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.

项目摘要 皮肤是抵御许多入侵微生物的第一道防线，不仅充当物理屏障， 作为强大的先天免疫反应的来源。为了避免皮肤中的自身免疫激活，哺乳动物 核酸酶作为重要的“监护人”，以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降解机制还不清楚。哺乳动物 胞质RNA exosome是由RNA解旋酶SKIV 2L和其他辅因子组成的多亚基复合体。 SKIV 2L功能丧失突变与人类毛肝肠综合征（THES）相关， 这些患者会出现明显的毛发和皮肤异常。在初步研究中，我们产生了一种诱导型 Skiv 2l敲除小鼠（iSkiv 2l-/-）。iSkiv 2l-/-小鼠出现严重的皮肤炎症以及快速和显著的 脱发（脱发）。iSkiv 2l-/-皮肤病与典型的皮炎或银屑病不同，因此代表了一种皮肤病。 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， 在iSkiv 2l-/-皮肤中激活IFN信号传导所需的内源性配体和先天性传感途径。目标2. 确定I型干扰素的先天免疫激活如何打破毛囊的免疫赦免。拟议的研究 这里将提供令人兴奋的机制的见解，如何失调的先天免疫反应，自我RNA， 导致皮肤炎症和毛囊免疫特权崩溃。iSkiv 2l-/-小鼠还可以具有更宽的 了解皮肤中的免疫特权和耐受性的实用性，可使其他自身免疫性皮肤受益 疾病