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DREAM Mediated Transcription Acts as a Biomarker for Pollutant Induced Calcium Signaling Disruption

DREAM 介导的转录作为污染物引起的钙信号传导破坏的生物标志物

基本信息

批准号：
10359744
负责人：
Erika B Holland
金额：
$ 10.84万
依托单位：
CALIFORNIA STATE UNIVERSITY LONG BEACH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-10 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359744
关键词：
Address Adult Agonist Air Animal Model Animals Behavior Binding Biological Assay Biological Markers Brain Calcium Signaling Cardiac Cardiac Output Cell Line Cell membrane Cell model Cell physiology Cells Chemical Exposure Chemicals Complex Coupling DNA DNA Binding Data Development Dust Embryo Endocrine Endoplasmic Reticulum Environment Environmental Pollutants Exposure to Functional disorder Gene Expression Genes Genetic Transcription Goals Growth Health Heart Homeostasis Huntington Disease Hypothalamic structure In Vitro Individual Knock-out Lead Learning Ligands Light Luciferases Mediating Membrane Memory Molecular Target Monitor Movement Muscle Muscle Contraction Nervous system structure Neurons Non-Insulin-Dependent Diabetes Mellitus Organism Outcome Pain Pancreas Pathway interactions Phenotype Physiological Pituitary Gland Poison Polychlorinated Biphenyls Primary Lateral Sclerosis Process Radiolabeled Regulatory Element Reporter Research Personnel Response Elements Risk Risk Assessment Role Ryanodine Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Science Screening procedure Signal Pathway Signal Transduction Signaling Molecule Skeletal Muscle Source Speed Structure of beta Cell of islet System Testing Thyroid Gland Time Tissues Toxic effect Toxicology Triclosan Validation Water Work Zebrafish antagonist base blood glucose regulation cellular targeting consumer product cost fluorescence imaging heart function high throughput screening in vitro Assay in vivo in vivo Model neuromuscular neuronal growth neurotransmission pollutant polybrominated diphenyl ether protein phosphatase inhibitor-2 receptor response screening sensor tool toxicant transcription factor transcriptome sequencing voltage

项目摘要

Summary/Abstract Chemicals such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and triclosan alter cellular Ca2+ signaling acting through L-type voltage-sensitive Ca2+ channels (CaV1) and/or ryanodine receptors (RyR), which regulate the entry of Ca2+ from external sources or the release of Ca2+ from internal stores, respectively. These channels alone are central to the function of a vast number of cellular signaling processes and chemical disruption of these targets is correlated with altered dendritic growth, altered neuromuscular health, and altered learning and memory in exposed model organisms. The list of toxicants, and their receptor targets, that lead to such Ca2+ signaling disruption (CSD; used for disruption and disrupting) is currently unknown. However, based on structural similarities to known CSD compounds, we hypothesize that a large number of chemicals currently in use or in the environment are capable of CSD representing a need for high-throughput tools able to screen individual chemicals and complex environmental mixtures. Recent work has identified the downstream regulatory element antagonistic modulator (DREAM) which is the only Ca2+ sensor identified to date that binds speciﬁcally to DNA and regulates transcription in a Ca2+-dependent manner. Thus the DREAM protein acts as a direct connection between changes in intracellular Ca2+- and gene transcription Our preliminary work demonstrates that select CSD compounds can alter DREAM mediated transcription in model cell lines representing a unique opportunity to establish a CSD screening assay. Here, we take a multi-tiered approach to extend our understanding of DREAM, in-light-of pollutant responses, by screening known and predicted CSD chemicals for their ability to drive DREAM transcription in luciferase transfected cell lines and evaluating the extent of DREAM mediated transcription or altered phenotypes in CSD exposed wildtype and DREAM knockout zebrafish. The proposed work will establish gene transcription as a toxic outcome due to CSD and lead to the development and validation of important cellular and animal tools able to cost and time effectively evaluate large numbers of compounds for CSD activity. This work has vast implications on the health of exposed organisms as DREAM is known to contribute to such processes as learning and memory, pain reception and endocrine signaling in the hypothalamus, pituitary and the thyroid gland and has been associated with Huntington’s disease, a myotrophic lateral sclerosis and type II diabetes. Understanding the role of CSD in these physiological and pathophysiological states would aid in pollutant associated risk assessment.

摘要/文摘