Identification of novel genes linking inflammation and insulin signaling

描述（由申请人提供）：近年来，全球范围内肥胖症患病率的增加带来了2型糖尿病的流行。肥胖个体的脂肪量增加如何导致糖尿病是一个基本的，未回答的问题。有相当多的支持的想法，肥胖症启动先天性免疫反应的脂肪组织，损害胰岛素作用的脂肪细胞，导致胰岛素抵抗的其他组织。这一领域的研究一直受到阻碍，因为很难找到将人类先天免疫与胰岛素信号联系起来的其他成分。在这个资助计划中，我们描述了使用一种遗传上易处理的生物体来利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促进从果蝇到人类的动物的生长和营养储存。值得注意的是，先天免疫和胰岛素信号传导途径之间的相互作用在遗传模式生物黑腹果蝇中也是保守的。通过在果蝇脂肪体中表达活化的Toll转基因来活化先天免疫信号传导不仅导致dAkt（胰岛素信号传导途径的关键下游激酶）的磷酸化降低，而且导致整个生物体的生长降低。脂肪体中免疫信号增加和胰岛素信号减少导致的生长减少形成了本文提出的正向遗传筛选的基础。我们的目标是确定基因，当表达与激活的Toll转基因，逆转Toll信号在脂肪体对生长的影响。这些基因可能编码新的分子，介导免疫信号和胰岛素信号之间的相互作用，或者它们可能编码允许脂肪体将其营养状态传达给苍蝇其他部位的分子。通过将我们的研究集中在具有明确的人类直系同源物的基因上，我们希望识别出与人类糖尿病相关的新基因。 公共卫生相关性：肥胖几乎总是先于2型糖尿病的发展，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传导可能是胰岛素抵抗的基础。免疫系统对胰岛素信号的负调节在果蝇的脂肪体中重现，导致整个动物的生长减缓。这项研究将在果蝇中采用无偏见的正向遗传方法来识别连接炎症和胰岛素信号的新基因，从而为2型糖尿病的研究和治疗提供新的靶点。

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.