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.

项目概要/摘要 红斑狼疮是一种慢性、使人衰弱的自身免疫性疾病，对女性的影响尤为严重 育龄期已被发现是该人群死亡的主要原因之一。系统性的 该疾病的一种形式，系统性红斑狼疮 (SLE)，具有异质性的临床表现， 几乎影响身体所有主要器官。当有皮肤受累时，该疾病被归类为 皮肤红斑狼疮（CLE）的类别。 CLE 可以单独发生，也可以与全身系统联合发生 高达 70% 的 SLE 患者出现皮肤受累。 SLE 和 CLE 都是 其特点是对紫外线 (UV) 光的敏感性增加。紫外线可以触发皮肤和全身 疾病爆发严重降低患者的生活质量并带来沉重的经济负担。作为 驱动这些反应的机制尚不清楚，治疗选择很少，主要是预防 基于避免阳光照射和使用防晒霜。 I 型干扰素 (IFN)，通常产生的一组细胞因子 作为对病毒感染的反应，在狼疮患者中长期过度表达，其循环水平与 伴有皮肤疾病活动。 I 型干扰素调节多个基因的表达，这些基因可能在 光敏性，包括促凋亡 Xaf1 和促进自然杀伤 (NK) 细胞募集的趋化因子 和激活。 Kahlenberg 实验室此前观察到，I 型干扰素 (IFN) 在 系统性红斑狼疮 (SLE) 角质形成细胞 (KC) 的基线，并在紫外线照射后促进细胞死亡。但具体途径 受 I 型 IFN 调节而增强 UV 驱动的 KC 死亡的机制尚不清楚。该提案将检验假设 狼疮皮肤中 I 型干扰素的长期过度表达会促使角质形成细胞增加 UVB 诱导的影响 通过上调 XAF1 表达并增强招募和激活外源性细胞凋亡 细胞毒性 NK 细胞。该假设将通过三个具体目标进行检验：（1）检查外在因素的激活 与 UVB 暴露后 I 型 IFN 引发的皮肤中的内在细胞凋亡相比，(2) 确定 XAF1 在类型中的作用 I IFN 驱动的 KC 凋亡，以及 (3) 鉴定 NK 细胞在 I 型 IFN 驱动的 KC 凋亡中的作用。为了完成 这些具体目标，人类细胞系和基因工程小鼠模型将用于在体外进行 和体内实验研究暴露于 I 型 IFN 引发的 KC 的细胞信号传导和遗传调控 紫外线并确定其如何影响招募到皮肤中的 NK 细胞。这些结果 研究将确定 I 型干扰素过量产生对狼疮皮肤光敏性的影响 未来的总体目标是为患有疾病的患者确定新的治疗方案目标 太阳。该项目将成为申请人进一步扩展其核心技能的重要机制 实验设计和数据分析、专业发展和科学交流。充足的 密歇根大学的可用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。