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.

项目摘要皮肤是针对许多入侵微生物的第一道防线，不仅是物理障碍，而且还充当充当强大的先天免疫响应的来源。为了避免皮肤中自身免疫性激活，哺乳动物核酸酶是防止自我核酸的先天免疫传感的重要“监护人”。的作用自身免疫性皮肤疾病中的RNass和RNA降解机尚不清楚。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纯子复合体。 SKIV2L失去功能的突变与人类的毛 - 霍帕托 - 结构综合征（THES）有关，并且这些患者会出现明显的头发和皮肤异常。在初步研究中，我们产生了一个可诱导的 SKIV2L敲除小鼠（ISKIV2L - / - ）。 ISKIV2L - / - 小鼠出现严重的皮肤感染以及快速和惊人的脱发（脱发）。 ISKIV2L - / - 皮肤病与典型的皮炎或牛皮癣不同，因此代表新的自身免疫性皮肤病小鼠模型。我们有两个具体的目标：目标1。确定单元格类型，在ISKIV2L - / - 皮肤中激活IFN信号所需的内源配体和先天灵敏度途径。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。研究提出这里将提供令人兴奋的机械见解，即对自我RNA的先天免疫反应如何导致皮肤感染和毛囊免疫特权崩溃。 ISKIV2L - / - 鼠标也可能具有更宽的理解皮肤中免疫特权和耐受性的实用性可能使其他自身免疫性皮肤受益疾病。