Determining the role of type I interferons in ultraviolet-B light induced keratinocyte death

确定 I 型干扰素在紫外线 B 光诱导的角质形成细胞死亡中的作用

• 批准号: 10456175
• 负责人: Shannon Loftus
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456175
• 关键词: Address; Affect; Apoptosis; Apoptotic; Autoimmune Diseases; Automobile Driving; CASP8 gene; CRISPR/Cas technology; CXCL10 gene; CXCL11 gene; Caspase; Caspase Inhibitor; Categories; Cause of Death; Cell Death; Cell Proliferation; Cells; Cessation of life; Chronic; Clinical; Communication; Cutaneous; Cutaneous Involvement; Cutaneous Lupus Erythematosus; Data; Data Analyses; Development; Disease; Economic Burden; Ensure; Experimental Designs; Exposure to; Female of child bearing age; Flare; Future; Generations; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Human Cell Line; IRF1 gene; Immune system; In Vitro; Inflammation; Inflammatory; Interferon Type I; Interferon-alpha; Interferons; Interleukin-15; Knock-out; Knowledge; Laboratories; Lead; Lesion; Light; Link; Lupus; Lupus Erythematosus; Measures; Mediating; Mentors; Michigan; Mutate; Natural Killer Cell toxicity; Natural Killer Cells; Organ; Pain; Pathogenesis; Pathway interactions; Patients; Photosensitivity; Play; Population; Prevention; Production; Quality of life; Reactive Oxygen Species; Regulation; Research; Research Training; Resources; Role; Signal Transduction; Skin; Small Interfering RNA; Stress; Sunlight; Sunscreening Agents; Systemic Lupus Erythematosus; Systemic disease; Testing; The Sun; UV Radiation Exposure; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Universities; Up-Regulation; Virus Diseases; Work; XAF1 gene; base; cell killing; cell motility; chemokine; cytokine; cytotoxic; cytotoxicity; experience; experimental study; in vivo; irradiation; keratinocyte; knock-down; lupus cutaneous; novel therapeutics; overexpression; prevent; pro-apoptotic protein; recruit; response; skills; skin disorder; therapeutic target; transcription factor; tumorigenesis; ultraviolet; x-linked inhibitor of apoptosis protein

PROJECT SUMMARY/ABSTRACT Lupus erythematosus is a chronic, debilitating autoimmune disease that disproportionately affects women of childbearing age and has been found to be among the leadings causes of death in this population. The systemic form of the disease, systemic lupus erythematosus (SLE), has heterogeneous clinical manifestations that can affect nearly all major organs of the body. When there is skin involvement, the disease is grouped under the category of cutaneous lupus erythematosus (CLE). CLE can occur on its own or in combination with systemic disease with up to 70% of SLE patients experiencing cutaneous involvement. Both SLE and CLE are characterized by increased sensitivity to ultraviolet (UV) light. UV light can trigger cutaneous and systemic disease flares that severely diminish patient quality of life and carry significant economic burdens. As the mechanisms driving these responses are not understood, few treatment options exist with prevention largely based on sun avoidance and sunscreen use. Type I interferons (IFNs), a group of cytokines generally produced in response to viral infection, are chronically overexpressed in lupus patients with circulating levels correlating with cutaneous disease activity. Type I IFNs regulate expression of several genes that may play a role in photosensitivity including pro-apoptotic Xaf1 and chemokines that promote natural killer (NK) cell recruitment and activation. The Kahlenberg laboratory previously observed that type I interferons (IFNs) are increased at baseline in SLE keratinocytes (KCs) and promote cell death after UV exposure. However, the specific pathways regulated by type I IFNs that enhance UV-driven KC death are not known. This proposal will test the hypothesis that chronic overexpression of type I IFNs in lupus skin primes keratinocytes for increased UVB-induced extrinsic apoptosis through upregulated XAF1 expression and enhanced recruitment and activation of cytotoxic NK cells. This hypothesis will be tested through three specific aims: (1) Examine activation of extrinsic vs. intrinsic apoptosis in type I IFN-primed skin following UVB exposure, (2) Determine the role of XAF1 in type I IFN-driven KC apoptosis, and (3) Identify the role of NK cells in type I IFN-driven KC apoptosis. To accomplish these specific aims, human cell lines and genetically engineered mouse models will be used to perform in vitro and in vivo experiments investigating cell signaling and genetic regulation of type I IFN-primed KCs exposed to UV light and to determine how this influences NK cells that are recruited into the skin. The results from these studies will establish the impacts of type I IFN overproduction in lupus skin in the context of photosensitivity with the overall future goal of identifying targets for new treatment options for patients whose disease is flared by the sun. This project will serve as a crucial mechanism through which the applicant will further expand her core skills in experimental design and data analysis, professional development, and scientific communication. The ample resources available at the University of Michigan together with experienced mentors and collaborators will ensure the applicant is able to successfully complete the proposed research and training plans.

项目摘要/摘要 红斑狼疮是一种长期衰弱的自身免疫性疾病，对女性的疾病不成比例 育龄，已被发现是该人群死亡原因之一。系统性 疾病的形式，全身性红斑狼疮（SLE）具有异质临床表现 影响身体的几乎所有主要器官。当皮肤受累时，该疾病将在 皮肤红斑狼疮的类别（CLE）。 CLE可以独立发生，也可以与全身性结合 多达70％的SLE患者患有皮肤性参与的疾病。 SLE和CLE都是 其特征是对紫外线（UV）光的敏感性提高。紫外线会触发皮肤和全身性 疾病会严重降低患者生活质量并带来巨大的经济负担。作为 尚不了解推动这些反应的机制，预防几乎没有治疗选择 根据避免太阳和防晒霜的使用。 I型干扰素（IFN），一组细胞因子通常产生 响应病毒感染，在循环水平相关的狼疮患者中长期表达 具有皮肤疾病活性。 I型IFN调节了几种可能在 光敏性包括促凋亡XAF1和趋化自然杀手（NK）细胞募集的趋化因子 和激活。 Kahlenberg实验室先前观察到I型干扰素（IFN）在 SLE角质形成细胞（KC）中的基线并促进紫外线暴露后的细胞死亡。但是，特定途径 未知由I型IFN调节，从而增强UV驱动的KC死亡。该建议将检验假设 狼疮皮肤素中I型IFN的慢性过表达，可增加UVB诱导的 通过上调XAF1表达和增强募集和激活的外在凋亡 细胞毒性NK细胞。该假设将通过三个特定目的进行检验：（1）检查外部的激活 在UVB暴露后，I型IFN引发皮肤的内在凋亡与内在凋亡，（2）确定XAF1在类型中的作用 I IFN驱动的KC凋亡，（3）确定NK细胞在I型IFN驱动的KC凋亡中的作用。完成 这些特定目的，人类细胞系和基因工程的小鼠模型将用于体外执行 并进行了研究细胞信号传导和I型IFN染色的KC的遗传调节的实验 紫外线光，并确定这如何影响募集到皮肤的NK细胞。这些结果 研究将在光敏性的背景下建立I型IFN型狼疮皮肤过量产生的影响 确定针对疾病爆发的患者的新治疗选择目标的总体未来目标 太阳。该项目将成为一种至关重要的机制，申请人将进一步扩大她的核心技能 在实验设计和数据分析，专业发展和科学沟通中。足够的 密歇根大学提供的资源以及经验丰富的导师和合作者将确保 申请人能够成功完成拟议的研究和培训计划。

项目成果

IFN-κ Is a Rheostat for Development of Psoriasiform Inflammation.

• DOI: 10.1016/j.jid.2021.05.029
• 发表时间: 2022-01
• 期刊: The Journal of investigative dermatology
• 作者: Gharaee-Kermani M;Estadt SN;Tsoi LC;Wolf-Fortune SJ;Liu J;Xing X;Theros J;Reed TJ;Lowe L;Gruszka D;Ward NL;Gudjonsson JE;Kahlenberg JM
• 通讯作者: Kahlenberg JM