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：
8066382
负责人：
ALFRED L FISHER
金额：
$ 23.62万
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/8066382
关键词：
Acute-Phase Reaction Affect Aging-Related Process Animals Arsenic Arsenites Binding Sites CREB1 gene 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 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 Nematoda Neurodegenerative Disorders Organism Outcome Output Oxidative Stress 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）：附件描述了一项为期5年的研究计划，旨在研究使用遗传学，转基因动物和RNAi元素对细胞代谢或特定外源毒素造成的蛋白质组损害的反应。蛋白质组的损害有助于环境和职业暴露的有害影响，包括神经退行性疾病，癌症和糖尿病的特定疾病的发病机理，甚至可能是衰老过程本身。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，例如重金属和亲电机化合物。我们最近发现，几种亲电酪氨酸代谢产物是蛋白质毒性应激的有效内源性来源。此外，这些代谢产物还诱导了AIRAP/AIP-1的表达，这是最近描述的蛋白质家族，该蛋白质由砷暴露诱导，并通过蛋白质体增加了受损蛋白质的清除。我们的发现使酪氨酸降解产物成为AIP-1途径的首次确定的内源性激活剂。 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引起的，这些暴露会对受影响的细胞产生氧化，ER和热休克样胁迫，但是经典的暴露，例如热，过氧化菌或女甲状腺素，产生更有限的损害损害的损害损坏的损害失败，无法引起Airap/aip-1的损害。因此，AIRAP/AIP-1的诱导具有很大的特异性，目前尚不清楚。我们确定了三个转录因子SKN-1，ELT-2和F57B10.1，这是酪氨酸代谢产物诱导AIP-1所必需的。我们的建议旨在了解如何感知AIRAP/AIP-1诱导剂的存在，并传达给这些转录因子，并导致AIP-1的激活以及可能其他共同调节的应激响应基因的激活。实验涉及使用转基因动物，酵母单杂交筛查和RNAi来研究AIP-1的调节。使用遗传学查找参与鉴定蛋白质组损伤的基因并中继此信息以产生AIP-1表达；并使用RNAi查看其他诱导剂是否使用类似的途径来诱导AIP-1表达。公共卫生相关性：我们的项目旨在研究细胞对外部毒素或细胞代谢的损害的反应，使用非寄生虫虫秀丽隐杆线虫。我们希望对这些反应提供新的见解，这可能会导致新的治疗方法，以预防诸如糖尿病之类的疾病。