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

重金属稳态和细胞生长相关信号网络的相互作用

基本信息

批准号：
10431618
负责人：
RAHUL WARRIOR
金额：
$ 30.5万
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/10431618
关键词：
Affect Affinity Apoptosis Binding Binding Sites Biochemistry Biological Assay Blood Cadmium Cell Proliferation Cell Survival Cell physiology Cells Cellular biology Cessation of life Child Copper 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 structure Nuclear Translocation Nucleic Acids Organ Organ Size Overdose Pathologic Processes Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Physiological Processes Physiology Planet Earth Play Process Proteins Regulation Research Role Series Signal Pathway Signal Transduction Stress System Testing Tissues Toxic Environmental Substances Toxic effect Zinc base 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).

项目摘要重金属是地球上的天然成分，但在环境中变得浓缩和有毒由于人为引起的活动。一词重金属包括许多必需的金属（例如人类的锌，铜，铁）和非必需的金属（例如镉，汞，铅），其过量导致毒性即使在微量量下也是如此。累积的重金属直接与各种细胞结合并干扰成分（例如蛋白质，核酸），并导致严重的细胞功能障碍甚至死亡。最多通常影响的器官包括肝，肾脏，肠，心脏，血液和神经系统。有孩子他们发育的神经系统特别容易受到重金属中毒的影响。重金属稳态也在人类正常生理学中起着至关重要的作用，其缺陷导致各种人类疾病。因此，了解对过量剂量重金属的微调细胞反应将导致开发针对重金属相关的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响应涉及的分子机制通过在此过程中建立河马路径为关键参与者。在过去的几十年中，河马小路已被认为是通过限制细胞来控制组织/器官大小的关键信号通路增殖和刺激细胞凋亡。有趣的是，我们的初步研究表明通过控制金属响应转录因子1，河马途径在重金属反应中的作用1 （MTF1）。此外，我们已经通过大餐揭示了对河马途径的新调节。基于这些调查结果，我们假设河马途径在重金属反应中起着至关重要的作用。在这个应用，我们建议1）表征体内河马途径介导的重金属反应（AIM 1）;; 2）通过河马途径阐明MTF1的调节（AIM 2）;; 3）研究重金属的河马途径（AIM 3）。