Interplay of heavy metal homeostasis and cell growth-related signaling networks

重金属稳态与细胞生长相关信号网络的相互作用

基本信息

批准号：
10676781
负责人：
RAHUL WARRIOR
金额：
$ 30.44万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676781
关键词：
Affect Affinity Apoptosis Binding Binding Sites Biochemistry Biological Assay Blood Cadmium Cell Survival Cell physiology Cells Cellular biology Cessation of life Child Copper Cytoprotection DNA Binding Data Defect Development Disease Drosophila genus Drug Metabolic Detoxication Environment Foundations Functional disorder Genes Genetic Diseases Genetic Transcription Goals Health Heart Heavy Metals Homeostasis Human In Vitro Intestines Intoxication Ions Iron Kidney Knock-out Knowledge Lead Learning Literature Liver Malignant Neoplasms Mass Spectrum Analysis Mediating Memory Mercury Metallothionein Metals Methods Molecular Mutagenesis Names Nerve Degeneration Nervous System Nuclear Translocation Nucleic Acids Organ Organ Size Overdose Pathologic Processes Pathway interactions Phosphorylation Phosphorylation Inhibition Phosphorylation Site Phosphotransferases Physiological Processes Physiology Planet Earth Play Process Proteins Regulation Research Role Series Signal Pathway Signal Transduction Stimulation of Cell Proliferation Stress System Testing Tissues Toxic Environmental Substances Toxic effect Zinc cell growth cysteine rich protein experimental study fly human disease in vivo mutant novel novel therapeutic intervention nuclear factor 1 reconstitution response therapeutically effective transcription factor transcription factor MTF-1

项目摘要

PROJECT SUMMARY Heavy metals are natural components in the earth but become concentrated and toxic in environment as a result of human-caused activities. The term heavy metals comprise a number of essential metals (e.g. zinc, copper, iron) and non-essential metals (e.g. cadmium, mercury, lead) for human, whose excess results in toxicity even under trace amount. Accumulated heavy metals directly bind to and interfere with various cellular components (e.g. proteins, nucleic acids), and lead to severe cellular dysfunction and even death. The most commonly affected organs include liver, kidney, intestine, heart, blood and nervous systems. Children with their developing nervous systems are particularly vulnerable to heavy metal intoxication. Heavy metal homeostasis also plays an essential role in human normal physiology, whose defect results in various human diseases. Therefore, understanding the fine-tuned cellular response to overdosed heavy metals will lead to the development of effective therapeutic methods against heavy metal-associated intoxication and diseases. In this application, we propose to elucidate the molecular mechanism involved in heavy metal response by establishing the Hippo pathway as a key player in this process. Over the past decades, the Hippo pathway has been recognized as a crucial signaling pathway that controls tissue/organ size by restricting cell proliferation and stimulating cell apoptosis. Interestingly, our preliminary studies have revealed an unexpected role of the Hippo pathway in heavy metal response by regulating metal-responsive transcription factor 1 (MTF1). Moreover, we have revealed a novel regulation of the Hippo pathway by heavy meals. Based on these findings, we hypothesize that the Hippo pathway plays a critical role in heavy metal response. In this application, we propose 1) to characterize the Hippo pathway-mediated heavy metal response in vivo (Aim 1);; 2) to elucidate the regulation of MTF1 by the Hippo pathway (Aim 2);; and 3) to study the regulation of the Hippo pathway by heavy metals (Aim 3).

项目概要重金属是地球中的天然成分，但在环境中会浓缩并有毒重金属一词包括许多必需金属（例如，人为活动的结果）。锌、铜、铁）和人类非必需金属（例如镉、汞、铅），其过量会导致即使微量积累的重金属也具有毒性，直接结合并干扰各种细胞。成分（例如蛋白质、核酸），并导致严重的细胞功能障碍，甚至死亡。常见受影响的器官包括肝、肾、肠、心脏、血液和神经系统。他们正在发育的神经系统特别容易受到重金属中毒的影响。体内平衡在人体正常生理中也起着至关重要的作用，其缺陷会导致人类的各种症状。因此，了解细胞对过量重金属的微调反应将导致疾病的发生。开发针对重金属相关中毒和疾病的有效治疗方法。在此应用中，我们建议阐明重金属反应所涉及的分子机制通过将 Hippo 途径确立为这一过程的关键参与者，在过去的几十年里，Hippo 途径。已被认为是通过限制细胞来控制组织/器官大小的重要信号通路增殖和刺激细胞凋亡。有趣的是，我们的初步研究揭示了一个意想不到的结果 Hippo 途径通过调节金属响应转录因子 1 在重金属响应中的作用 (MTF1)此外，我们还基于这些揭示了Hippo通路的新调节。研究结果表明，Hippo 途径在重金属反应中发挥着关键作用。应用中，我们建议 1) 表征 Hippo 通路介导的体内重金属反应（目标 1）；； 2) 阐明 Hippo 通路对 MTF1 的调节（目标 2）；以及 3) 研究 MTF1 的调节重金属的河马途径（目标 3）。