Stress signaling in Insulin Producing Cells

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。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（ILP），并因此在几种不同的IIP靶组织中系统地调节一系列生物过程。更好地了解胰岛素的产生是如何调节环境参数是合理的方法来治疗和预防由IIS失调引起的代谢疾病，如糖尿病。申办方的初步研究表明，应激反应性Jun-N-末端激酶（JNK）信号通路抑制果蝇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通路作为应激代谢反应的中继。然而，JNK如何在IPC中被激活仍不清楚。本申请提出研究这种激活的潜在机制。目的1中提出的实验将鉴定哪些由果蝇基因组编码的JNK激活激酶（JNKKK）是IPC特异性JNK激活和胰岛素调节所需的。Aim 2旨在评估IPC中JNK激活是否直接由氧化应激或由外周组织分泌的激素启动。在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信号传导的潜在调节剂的作用。相反，在目标3中，提出了一种无偏的遗传筛选来鉴定IPC中JNK和胰岛素产生的新调节剂。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。公共卫生相关性：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信号传导的进化保守性，以及IPC和胰腺B细胞的功能相似性，可以预期，果蝇研究产生的见解将有助于了解该调节系统、其组成部分及其生理和病理影响脊椎动物的代谢稳态和衰老。

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.