Identification of BATF2 as a Regulator of Interferon-Enhanced Inflammatory Responses in Lupus Skin

鉴定 BATF2 作为狼疮皮肤中干扰素增强炎症反应的调节剂

• 批准号: 9375222
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375222
• 关键词: Apoptotic; Binding; Biology; Cells; ChIP-seq; Cutaneous; Cutaneous Lupus Erythematosus; Data; Development; Discoid Lupus Erythematosus; Disease; Exhibits; Family; Flare; Fostering; Funding; Gene Expression Regulation; Genes; Goals; IRF1 gene; Immunoprecipitation; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interferon-alpha; Interferons; Interleukin-6; Lead; Lesion; Lupus; Mainstreaming; Mediating; Mediator of activation protein; Microscopy; Mission; Mus; Myeloid Cells; Nuclear; Organ; Pathogenesis; Patients; Phenotype; Play; Production; Public Health; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Skin; Small Interfering RNA; Stimulus; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Time; Transcription Factor AP-1; Transcriptional Regulation; Ultraviolet B Radiation; Ultraviolet Rays; United States National Institutes of Health; Up-Regulation; career; chemokine; cofactor; cytokine; disability; improved; in vivo; innovation; keratinocyte; knock-down; lupus cutaneous; novel; novel therapeutics; overexpression; prevent; response; skin disorder; therapeutic development; therapeutic target; therapy outcome; transcription factor; transcriptome sequencing

ABSTRACT/PROJECT SUMMARY Cutaneous inflammation is a prevalent and often difficult to treat manifestation of systemic lupus erythematosus (SLE) that is frequently associated with and may lead to exacerbation of systemic disease. There is a critical need to understand the mechanisms behind why SLE skin is prone to inflammation in order to improve therapies and outcomes for skin disease patients. Type I interferon (IFN) responses are elevated in cutaneous lupus erythematosus (CLE) lesions and prime keratinocytes for inflammatory responses to ultraviolet light exposure. Importantly, SLE keratinocytes display an exaggerated response to IFNα for some, but not all, type I IFN regulated genes. These SLE-IFN-skewed genes likely play a critical role in promoting the enhanced inflammatory response in SLE keratinocytes One of these SLE-IFN-skewed genes is BATF2, an understudied transcription factor that interacts with interferon regulatory factor 1 (IRF-1) to regulate inflammatory gene production. These preliminary data suggest that BATF2 may serve as an excellent target to modulate inflammatory responses in the skin and thus to prevent and treat cutaneous inflammation in SLE. We hypothesize that exaggerated inflammatory responses in SLE keratinocytes are driven through IFN- mediated hyper-upregulation of BATF2. Testing of this hypothesis through the following Aims will identify a mechanism by which IFNs promote inflammatory signaling in SLE keratinocytes and identify BATF2 as a potential therapeutic target for controlling cutaneous inflammation in SLE Aim 1: Identify BATF2 as a crucial mediator of pro-inflammatory cytokines and chemokines following type I IFN priming of keratinocytes. Aim 2: Identify the role of BATF2 in regulation of type I vs. type II IFN responses in keratinocytes and how this is regulated by IRFs. Completion of these Aims will identify BATF2 as a regulator of inflammatory responses in keratinocytes and as a target for decreasing keratinocyte-derived inflammation in lupus skin. Further, this project will compare how type I and type II IFNs, both of which are identified as important in SLE skin, induce inflammatory changes through BATF2. This information will have important implications as type I IFN-directed therapy becomes mainstream in SLE.

抽象/项目总结