Stress signaling in Insulin Producing Cells

胰岛素生产细胞中的应激信号传导

• 批准号: 7692881
• 负责人: Jason S Karpac
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692881
• 关键词: Address; Adipose tissue; Adult; Affect; Aging; Beta Cell; Biological Assay; Biological Process; Candidate Disease Gene; Cell physiology; Cells; Cues; Defect; Demographic Analyses; Development; Diabetes Mellitus; Drosophila genome; Drosophila genus; Dyslipidemias; Endocrine; Endocrinology; Functional disorder; Genes; Genetic; Genetic Screening; Genetic Transcription; Genotype; Growth; Homeostasis; Hormonal; Hormones; Human; Inflammatory; Insulin; Insulin Resistance; Longevity; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Mitogen-Activated Protein Kinase Kinases; Monitor; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organism; Oxidative Stress; Pancreas; Pathway interactions; Peptides; Peripheral; Phosphotransferases; Physiological; Physiology; Population; Production; Public Health; RNA Interference; Reactive Oxygen Species; Regulation; Reporter; Reporting; Resources; Role; Screening procedure; Signal Pathway; Signal Transduction; Stress; Structure of beta Cell of islet; System; Testing; Thioredoxin; Time; Tissues; Tumor Necrosis Factor Receptor; Vertebrates; Xenobiotics; activating transcription factor; age related; base; biological adaptation to stress; cytokine; design; fly; gain of function; in vivo; insight; insulin signaling; loss of function; mortality; novel; overexpression; peroxiredoxin; prevent; receptor; research study; response; stress tolerance; therapeutic target

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.

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)，从而系统地调节几种不同 IIP 靶组织中的一系列生物过程。需要更好地了解环境参数如何调节胰岛素的产生，才能采取合理的方法来治疗和预防由 IIS 失调引起的代谢疾病（例如糖尿病）。申办者的初步研究表明，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 通路是压力代谢反应的中继。然而，目前尚不清楚 JNK 如何在 IPC 中被激活。本申请旨在研究这种激活的潜在机制。目标 1 中提出的实验将确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必需的。 Aim2 旨在评估 IPC 中的 JNK 激活是直接由氧化应激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 信号传导潜在调节剂的作用。相反，在目标 3 中，提出了一种公正的基因筛选，以鉴定 IPC 中 JNK 和胰岛素生产的新调节因子。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，以及暴露于各种环境条件的不同基因型群体的死亡率的人口统计分析。公共卫生相关性：这里提出的研究将评估完整有机体中应激信号对胰岛素产生和生理学的调节。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理解这一调节系统、其组成部分及其生理学。对脊椎动物代谢稳态和衰老的病理影响。