Cross regulation between JNK and Insulin Signaling

描述（由申请人提供）：胰岛素和IGF信号传导（IIS）的失调与代谢疾病（如糖尿病）相关，并可增加癌症发病率。胰岛素信号传导受营养输入调节，IIS控制细胞生长和代谢。对遗传模式生物的研究表明，除了这些代谢和生长控制功能外，IIS还可以增加对氧化应激的敏感性并加速衰老。相反，IIS活性的降低可以促进环境应激耐受性，并使蠕虫、苍蝇和小鼠长寿。因此，代谢和应激信号都可以调节IIS通路反应是合理的。由于这种机制将控制生长和衰老的过程直接联系起来，因此将具有重要的生物医学意义。申请人在对黑腹果蝇的初步研究中发现，分别经由Jun-N-末端激酶（JNK）和IIS途径转导的应激和代谢信号传导会聚在Foxo上，Foxo是一种已显示促进多细胞生物体的应激抗性和寿命的转录因子。该提案描述了将测试JNK信号传导激活Foxo以抑制IIS介导的生长并促进修复机制以响应压力的假设的实验，从而增加压力耐受性和寿命。这个模型的验证和JNK和IIS信号之间的潜在监管相互作用的详细分析，是高度优先。这项工作将深入了解异常胰岛素信号传导的可能分子原因，并为针对代谢功能障碍（如胰岛素抵抗）的治疗干预提供潜在途径。该建议是组织沿着三个具体的目标相结合的遗传和生物化学方法在果蝇系统：阐明JNK信号激活Foxo和拮抗IIS的分子机制。研究JNK和IIS信号通路之间的相互作用如何调节生物体的生长和衰老。验证寿命调节因子Sir 2与JNK协同激活Foxo并介导其生物学效应的假设。

DESCRIPTION (provided by applicant): Misregulation of insulin and IGF signaling (IIS) is associated with metabolic diseases such as diabetes and can increase cancer incidence. Insulin signaling is modulated by nutritional inputs, and IIS controls both cell growth and metabolism. Research in genetic model organisms has revealed that, in addition to these metabolic and growth control functions, IIS can increase the sensitivity to oxidative stress and accelerate senescence. Conversely, a decrease in IIS activity can promote environmental stress tolerance and confer longevity to worms, flies, and mice. It is thus plausible that both metabolic and stress signals can modulate IIS pathway responses. Since such mechanisms would directly link processes controlling growth and senescence, they would be of pivotal biomedical interest. The applicants have found in preliminary studies on Drosophila melanogaster that stress and metabolic signaling - transduced via the Jun-N-terminal Kinase (JNK) and the IIS pathway, respectively - converge on Foxo, a transcription factor that has been shown to promote the stress resistance and longevity of multi cellular organisms. This proposal describes experiments that will test the hypothesis that JNK signaling activates Foxo to repress IIS-mediated growth and promote repair mechanisms in response to stress, thus increasing stress tolerance and longevity. A validation of this model and a detailed analysis of the underlying regulatory interactions between JNK and IIS signaling, is of high priority. This work will provide insight into possible molecular causes of aberrant insulin signaling and offer potential avenues for therapeutic intervention targeted towards metabolic dysfunctions such as insulin resistance. The proposal is organized along three specific aims combining genetic and biochemical approaches in the Drosophila system: To elucidate the molecular mechanism by which JNK signaling activates Foxo and antagonizes IIS. To examine how the interplay between JNK and IIS signaling regulates organism growth and senescence. To test the hypothesis that the life span regulator Sir2 cooperates with JNK in the activation of Foxo and the mediation of its biological effects.