Systemic coordination of stress responses by insulin signaling

描述（由申请人提供）：应激信号传导途径对胰岛素/IGF信号传导（IIS）的抑制是促进后生动物应激耐受性和代谢稳态、延长寿命的中心机制。最近在小鼠早衰症模型中的研究表明，DNA损伤是IIS系统性抑制的重要刺激，并且这种抑制增加了胰岛素靶组织中的细胞保护过程，作为一种适应性机制。通过DNA损伤抑制IIS的机制尚不清楚。作者引入果蝇模型来解决这个问题，并提出炎症细胞因子的内分泌信号网络通过调节大脑胰岛素产生细胞中胰岛素样肽的表达来调节IIS活性。这个网络被认为会显著影响果蝇的组织和代谢稳态以及寿命。为了验证这一假设并探索所提出的信号传导层次，作者提出了解决以下问题的遗传学研究：（i）从应激组织释放的炎性细胞因子是否通过调节胰岛素样肽表达来全身抑制胰岛素信号传导？(ii)NF κ B样因子的信号传导是否调节了应激后恢复胰岛素活性的次级反应？(iii)控制DNA损伤的系统反应的内分泌信号相互作用的时间和空间序列能被表征吗？(iv)已建立的内分泌信号网络是否调节衰老果蝇的代谢和增殖稳态及寿命？预计拟议的实验将提供重要的洞察信号网络调节胰岛素信号响应DNA损伤和其他压力的挑战，在后生动物。预计这些相互作用在进化上是保守的，并可能影响脊椎动物的应激耐受性和寿命，同时在慢性炎症条件下促进代谢功能障碍中发挥重要作用，如在肥胖动物中观察到的。

DESCRIPTION (provided by applicant): The repression of Insulin/IGF signaling (IIS) by stress signaling pathways is a central mechanism to promote stress tolerance and metabolic homeostasis in metazoans, extending lifespan. Recent studies in mouse progeria models demonstrate that DNA damage is an important stimulus for the systemic repression of IIS, and that this repression increases cytoprotective processes in insulin target tissues, serving as an adaptive mechanism. The mechanisms governing the repression of IIS by DNA damage remain unclear. The authors introduce a Drosophila model to address this question and propose that a network of endocrine signaling by inflammatory cytokines modulates IIS activity by regulating expression of insulin-like peptides in Insulin Producing Cells of the brain. This network is proposed to significantly influence tissue and metabolic homeostasis, as well as lifespan in the fly. To test this hypothesis and to explore the proposed signaling hierarchies, the authors propose genetic studies addressing the following questions: (i) Does release of inflammatory cytokines from stressed tissues repress Insulin signaling systemically by regulating Insulin-like peptide expression? (ii) Does signaling by NFkappaB-like factors regulate a secondary response that allows restoring Insulin activity after stress? (iii) Can a temporal and spatial sequence of endocrine signaling interactions that control the systemic response to DNA damage be characterized? (iv) Does the established endocrine signaling network regulate metabolic and proliferative homeostasis and longevity in aging flies? The proposed experiments are expected to provide important insight into the signaling network regulating insulin signaling in response to DNA damage and other stressful challenges in metazoans. These interactions are expected to be evolutionarily conserved and potentially influence stress tolerance and lifespan in vertebrates, while at the same time playing significant roles in promoting metabolic dysfunction under chronic inflammatory conditions, as observed in obese animals.