Cross regulation between JNK and Insulin Signaling

JNK 和胰岛素信号传导之间的交叉调节

• 批准号: 7093798
• 负责人: Dirk Bohmann
• 金额: $ 28.78万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093798
• 关键词: Drosophilidae; JUN kinase; amidohydrolases; arthropod genetics; autophagy; biological signal transduction; cell cycle; fat body; hormone regulation /control mechanism; insulin; insulinlike growth factor; longevity; oxidative stress; phosphorylation; tissue /cell culture; transcription factor

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.

描述（由申请人提供）：胰岛素和 IGF 信号传导 (IIS) 的失调与糖尿病等代谢性疾病有关，并可能增加癌症发病率。胰岛素信号传导受营养输入的调节，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压力耐受性并赋予蠕虫、苍蝇和小鼠长寿。因此，代谢信号和应激信号都可以调节 IIS 途径反应，这似乎是合理的。由于此类机制将直接连接控制生长和衰老的过程，因此它们将具有关键的生物医学意义。申请人在对果蝇的初步研究中发现，应激和代谢信号（分别通过 Jun 氨基末端激酶 (JNK) 和 IIS 途径转导）汇聚在 Foxo 上，Foxo 是一种已被证明可以促进应激的转录因子多细胞生物的抵抗力和寿命。该提案描述的实验将检验 JNK 信号传导激活 Foxo 抑制 IIS 介导的生长并促进响应压力的修复机制，从而提高压力耐受性和寿命的假设。对该模型的验证以及对 JNK 和 IIS 信号传导之间潜在调控相互作用的详细分析是当务之急。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，并为针对胰岛素抵抗等代谢功能障碍的治疗干预提供潜在途径。该提案围绕果蝇系统中结合遗传和生化方法的三个具体目标进行组织： 阐明 JNK 信号传导激活 Foxo 并拮抗 IIS 的分子机制。研究 JNK 和 IIS 信号传导之间的相互作用如何调节生物体生长和衰老。检验寿命调节因子 Sir2 与 JNK 合作激活 Foxo 并介导其生物效应的假设。