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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).

项目总结