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Redox Regulation of Intracellular Calcium Signaling

细胞内钙信号传导的氧化还原调节

基本信息

批准号：
9022475
负责人：
Gyorgy Hajnoczky
金额：
$ 35.1万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022475
关键词：
Address Affect Agonist Apoptosis Binding Biochemical Biological Assay C-terminal Calcium Calcium Signaling Cardiovascular Diseases Cell Death Cell Fractionation Cell physiology Cells Cellular Stress Collaborations Cysteine Data Diabetes Mellitus Disease Drug or chemical Tissue Distribution Endoplasmic Reticulum Experimental Models Fluorescence Frequencies Fructose Gene Expression Goals Health Heart Diseases Homo ITPR1 gene Image Inositol Ion Channel Life Ligand Binding Domain Ligands Liver Location Malignant Neoplasms Maps Mass Spectrum Analysis Measurement Measures Mediating Membrane Metabolism Methods Mitochondria Modeling Modification Molecular Mutate N-terminal NADPH Oxidase Neurodegenerative Disorders Neurotransmitters Oxidants Oxidation-Reduction Oxidative Stress Pathway interactions Play Production Property Protein Isoforms Proteins Proteome Regulation Role Signal Transduction Sirolimus Somatotropin Source Stress Sulfhydryl Compounds System Tacrolimus Binding Proteins Testing Tissues Transmembrane Domain Work base catalase cell motility design endoplasmic reticulum stress imaging modality in vivo mutant novel novel therapeutic intervention palmitoylation receptor response

项目摘要

DESCRIPTION (provided by applicant): An elevation of cytosolic free calcium concentration is an integral component of the mechanism by which cells respond to hormones, growth factors and neurotransmitters. D-myo-inositol 1,4,5-trisphosphate ( IP3 ) is an intracellular messenger mediating the mobilization of Ca2+ from intracellular stores by interaction with an ubiquitous receptor ( IP3R ) that acts as a ligand-gated Ca2+ channel. IP3Rs are redox sensitive channels and are sensitized by oxidative stress. However, the molecular basis of this regulation is poorly understood. Ca2+ released from IP3Rs is locally transmitted to the mitochondria and can stimulate metabolism, and in higher amounts, can also initiate cell death. The overarching hypothesis of this study is that redox modulation of IP3Rs is an important component of the regulation of Ca2+ signals in cell death pathways. The proposal encompasses the following three specific aims: 1] To measure and map redox changes in IP3Rs. We have developed methods to determine the redox state of IP3Rs in vivo which will be used to quantitate the effects of exogenous and endogenous agents causing oxidative stress. Preliminary studies using mass-spectroscopy identify a subset of 11 cysteines that become oxidized in IP3R-1. The type of oxidative modifications occurring will be identified. Redox-sensitive thiols will be mutate and the functional sensitivity to oxidative stress will be assessed. 2] To measure IP3R redox state at the ER/mitochondrial junction. We will test the hypothesis that the pool of IP3Rs located at the ER/mito junction is particularly prone to ROS modifications. We will employ subcellular fractionation and imaging methods utilizing targeted IP3Rs, ROS-sensitive fluorescent proteins, ROS-producing photosensitive probes and targeted catalases. 3] To investigate the role of IP3R redox changes in models of ER stress/apoptosis. We will test the hypothesis that ER-resident NADPH oxidases play an important role in IP3R redox regulation. Liver will be used as an experimental model to induce ER stress. The role of IP3R redox regulation in ER stress pathways activated by fructose will be examined. The long-term goal of the proposal is to obtain a detailed understanding of how oxidative stress impacts intracellular Ca2+ signaling under normal and disease conditions.