Identification of Novel Genes Linking Inflammation and Insulin Signaling

描述(申请人提供)：近年来，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。肥胖人群中脂肪质量的增加是如何导致糖尿病的，这是一个根本的、尚未回答的问题。有相当多的观点支持这样的观点，即肥胖在脂肪组织中引发先天免疫反应，从而削弱脂肪细胞中的胰岛素作用，导致其他组织中的胰岛素抵抗。这一领域的研究一直受到难以找到更多将先天免疫与人类胰岛素信号联系起来的成分的阻碍。在这项拨款提案中，我们描述了使用遗传易驯化的生物体来使用经典遗传学来识别此类基因。高度保守的胰岛素信号通路促进了从果蝇到人类的各种动物的生长和营养储存。值得注意的是，先天性免疫和胰岛素信号通路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激活的Toll转基因来激活先天免疫信号，不仅会导致胰岛素信号通路的关键下游激酶DAKT的磷酸化水平降低，而且还会导致整个生物体的生长受阻。脂肪体中免疫信号的增加和胰岛素信号的减少所导致的生长减少构成了这里提出的正向遗传筛查的基础。我们的目标是识别当与激活的Toll转基因一起表达时，逆转脂肪体内Toll信号对生长的影响的基因。这些基因可能编码新的分子，调节免疫信号和胰岛素信号之间的相互作用，或者它们可能编码分子，允许脂肪身体将其营养状态传递给苍蝇的其他部位。通过将我们的研究重点放在与人类明确同源的基因上，我们希望识别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递可能是胰岛素抵抗的基础。免疫系统对胰岛素信号的负调控在果蝇的脂肪体中重现，导致整个动物的生长减慢。这项研究将在果蝇身上采用一种无偏见的、正向的遗传学方法，以确定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.