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Heavy metal-stimulated signal transduction: new metal-regulatory and -responsive mechanisms

重金属刺激的信号转导：新的金属调节和响应机制

基本信息

批准号：
10592144
负责人：
Matthew Oliver Ross
金额：
$ 8.76万
依托单位：
UNIVERSITY OF CHICAGO
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：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592144
关键词：
A549 Airborne Particulate Matter Antineoplastic Agents Binding Binding Sites Biochemical Biological Biological Markers Biophysical Process Biophysics Cancer Prognosis Categories Cell Line Cell Surface Receptors Cells ChIP-seq Chelating Agents Cisplatin Complement Complex Development Disease EGF gene Elements Environment Environmental Exposure Environmental Pollutants Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Exhibits Exposure to Extracellular Domain Fingers Foundations Functional disorder Gene Expression Profile Genetic Transcription Genomics Geometry Goals Growth Health Heavy Metals Heme Human Human Cell Line In Vitro Link Location Lung MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Metal exposure Metals Modification Molecular Molecular Chaperones Mus Nerve Growth Factors Non-Small-Cell Lung Carcinoma Nutrient Pathway interactions Phenotype Phosphorylation Physiological Platinum Post-Transcriptional Regulation Prognostic Marker Proteins Receptor Protein-Tyrosine Kinases Regulation Regulator Genes Regulatory Pathway Repression Research Role SP1 gene Signal Transduction Signal Transduction Pathway Supplementation Techniques Tissue Sample Tissue-Specific Gene Expression Tissues Toxicology Transcript WT1 gene Work Xenograft Model anti-cancer biomarker identification carcinogenesis career cellular imaging colon cancer cell line crosslink experimental study exposure pathway extracellular gene repression genetic corepressor human disease human tissue in vivo inhibitor insight mutant next generation sequencing novel programs promoter receptor binding response sensor stable cell line stoichiometry synergism toxic metal trafficking transcription factor transcriptome sequencing transcriptomics tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT From a human physiological perspective, heavy metals (HM) are divided into two groups: essential (eHM) and toxic (tHM). eHM and tHM overexposure are both linked to numerous pathophysiological conditions; however, the signal transduction pathways and genomic activities stimulated by eHM dyshomeostasis and tHM exposure have yet to be adequately established. For example, the mammalian Cu-sensor protein responsible for relaying changes in extracellular Cu levels into signaling responses has not been identified. The goals of this application are to define (i) eHM- and tHM-stimulated and -regulatory signaling networks (including resultant genomic activities), and (ii) the underlying molecular biological, biochemical, and biophysical mechanisms. Through the work in this application, I have characterized the signaling and genomic responses induced by Cu exposure and identified a mechanism of Cu-stimulated epidermal growth factor receptor (EGFR, a cell surface receptor tyrosine kinase (RTK)) signal transduction along the MAPK/ERK pathway, thereby identifying EGFR as a candidate Cu- sensor protein. Biochemical experiments are underway investigating the EGFR-Cu binding site and geometry. Relatedly, through application of newly-developed next generation sequencing (NGS), molecular biological, and transcriptomic (in vitro and in vivo) techniques, I discovered a novel mechanism by which intracellular Cu levels are regulated. Elevated extracellular Cu levels stimulate EGFR/MAPK/ERK activation, which induces expression of the transcription factor (TF) EGR1 and EGR1-corepressor NAB1/2; the EGR1-NAB1/2 complex subsequently represses transcription of the mammalian Cu-importer, CTR1. EGR1 ChIP-seq experiments are underway for further corroboration. This work will pair with experiments assessing synergism of an inhibitor of Cu-chaperones and MAPK/ERK signaling (to increase CTR1 levels) with a platinum anticancer drug (cisplatin, imported via CTR1), as well as genomic insights into the TF activities of EGR1 in EGFR-driven lung cancer (a role that is currently unknown). My research establishing the Cu-regulatory network lays the foundation for my planned independent career (i) evaluating eHM- and tHM-regulatory and -responsive mechanisms and (ii) characterizing disruption of native signaling by tHM. In my independent career, I will apply phosphorylation arrays and NGS techniques to cells stimulated with non-Cu eHM and high-priority environmental pollutant tHM, with emphasis on the effects of tHM exposure in disrupting the eHM-regulatory and -responsive signal transduction networks. In summary, my identification of EGFR as a conduit for relaying elevated extracellular Cu levels into genomic activities via the MAPK/ERK pathway has linked a major signal transduction network (implicated in cancer pathophysiology, for example) to eHM-regulation, and thereby opens new avenues of understanding HM- regulatory networks in general. More broadly, the comprehensive research program established in this proposal stands to identify biomarkers of harm preceding development and progression of cancer and other human diseases, establish novel HM-regulatory mechanisms, and enrich tHM-toxicological mechanistic understanding.

项目总结/文摘