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

基本信息

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
项目类别：
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

项目摘要

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，以避免哺乳动物皮肤的自身免疫激活。核酸酶充当重要的“守护者”，阻止自身核酸的先天免疫感应。哺乳动物自身免疫性皮肤病中的 RNA 酶和 RNA 降解机制尚不清楚。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，并且在初步研究中，这些患者出现了明显的头发和皮肤异常。 Skiv2l 基因敲除小鼠 (iSkiv2l-/-) 会出现严重的皮肤炎症以及快速且显着的症状。 iSkiv2l-/- 皮肤病与典型的皮炎或牛皮癣不同，因此代表一种脱发。新的自身免疫性皮肤病小鼠模型有两个具体目标：目标 1. 确定细胞类型，激活 iSkiv2l-/- 皮肤中的 IFN 信号传导所需的内源配体和先天传感途径。确定 I 型干扰素的先天免疫激活如何破坏毛囊的免疫特权研究提出。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的iSkiv2l-/-小鼠也可能有更广泛的影响。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。