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Epigenetic regulation of proinflammatory responses in the skin

皮肤促炎症反应的表观遗传调控

基本信息

批准号：
9313788
负责人：
KATIA GEORGOPOULOS
金额：
$ 36.29万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-11 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313788
关键词：
Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigens Biology Cells Chromatin DNA Binding Data Defect Disease Environment Environmental Monitoring Epidermis Epigenetic Process Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Homeostasis Human Immune Immune system In Vitro Inflammatory Inflammatory Response Maintenance Mechanics Molecular Mus Nucleic Acid Regulatory Sequences Outcome Study Pathway interactions Physiological Process Recruitment Activity Regulation Regulator Genes Regulatory Element Regulatory T-Lymphocyte Repression Role Signal Pathway Signal Transduction Skin Stress Structure TSLP gene Testing Therapeutic Intervention Time Transcriptional Regulation Translations Up-Regulation Work arm base biological adaptation to stress chemokine cytokine design effective therapy epigenetic regulation gene repression genome-wide genome-wide analysis immune activation in vivo insight keratinocyte leukemia novel novel therapeutic intervention prevent repaired response skin barrier skin disorder transcription factor

项目摘要

ABSTRACT We have shown that loss of the chromatin remodeler Mi-2β in the basal epidermis causes rapid up-regulation of pro-inflammatory and stress response genes in the absence of any overt environmental signals or a skin barrier defect. These data support the hypothesis that immune cell regulatory genes, normally induced in the epidermis by environmental insults, are directly and actively repressed by chromatin regulators, under conditions of epidermal homeostasis. We now propose to study the chromatin-based mechanisms by which immune-regulatory genes are kept poised for expression in keratinocytes and to determine how activation of signaling pathways by mechanical or environmental insult reverses these mechanisms. In the first aim, we will establish the “anti-inflammatory” chromatin landscape and transcription factor network that control keratinocyte homeostasis. Genome-wide approaches will be used in keratinocytes to establish the gene networks that are directly and functionally controlled by Mi-2β. The types of regulatory elements that Mi-2β associates with, and the chromatin configuration that they are in will be established. The sequence- specific DNA binding factors that functionally interact in a synergistic or antagonistic fashion with Mi-2β will be identified. Finally, the repertoire of chromatin regulators and transcription factors involved in pro-inflammatory gene regulation in a Mi-2β−independent fashion will be also established. In the second aim, we will determine how environmental signals induce pro- inflammatory gene expression in keratinocytes. The effect of environmental signals on altering the activity of both chromatin regulators and transcription factors will be studied. We will first examine the cause-effect relationship between Mi-2β and the epigenetic and transcription factor makeup at the regulatory domains of its target genes. We will then test how environmental signals induce pro-inflammatory genes by altering the activities of Mi- 2β and associated chromatin regulators and transcription factors. The role of key regulatory candidates in this molecular process will be further evaluated by genetic interference studies in mouse and human keratinocytes. The outcome of these studies will allow us to probe into conserved mechanisms that contribute to human skin disease with a pro-inflammatory basis and provide new avenues for therapeutic intervention.

摘要