Cross regulation between JNK and Insulin Signaling

描述(由申请人提供)：胰岛素和胰岛素样生长因子信号(IIS)调节不当与糖尿病等代谢性疾病有关，并可增加癌症发病率。胰岛素信号受营养输入调节，IIS控制细胞生长和新陈代谢。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，加速衰老。相反，IIS活性的降低可以提高对环境压力的耐受性，并赋予蠕虫、苍蝇和老鼠更长的寿命。因此，代谢和应激信号都可以调节IIS途径的反应，这是合理的。由于这种机制将控制生长和衰老的过程直接联系在一起，它们将具有关键的生物医学价值。申请人在对黑腹果蝇的初步研究中发现，应激信号和代谢信号分别通过Jun-N末端激酶(JNK)和IIS途径传递到FOXO上，FOXO是一种转录因子，已被证明可以促进多细胞生物体的应激抗性和寿命。这项建议描述了一些实验，这些实验将检验JNK信号激活FOXO以抑制IIS介导的生长并促进修复机制以应对压力，从而提高应激耐受性和寿命的假设。验证这一模型并详细分析JNK和IIS信号之间的潜在调控相互作用是当务之急。这项工作将深入了解胰岛素信号异常的可能分子原因，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的途径。该提案围绕三个特定目标组织起来，结合遗传和生化方法在果蝇系统中：阐明JNK信号激活FOXO和拮抗IIS的分子机制。研究JNK和IIS信号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Sir2与JNK协同激活FOXO及其生物学效应的假说。

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.