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; 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，生长和环境压力反应，并影响多细胞生物的寿命。专门的内分泌细胞（脊椎动物或胰岛素产生细胞的胰腺B细胞，果蝇的IPC）产生胰岛素样肽（ILP），因此在几种不同的IIP IIP靶向组织中系统地调节了一系列生物过程。需要更好地理解胰岛素的产生如何受环境参数的调节，以治疗和预防由IIS失调引起的代谢疾病（例如糖尿病）引起的代谢疾病。赞助商的初步研究表明，应力响应性的JUN-N-末端激酶（JNK）信号传导途径抑制果蝇IPC中的ILP表达，从而调节整个生物体中的IIS活性。这些发现表明JNK途径是对压力的代谢反应的继电器。但是，尚不清楚如何在IPC中激活JNK。该应用建议研究这种激活的潜在机制。 AIM 1中提出的实验将确定由果蝇基因组编码的JNK激活激活（JNKKK）是IPC特异性JNK激活和胰岛素调节所必需的。 AIM2打算评估IPC中的JNK激活是直接由氧化应激还是由外周组织分泌的激素引发的。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AIM 3中，提出了一个公正的遗传筛选，以鉴定IPC中JNK和胰岛素产生的新调节剂。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。公共卫生问题：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生产和生理的调节。由于IIS和JNK信号的进化保守性，以及IPC和胰腺B细胞的功能类比，可以预期，果蝇研究中研究产生的见解将有助于了解该调节系统，其成分，其成分以及其生理和病理对代谢稳态的影响。