Stress signaling in Insulin Producing Cells

描述(申请人提供)：胰岛素信号(IIS)调节新陈代谢、生长和环境应激反应，并影响多细胞生物体的寿命。专门的内分泌细胞(脊椎动物的胰腺b细胞或果蝇的胰岛素产生细胞，IPC)产生胰岛素样肽(ILPS)，从而系统地调节几个不同的IIP靶组织中的一系列生物学过程。为了合理地治疗和预防由IIS失调引起的代谢性疾病，如糖尿病，需要更好地了解环境参数如何调节胰岛素的产生。发起人的初步研究表明，应激反应Jun-N末端激酶(JNK)信号通路抑制果蝇IPC中ILP的表达，从而调节整个生物体的IIS活性。这些发现表明，JNK途径是应激代谢反应的中继器。然而，目前尚不清楚JNK是如何在IPC中激活的。这项申请建议研究这种激活的潜在机制。目标1中提出的实验将确定果蝇基因组编码的哪些JNK激活蛋白(JNKKK)是IPC特异性JNK激活和胰岛素调节所必需的。AIM2旨在评估IPC中JNK的激活是由氧化应激直接启动还是由外周组织分泌的激素启动。前两个目标中提出的实验将使用候选方法来识别和表征JNK信号的潜在调节者的角色。相反，在目标3中，提出了一种无偏见的遗传筛选，以确定JNK和胰岛素在IPC中产生的新调节因子。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，以及对暴露在各种环境条件下的不同基因型种群的死亡率进行人口统计学分析。公共健康评估：这里提出的研究将评估在一个完整的生物体中，应激信号对胰岛素产生和生理的调节作用。由于IIS和JNK信号在进化上的保守性，以及IPC和胰腺b细胞的功能相似，可以预期，通过对果蝇的研究所产生的见解将有助于理解这一调控系统、其组成部分及其对脊椎动物代谢平衡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. Specialized endocrine cells (pancreatic b cells of vertebrates or insulin producing cells, IPCs, of Drosophila) produce Insulin-like peptides (ILPs) and thus systemically regulate a range of biological processes in several distinct IIP target tissues. A better understanding of how insulin production is regulated by environmental parameters is required for rational approaches to treat and prevent metabolic diseases that are caused by IIS dysregulation, such as diabetes. Preliminary studies by the sponsor have shown that the stress-responsive Jun-N-terminal Kinase (JNK) signaling pathway represses ILP expression in IPCs of Drosophila and thereby regulates IIS activity throughout the organism. These findings suggest the JNK pathway as a relay for metabolic responses to stress. It remains unclear, however, how JNK is activated in IPCs. This application proposes to investigate potential mechanisms of this activation. The experiments proposed in aim 1 will identify which of the JNK - activating kinases (JNKKKs) encoded by the Drosophila genome are required for IPC-specific JNK activation and Insulin regulation. Aim2 intends to assess whether JNK activation in IPCs is initiated by oxidative stress directly or by hormones secreted from peripheral tissues. The experiments proposed in the first two aims will use a candidate approach to identify and characterize the role of potential regulators of JNK signaling. In aim 3, in contrast, an unbiased genetic screen to identify novel regulators of JNK and Insulin production in IPCs is proposed. 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. PUBLIC HEALTH REALEVANCE: 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 b 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.