Systemic coordination of stress responses by insulin signaling

通过胰岛素信号传导应激反应的系统协调

• 批准号: 7080346
• 负责人: Heinrich Jasper
• 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: 2006-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080346
• 关键词: Drosophilidae; JUN kinase; aging; biological signal transduction; endocrine gland /system; environmental stressor; enzyme activity; gene induction /repression; genetically modified animals; heat; insulin; insulinlike factor; invertebrate endocrinology; longevity; metabolomics; oxidative stress; pancreatic islets; protein biosynthesis; protein localization; starvation; stressor; transcription factor

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 New unpublished data by the applicant suggest that the regulation of ILP expression by JNK signaling in IPCs deteriorates as animals age, an effect that might cause or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.

描述（由申请人提供）：胰岛素信号传导（IIS）调节新陈代谢，生长和环境压力反应，并影响多细胞生物的寿命。 IIS由胰岛素（ILP）（ILP）触发，这些肽（ILP）是由专门的内分泌细胞（脊椎动物的胰腺β细胞或产生果蝇的胰岛素产生细胞）根据营养和​​环境提示而产生的。这些细胞在几个不同的ILP靶组织中系统地调节了一系列生物过程。要了解胰岛素产生的控制如何整合多个外部和内部信号以调节适当的系统性反应是一个高度优先级。对于治疗和预防由胰岛素失调引起的代谢疾病的理性方法需要这种理解。申请人的初步研究表明，应力响应性的Jun-N末端激酶（JNK）信号通路抑制了果蝇Melanogaster 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途径是有机胁迫代谢作用的继电器。这个想法将被实验提出。申请人的新未发表的数据表明，随着动物的年龄，IPC中JNK信号对ILP表达的调节会恶化，这种作用可能导致或导致衰老期间代谢变化。 AIM 1中提出的实验将检验以下假设：JNK介导的对ILP表达的抑制需要系统地协调细胞对环境应力的反应。将探讨引起IPC反应的潜在环境应力信号的性质，并评估IIS抑制的组织自主和体液机制在细胞对压力反应中的参与。 AIM 2中的实验将检查JNK对IIS活性的全身性和组织自治抑制对胁迫耐受性和寿命的相对贡献。 AIM 3旨在测试IPC中JNK活性的年龄变化是否有助于衰老动物中代谢控制的总体恶化，以及IPC中正常JNK信号的恢复是否会延迟此类变化。所有目标均基于使用果蝇的遗传方法，包括转录和代谢分析，以及对暴露于各种环境条件的不同基因型人群中死亡率的人口统计学分析。这里提出的研究将通过完整生物体中的压力信号来评估胰岛素产生和生理的调节。由于IIS和JNK信号的进化保护以及IPC和胰腺β细胞的功能类比，可以预期，果蝇研究产生的见解将有助于理解该调节系统，其成分及其生理学及其生理学的洞察力以及对脊椎动物代谢稳态和衰老的病理影响。