Systemic coordination of stress responses by insulin signaling

描述（由申请人提供）：胰岛素信号传导（IIS）调节代谢、生长和环境应激反应，并影响多细胞生物体的寿命。IIS由胰岛素样肽（ILP）触发，所述胰岛素样肽由专门的内分泌细胞（脊椎动物的胰腺β细胞或果蝇的胰岛素产生细胞，IPC）根据营养和环境线索产生。这些细胞在几种不同的ILP靶组织中系统地调节一系列生物学过程。了解胰岛素产生的控制如何整合多种外部和内部信号以介导适当的全身反应是一个高度优先事项。这种理解是治疗和预防由胰岛素失调引起的代谢疾病的合理方法所必需的。申请人的初步研究已经表明，应激响应性Jun-N-末端激酶（JNK）信号传导途径抑制黑腹果蝇的IPC中的ILP表达，从而调节整个生物体的IIS活性。这些发现表明JNK通路作为器官应激的代谢效应的中继。这一想法将在实验中加以研究。申请人新的未发表的数据表明，IPC中JNK信号传导对ILP表达的调节随着动物年龄的增长而恶化，这种影响可能导致或促成衰老期间的代谢变化。目的1中提出的实验将检验JNK介导的ILP表达的抑制是系统地协调细胞对环境应激的反应所必需的这一假设。将探索引发IPC反应的潜在环境应激信号的性质，并将评价IIS抑制的组织自主和体液机制在细胞应激反应中的参与。目的2中的实验将检查JNK对IIS活性的系统和组织自主抑制对生物体的胁迫耐受性和寿命的相对贡献。目的3旨在测试IPC中JNK活性的年龄依赖性变化是否有助于衰老动物代谢控制的总体恶化，以及IPC中正常JNK信号传导的恢复是否可以延迟这种变化。所有目标都是基于使用果蝇的遗传方法，包括转录和代谢分析，以及暴露于各种环境条件下的不同基因型人群的死亡率的人口统计学分析。本文提出的研究将评估完整生物体中应激信号对胰岛素产生和生理的调节。由于IIS和JNK信号转导的进化保守性，以及IPC和胰腺β细胞的功能相似性，可以预期，在果蝇中的研究产生的见解将有助于理解这种调节系统，其组成部分，以及其对脊椎动物代谢稳态和衰老的生理和病理影响。

DESCRIPTION (provided by applicant): Insulin signaling (IIS) regulates metabolism, growth, and environmental stress responses and influences longevity in multicellular organisms. IIS is triggered by insulin like peptides (ILPs) that are produced by specialized endocrine cells (pancreatic beta cells of vertebrates or insulin producing cells, IPCs, of Drosophila) according to nutritional and environmental cues. These cells systemically regulate a range of biological processes in several distinct ILP target tissues. To understand how the control of insulin production integrates multiple external and internal signals to mediate an appropriate systemic response is a high priority. Such understanding is required for rational approaches to treat and prevent metabolic diseases that are caused by insulin dysregulation. Preliminary studies by the applicant have shown that the stress-responsive Jun-N-terminal Kinase (JNK) signaling pathway represses ILP expression in IPCs of Drosophila melanogaster and thereby regulates IIS activity throughout the organism. These findings suggest the JNK pathway as a relay for metabolic effects of organismic stress. This idea will be pursued experimentally. New unpublished data by the applicant suggest that the regulation of ILP expression by JNK signaling in IPCs deteriorates as animals age, an effect that might cause or contribute to metabolic changes during aging. The experiments proposed in aim 1 will test the hypothesis that JNK-mediated repression of ILP expression is required to coordinate cellular responses to environmental stress systemically. The nature of potential environmental stress signals that elicit an IPC response will be explored, and the involvement of tissue- autonomous and humoral mechanisms of IIS repression in cellular responses to stress will be evaluated. Experiments in aim 2 will examine the relative contributions of systemic and tissue-autonomous repression of IIS activity by JNK to stress tolerance and longevity of the organism. Aim 3 is designed to test whether age-dependent changes of JNK activity in IPCs contribute to the general deterioration of metabolic control in aging animals, and whether a restoration of normal JNK signaling in IPCs may delay such changes. All aims are based on genetic approaches using Drosophila and include transcriptional and metabolic analysis, as well as demographic analysis of mortality in populations of different genotypes exposed to a variety of environmental conditions. The studies proposed here will assess the regulation of insulin production and physiology by stress signaling in an intact organism. Due to the evolutionary conservation of IIS and JNK signaling, as well as the functional analogy of IPCs and pancreatic beta cells, it can be expected that the insight generated by studies in Drosophila will help to understand this regulatory system, its components, and its physiological and pathological impact on metabolic homeostasis and aging in vertebrates.