabetes. PUBLIC HEALTH RELEVANCE: Obesity almost always precedes the development of type 2 diabetes, and a growing body of evidence indicates that inflammation of obese adipose tissue and signaling between macrophages and adipocytes may underlie insulin resistance. The negative regulation of insulin signaling by the immune system is recapitulated in the fat body of the fruit fly Drosophila melanogaster, leading to decreased growth of the whole animal. The study proposed here will employ an unbiased, forward genetic approach in Drosophila to identify novel genes that link inflammation and insulin signaling, thereby providing new targets for the study and treatment of type 2 diabetes.

描述（由申请人提供）：近年来，全球肥胖症的越来越多，它引起了2型糖尿病的流行。肥胖个体的脂肪量增加导致糖尿病是一个基本的，未解决的问题。肥胖症在脂肪组织中引发先天免疫反应的想法有很大的支持，这会损害脂肪细胞中的胰岛素作用，从而导致其他组织中的胰岛素抵抗。难以找到将天生免疫力与人类胰岛素信号联系起来的其他组件的困难，这一领域的研究受到了阻碍。在这项赠款提案中，我们描述了在遗传上使用经典遗传学在这种基因鉴定中的使用。高度保守的胰岛素信号通路促进了从果蝇到人类的动物的生长和养分储存。值得注意的是，在遗传模型有机体果蝇中，先天免疫和胰岛素信号通路之间的相互作用也是保守的。通过表达果蝇脂肪体中激活的TOLL转基因的激活TOLL转基因来激活先天免疫信号传导不仅导致DAKT的磷酸化降低，DAKT是胰岛素信号通路的关键下游激酶，还导致整个生物体的生长降低。脂肪体中免疫信号传导增加和胰岛素信号降低而产生的生长减少构成了此处提出的正向遗传筛查的基础。我们的目的是确定用激活的Toll Transgene表达的基因，它会逆转脂肪体对生长的收费信号的影响。这种基因可能编码新的分子，这些新分子介导免疫信号传导和胰岛素信号传导之间的相互作用，或者可以编码允许脂肪体将其养分状态传达到苍蝇其他部位的分子。通过将我们的研究重点放在具有清晰人类直系同源物的基因上，我们希望确定与人类糖尿病相关的新型基因。公共卫生相关性：肥胖几乎总是先于2型糖尿病的发展，并且越来越多的证据表明肥胖脂肪组织的炎症以及巨噬细胞和脂肪细胞之间的信号可能是胰岛素抵抗的基础。免疫系统对胰岛素信号传导的负调控在果蝇果蝇的脂肪体中概括，导致整个动物的生长降低。这里提出的研究将在果蝇中采用公正的前瞻性遗传方法来识别将炎症和胰岛素信号传导联系起来的新基因，从而为2型糖尿病的研究和治疗提供了新的靶标。