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The Role of Ca-dependent Transcription Factor NFAT in Pain Control

Ca 依赖性转录因子 NFAT 在疼痛控制中的作用

基本信息

批准号：
9064863
负责人：
Yuriy M Usachev
金额：
$ 19.05万
依托单位：
UNIVERSITY OF IOWA
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：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064863
关键词：
Action Potentials Afferent Neurons Applications Grants Binding Biological Assay Bradykinin Brain-Derived Neurotrophic Factor Calcineurin Calcitonin Gene-Related Peptide Capsaicin Cell Nucleus Cells Coupling Data Development Freund&apos s Adjuvant Gene Expression Gene Expression Regulation Genes Genetic Transcription Hypersensitivity Immune Immunoassay Inflammation Injection of therapeutic agent Injury Interleukin-6 Ion Channel Knock-out Knockout Mice Label Lead Luciferases Maintenance Mechanics Mediating Modeling Monitor Muscle Cells Mutate Neuromodulator Receptors Neurons Nociception Nociceptors Nuclear Localization Signal Operative Surgical Procedures PTGS2 gene Pain Pain management Pathogenesis Persistent pain Play Process Protein Dephosphorylation Protein Isoforms Protein phosphatase Public Health Regulation Reporter Reporter Genes Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Spinal Ganglia Surgical incisions T-Cell Activation TRPV1 gene Testing Tissues Transcription Initiation Trauma Western Blotting Work base cell type chemokine receptor chronic pain inflammatory neuropathic pain nerve injury novel therapeutic intervention nuclear factors of activated T-cells patch clamp prevent receptor response spared nerve transcription factor transcription factor NF-AT c3 voltage

项目摘要

DESCRIPTION (provided by applicant): Activity-dependent changes in gene expression in nociceptors play a crucial role in the pathogenesis of pain. These changes are triggered by increased electrical activity following tissue or nerve injury, or inflammation. Dozens of genes associated with the development of persistent pain have been identified (e.g., ion channels, receptors and neuromodulators). Pharmacological targeting of the expression of groups of genes that depend on common transcription factors may allow preventing the development or maintenance of chronic pain states. Yet, the specific mechanisms and transcription factors responsible for activity-dependent gene regulation in nociceptors are largely unknown. Ca2+ and Ca2+-dependent transcription factors play key roles in excitation- transcription coupling in neurons. Here, we focus on the Ca2+-dependent transcription factor NFAT as an attractive candidate for regulating gene expression in nociceptors for the following reasons. First, four NFAT isoforms (NFATc1-c4; NFATc3 being the predominant) are expressed in DRG neurons and regulated by action potentials and pain producing compounds such as capsaicin, bradykinin and NGF. Second, NFAT is highly sensitive to [Ca2+]i elevations in DRG neurons (activation trheshold~300 nM) mediated by Ca2+ entry via voltage-gated Ca2+ channels and TRPV1 receptors. Third, NFAT regulates the expression of a number of genes implicated in pain, such as COX-2, BDNF, GluA2, IL-6, chemokine receptor CCR2, and based on our pilot data, CGRP and voltage-gated Na+ channel Nav1.7. Fourth, our preliminary studies using NFATc3 KO mice indicate that NFATc3 contributes to inflammation-induced pain sensitization. Collectively, these observations suggest that NFAT plays an important role in pain control. However the roles of specific NFAT isoforms in this process and the underlying mechanisms are not known. We hypothesize that NFATc3 plays a critical role in activity-dependent gene regulation in DRG neurons, which contributes to inflammation- and injury-induced nociceptor sensitization and to the pathogenesis of inflammatory and neuropathic pain. This hypothesis will be tested in two specific aims. In Aim 1, we will examine the functional significance of NFATc3 in pain hypersensitivity following inflammation, tissue and nerve injury by comparing thermal and mechanical sensitization in WT and NFATc3 KO (complete and sensory-neuron-specific KO) mice using models of persistent pain produced by inflammation (intraplantar complete Freund's adjuvant/CFA), tissue injury (postincisional pain) and nerve injury (spared nerve injury/SNI), respectively. In Aim 2, we will establish the role of NFATc3 in regulating the expression of two important molecules implicated in pain, CGRP and Nav1.7, by testing the effects of depolarization on the expression of CGRP and Nav1.7 in DRG neurons from WT and NFATc3 KO mice. These studies will advance our understanding of the mechanisms that control activity- dependent gene regulation in nociceptors and pain sensitization, and are expected to lead to the development of new strategies for alleviating pain by targeting specific NFAT isoforms and their regulatory mechanisms. RELEVANCE: Pain management remains one of the most serious public health problems. The proposed studies will help to better understand how the activity-dependent gene regulation in primary nociceptors, and specifically, the Ca2+ -dependent transcription factor NFAT, contribute to the pathogenesis of pain caused by surgical trauma, inflammation or nerve injury, and may lead to the development of new therapeutic strategies targeting NFAT and the associated signaling mechanisms to alleviate pain.