Identification of novel genes linking inflammation and insulin signaling

描述（由申请人提供）：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。 肥胖的增加是如何 肥胖个体导致糖尿病是一个基本的，未回答的问题。大量证据支持肥胖脂肪组织的炎症损害脂肪细胞中的胰岛素作用，导致肌肉和肝脏中的胰岛素抵抗。 然而，很难确定将先天免疫与人类胰岛素信号传导联系起来的其他成分。在这项资助计划中，我们描述了使用遗传学上易于处理的模式生物黑腹果蝇（Drosophila melanogaster）来采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起作用， 促进整个动物的营养储存和生长。 这个器官也是先天免疫反应的体液分支的指挥者。值得注意的是，先天免疫和胰岛素信号通路之间的相互作用在果蝇中是保守的。通过感染或通过脂肪体中活化的Toll受体的转基因表达来活化先天免疫信号传导导致胰岛素信号传导途径的关键下游组分dAkt的磷酸化降低，并且还导致整个动物的生长和生存力降低。 由胰岛素信号传导的先天性免疫抑制导致的生长障碍和活力降低形成了正向遗传调节的基础。 屏幕在这里提出。 在小规模实施时，这种方法已经产生了炎症和胰岛素信号的新型调节剂。 通过大规模进行拟议的遗传筛选，我们的目标是确定基因，当过表达或与脂肪体中激活的Toll受体一起敲低时，逆转炎症信号对生长的影响。 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信的方式将其营养状态传达给苍蝇的其他部分的分子。 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疾病相关的新基因。

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.