Mammalian RNA Exosome in Maintaining Skin Homeostasis and Hair Follicle Immune Privilege

哺乳动物 RNA 外泌体维持皮肤稳态和毛囊免疫特权

• 批准号: 10205886
• 负责人: Nan Yan
• 金额: $ 39.69万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205886
• 关键词: Adoptive Transfer; Affect; Alopecia; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Binding; Biochemical; Biological Assay; Biology; Cafe-au-Lait Spot; Cells; Child; Clinical; Complex; DNA; Deoxyribonucleases; Dermatitis; Discrimination; Disease; Enteral; Enzymes; Exonuclease; Exploratory/Developmental Grant; Genes; Hair; Hair follicle structure; Homeostasis; Human; Immune; Immune signaling; Immunity; Immunologic Receptors; Immunoprecipitation; In Vitro; Individual; Infection; Inflammation; Inherited; Innate Immune Response; Interferons; Invaded; Knockout Mice; Lead; Ligands; Lymphatic; Microbe; Molecular; Monitor; Mus; Mutation; Names; Nature; Nucleic Acids; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Population; Psoriasis; RNA; RNA Binding; RNA Degradation; RNA Helicase; Research; Ribonucleases; Role; SKIV2L gene; Secondary to; Signal Pathway; Signal Transduction; Skin; Skin Abnormalities; Source; Structure; Syndrome; Tamoxifen; Tissues; WD Repeat; cell type; cofactor; cytotoxicity; exosome; immune activation; immunogenic; in vivo; innate immune sensing; insight; loss of function mutation; mouse model; next generation sequencing; nuclease; prevent; response; scaffold; sensor; skin disorder; therapeutic development

Project Summary Skin is the first line of defense against many invading microbes, not only acting as a physical barrier, but also acting as a source of powerful innate immune response. To avoid autoimmune activation in the skin, mammalian nucleases act as important ‘guardians’ to prevent innate immune sensing of self-nucleic acids. The role of RNases and RNA degradation machineries in autoimmune skin disease is not well understood. The mammalian cytoplasmic RNA exosome is a multi-subunits complex consists of RNA helicase SKIV2L and other cofactors. SKIV2L lost-of-function mutations are associated with Tricho-hepato-enteric Syndrome (THES) in humans, and THES patients develop remarkable hair and skin abnormalities. In preliminary studies, we generated an inducible Skiv2l knockout mice (iSkiv2l-/-). iSkiv2l-/- mice develop severe skin inflammation as well as rapid and phenomenal hair loss (alopecia). The iSkiv2l-/- skin disease is distinct from typical dermatitis or psoriasis, thus representing a new autoimmune skin disease mouse model. We have two specific aims: Aim 1. Determine the cell type, endogenous ligand and innate sensing pathway required for activating IFN signaling in iSkiv2l-/- skin. Aim 2. Determine how innate immune activation of type I IFN breaks immune privilege of hair follicles. Studies proposed here will provide exciting mechanistic insights in how dysregulated innate immune response to self-RNA could lead to skin inflammation and hair follicle immune privilege collapse. The iSkiv2l-/- mouse may also have broader utility in understanding immune privilege and tolerance in the skin that could benefit other autoimmune skin diseases.

项目概要 皮肤是抵御许多入侵微生物的第一道防线，不仅起到物理屏障的作用，而且 作为强大的先天免疫反应的来源。为了避免皮肤的自身免疫激活，哺乳动物 核酸酶充当重要的“守护者”，防止自身核酸的先天免疫感应。的作用 自身免疫性皮肤病中的 RNA 酶和 RNA 降解机制尚不清楚。哺乳动物 细胞质RNA外泌体是由RNA解旋酶SKIV2L和其他辅助因子组成的多亚基复合物。 SKIV2L 功能丧失突变与人类毛肝肠综合征 (THES) 相关，并且 这些患者出现明显的头发和皮肤异常。在初步研究中，我们产生了一种诱导型 Skiv2l 基因敲除小鼠 (iSkiv2l-/-)。 iSkiv2l-/- 小鼠出现严重的皮肤炎症以及快速且惊人的症状 脱发（脱发）。 iSkiv2l-/- 皮肤病与典型的皮炎或牛皮癣不同，因此代表一种 新的自身免疫性皮肤病小鼠模型。我们有两个具体目标： 目标 1. 确定细胞类型， 激活 iSkiv2l-/- 皮肤中 IFN 信号传导所需的内源配体和先天传感途径。目标2。 确定 I 型 IFN 的先天免疫激活如何破坏毛囊的免疫特权。提出的研究 这里将提供令人兴奋的机制见解，说明对自身 RNA 的先天免疫反应失调如何可能 导致皮肤炎症和毛囊免疫特权崩溃。 iSkiv2l-/- 鼠标也可能具有更广泛的 有助于了解皮肤的免疫特权和耐受性，这可能有益于其他自身免疫性皮肤 疾病。