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: 10254276
• 负责人: Shannon Loftus
• 金额: $ 3.84万
• 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/10254276
• 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 红斑狼疮是一种慢性、衰弱的自身免疫性疾病，对 育龄，已被发现是导致该人群死亡的主要原因之一。系统性的 这种疾病的形式是系统性红斑狼疮(SLE)，具有不同的临床表现，可以 几乎影响到身体的所有主要器官。当有皮肤受累时，疾病被归类为 皮肤红斑狼疮(CLE)的分类。CLE可以单独发生，也可以与全身性 高达70%的系统性红斑狼疮患者皮肤受累。SLE和CLE都是 具有对紫外线(UV)光的敏感度增加的特点。紫外线会引发皮肤和全身 严重降低患者生活质量并带来重大经济负担的疾病爆发。作为 驱动这些反应的机制尚不清楚，在很大程度上存在预防的治疗选择 基于防晒和防晒霜的使用。I型干扰素(IFN)，一组通常产生的细胞因子 作为对病毒感染的反应，在狼疮患者中慢性过度表达，与循环水平相关 有皮肤病活跃性。I型干扰素调节几个基因的表达，这些基因可能在 促进自然杀伤(NK)细胞募集的光敏性，包括促凋亡的Xaf1和趋化因子 和激活。Kahlenberg实验室之前观察到，I型干扰素(IFN)在 在紫外线照射后，红斑狼疮角质形成细胞(KCs)的基线和促进细胞死亡。然而，具体的路径是 由I型IFN调控的增强紫外线驱动的KC死亡的IFN尚不清楚。这项提议将检验这一假设 中波紫外线诱导狼疮皮肤初级角质形成细胞中I型干扰素的慢性过表达 上调XAF1表达促进细胞募集和激活的外源性细胞凋亡 细胞毒NK细胞。这一假说将通过三个具体的目的来检验：(1)检验外在因素的激活 中波紫外线照射后I型干扰素诱导皮肤的内源性细胞凋亡的比较，(2)确定XAF1在类型中的作用 I-干扰素诱导的KC凋亡；(3)NK细胞在I型干扰素诱导的KC凋亡中的作用。要完成 这些特定的目标、人类细胞系和基因工程小鼠模型将用于体外实验 以及体内实验，研究暴露于I型干扰素诱导的KCs的细胞信号和遗传调控 并确定这如何影响被招募到皮肤中的NK细胞。这些研究的结果 研究将确定狼疮皮肤中I型干扰素过度产生的影响与光敏性 未来的总体目标是为疾病由疾病突发的患者确定新治疗选择的目标 太阳。该项目将成为申请人进一步拓展其核心技能的重要机制。 在实验设计和数据分析、专业发展和科学交流方面。充裕的 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。