Regulation on of the AIRAP/aip-1 pathway by metabolic stress

代谢应激对 AIRAP/aip-1 通路的调节

基本信息

批准号：
7898185
负责人：
ALFRED L FISHER
金额：
$ 20.45万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898185
关键词：
Acute-Phase Reaction Affect Aging-Related Process Animals Arsenic Arsenites Binding Sites Caenorhabditis elegans Cells Cellular Stress Chemicals Citric Acid Cycle DNA Data Degradation Pathway Diabetes Mellitus Disease Elements Environmental Exposure Environmental and Occupational Exposure Enzymes Exposure to Fumarylacetoacetase Fumarylacetoacetase Deficiency Disease Gene Activation Gene Expression Genes Genetic Heat-Shock Response Heating Heavy Metals Helminths Homologous Gene Hybrids Impairment Individual Infection Inflammation Inflammatory Intestines Lead Libraries Liver Malignant Neoplasms Measures Medical Metabolic Metabolic Pathway Metabolic stress Metabolism Modeling Muscle Mutagenesis Mutation Natural Immunity Neurodegenerative Disorders Organism Outcome Output Oxidative Stress Parasitic nematode Pathogenesis Pathway interactions Peroxides Play Protein Family Proteins Proteome RNA RNA Interference Regulation Research Role Signal Pathway Signal Transduction Site Source Specificity Stimulus Stress System Testing Time Tissues Toxic Environmental Substances Toxin Transgenic Animals Tunicamycin Tyrosine Tyrosine Metabolism Pathway Yeasts age related biological adaptation to stress combinatorial common cellular transcription factor ATF cytokine design endoplasmic reticulum stress human disease in vivo insight interest knock-down multicatalytic endopeptidase complex polyglutamine prevent promoter public health relevance repaired research study response stressor thermal stress transcription factor

项目摘要

DESCRIPTION (provided by applicant): The attached proposal describes a 5 year research plan designed to investigate responses in C.elegans to proteome damage resulting from cellular metabolism or specific exogenous toxins using genetics, transgenic animals, and RNAi. Damage to the proteome contributes to the harmful effects of environmental and occupational exposures, the pathogenesis of specific diseases including neurodegenerative diseases, cancer, and diabetes, and likely even the aging process itself. Sources of proteome damage include oxidative stress, unstable proteins, infections, and exogenous chemicals such as heavy metals and electrophilic organic compounds. We have recently found that several electrophilic tyrosine metabolites are a potent endogenous source of proteotoxic stress. Further, these metabolites also induce the expression of AIRAP/aip-1 which is a recently described family of proteins that are induced by arsenic exposure and serve to augment the clearance of damaged proteins via the proteosome. Our finding makes tyrosine degradation products the first identified endogenous activator of the aip-1 pathway. The AIRAP/aip-1 genes are also interesting in that they are induced by exposures, like arsenic or tyrosine metabolites, that produce oxidative, ER, and heat shock-like stresses to affected cells, but classic exposures, like heat, peroxide, or tunicamycin, that produce a more limited spectrum of damage fail to induce AIRAP/aip-1. Hence, the induction of AIRAP/aip-1 has a great deal of specificity which is currently not understood. We identified three transcription factors, skn-1, elt-2, and F57B10.1, as being required for the induction of aip-1 by tyrosine metabolites. Our proposal seeks to understand how the presence of AIRAP/aip-1 inducers is perceived, is communicated to these transcription factors, and leads to the activation of aip-1 and perhaps additional co-regulated stress response genes. The experiments involve using transgenic animals, a yeast one-hybrid screen, and RNAi to study how aip-1 is regulated; using genetics to find genes involved in identifying proteome damage and relaying this information to produce aip-1 expression; and using RNAi to see if other inducers, such arsenic, utilize similar pathways to induce aip-1 expression. PUBLIC HEALTH RELEVANCE: Our project aims to study how cells respond to damage from external toxins or cellular metabolism using the non-parasitic worm C. elegans. We hope to provide new insights into these responses which might lead to new treatments to prevent diseases like diabetes.

描述（由申请人提供）：所附提案描述了一项为期 5 年的研究计划，旨在利用遗传学、转基因动物和 RNAi 来研究线虫对细胞代谢或特定外源毒素引起的蛋白质组损伤的反应。蛋白质组的损伤会导致环境和职业暴露的有害影响，以及神经退行性疾病、癌症和糖尿病等特定疾病的发病机制，甚至可能导致衰老过程本身。蛋白质组损伤的来源包括氧化应激、不稳定的蛋白质、感染和外源化学物质，如重金属和亲电子有机化合物。我们最近发现几种亲电子酪氨酸代谢物是蛋白毒性应激的有效内源性来源。此外，这些代谢物还诱导 AIRAP/aip-1 的表达，这是最近描述的一个蛋白质家族，由砷暴露诱导，并通过蛋白酶体增强受损蛋白质的清除。我们的发现使酪氨酸降解产物成为第一个确定的 aip-1 途径的内源性激活剂。 AIRAP/aip-1 基因也很有趣，因为它们是由砷或酪氨酸代谢物等暴露诱导的，这些暴露会对受影响的细胞产生氧化、内质网和热休克样应激，但经典的暴露，如热、过氧化物或衣霉素产生的损伤范围更有限，不能诱导 AIRAP/aip-1。因此，AIRAP/aip-1的诱导具有很多目前尚不清楚的特异性。我们确定了酪氨酸代谢物诱导 aip-1 所需的三种转录因子 skn-1、elt-2 和 F57B10.1。我们的建议旨在了解如何感知 AIRAP/aip-1 诱导剂的存在，将其传达给这些转录因子，并导致 aip-1 以及可能的其他共同调节的应激反应基因的激活。实验涉及使用转基因动物、酵母单杂交筛选和 RNAi 来研究 aip-1 的调节方式；利用遗传学来寻找参与识别蛋白质组损伤的基因，并传递此信息以产生 aip-1 表达；并使用 RNAi 来观察其他诱导剂（例如砷）是否利用类似的途径来诱导 aip-1 表达。公共健康相关性：我们的项目旨在利用非寄生性线虫研究细胞如何应对外部毒素或细胞代谢造成的损害。我们希望对这些反应提供新的见解，这可能会带来预防糖尿病等疾病的新疗法。