A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin

α-T-连环蛋白突变患者的一种新型自身炎症性皮肤病

基本信息

批准号：
10055124
负责人：
Bryce Binstadt
金额：
$ 23.68万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055124
关键词：
10 year old Actin-Binding Protein Actins Affect Affinity Anatomy Architecture Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Bacteria Binding Proteins Biochemistry Biological Process Biology Biopsy Specimen Blood CRISPR/Cas technology Cadherins Cell Line Cell-Cell Adhesion Cells Child Complex Cultured Cells Cytoskeleton Data Disease Environment Eye Eyelid structure Fever Functional disorder Gene Expression Genes Genetic Gland Growth Hair follicle structure Heart Heart Diseases Hereditary Disease Homodimerization Host Defense Human Hyperkeratosis Immune Immune system Immunity Immunologics Impairment Infection prevention Inflammation Inflammatory Intercalated disc Interferon Type I Interferons Knowledge Lead Life Ligands Link Lipids Maps Measures Mediating Missense Mutation Mucous Membrane Mus Mutagenesis Mutation Nonsense Codon Nutrient Ocular Pathology Organ Organism Patients Pattern Phenotype Production Proteins Recombinants Recording of previous events Recurrence Reporter Reporting Sebaceous Glands Sebum Site Skin Skin colonization Sterility Structure System Testing Tissues Up-Regulation Viral alpha catenin alphaT catenin antimicrobial peptide appendage autoinflammatory beta catenin boys chemokine cohesion commensal microbes cytokine genetic signature human disease immunomodulatory therapies improved in vitro testing insight keratinocyte link protein meibomian gland dysfunction metagenomic sequencing mutant novel pathogen premature protein function skin barrier skin disorder skin microbiome skin microbiota stem three dimensional cell culture

项目摘要

Abstract Inborn errors of immunity comprise over 300 distinct disorders. Among these are an expanding number of monogenic auto-inflammatory disorders, characterized by sterile inflammation systemically or in specific organs. This proposal stems from the identification of a child who appears to have a novel autoinflammatory disease characterized by inflammatory skin disease and associated with increased type I interferon production but without recurrent fever. This patient has compound heterozygous mutations in the gene encoding αT- catenin: CTNNA3. The α-catenins are actin-binding proteins that interact with cadherins to mediate cell-cell adhesion and tissue organization. Different mutations in CTNNA3 are linked with a specific cardiac disease in humans, arrhythmogenic right ventricular dysplasia, but this child does not have cardiac disease. Importantly, there are no prior associations of mutations in CTNNA3 with inflammatory skin disease. Here we seek to understand how this patient’s mutant αT-catenin drives skin inflammation and increased type I interferon production. Our preliminary data demonstrate that αT-catenin is highly expressed in sebaceous glands in healthy human skin. The skin serves as a barrier between an organism and the surrounding environment. Hair follicles breach this anatomic barrier and provide a potential portal of entry for pathogens; they are thus a site of much immunologic activity. Anatomically associated with hair follicles, sebaceous glands secrete lipids that contribute to skin barrier function and serve as nutrients for commensal microbiota. Sebaceous glands also produce antimicrobial peptides, cytokines, and chemokines to modulate skin immunity. Mice lacking sebaceous glands develop a phenotype similar to this patient. The central hypothesis of this proposal is that αT-catenin is critical for normal sebaceous gland function. Further, we propose that this patient’s CTNNA3 mutations disrupt αT-catenin function, altering sebaceous gland activity and culminating in inflammatory skin disease. We will first determine how this patient’s CTNNA3 mutations affect the fundamental biology of αT- catenin, its association with binding proteins, and its subcellular localization. Next we will characterize how the mutant αT-catenin affects sebaceous gland structure and function, using a combination of patient skin biopsy samples and cultured human sebaceous gland cells (sebocytes). Finally, we will test the hypothesis that the increased type I interferon signature in this patient stems either from a direct effect on skin cells or indirectly through effects of altered sebaceous gland activity on the skin flora. The proposed studies will allow us to characterize a novel autoinflammatory skin disease and the first human disease associated with reduced sebaceous gland function; they may also provide insight to improve treatment of this patient’s skin disease. Additionally, we will gain new knowledge of how the skin and its appendages (e.g. sebaceous glands) interface with the environment, the immune system, and commensals to provide sophisticated barrier immunity.

抽象的先生的免疫力损失超过300种不同的疾病。其中有一个不断扩大的单基自发炎症性疾病，以无菌炎症为特征器官。该提议源于对似乎有新型自身炎症的孩子的识别以炎症性皮肤疾病为特征，与I型干扰素产生增加有关但是没有复发性发烧。该患者在编码αT-的基因中具有复合的杂合突变 Catenin：CTNNA3。 α-catenin是肌动蛋白结合蛋白，与钙粘着蛋白相互作用以介导细胞细胞粘附和组织组织。 CTNNA3中的不同突变与特定心脏病有关人类，心律不齐的右心室发育不良，但这个孩子没有心脏疾病。重要的是， CTNNA3中没有事先与炎症性皮肤疾病有关。我们在这里寻求了解该患者的突变体αT-catenin如何驱动皮肤感染并增加I型干扰素生产。我们的初步数据表明，αT-catenin在皮脂手套中高度表达健康的人类皮肤。皮肤是生物体和周围环境之间的障碍。头发 Follices违反了此解剖障碍，并为病原体提供了潜在的入口门户；因此他们是一个网站许多免疫学活动。与毛发相关的解剖学，皮脂手套分泌脂质有助于皮肤屏障功能，并充当共生微生物群的营养。皮脂腺也是如此产生抗菌胡椒，细胞因子和趋化因子来调节皮肤免疫。小鼠缺乏皮脂腺发展出类似于该患者的表型。该提议的核心假设是 αT-catenin对于正常皮脂腺功能至关重要。此外，我们建议该患者的CTNNA3 突变破坏αT-catenin功能，改变皮脂腺活性并在炎症皮肤中达到顶点疾病。我们将首先确定该患者的CTNNA3突变如何影响αT-的基本生物学 Catenin，与结合蛋白的关联及其亚细胞定位。接下来我们将表征突变αT-catenin使用患者皮肤活检的组合影响皮脂腺结构和功能样品和培养的人皮脂腺细胞（皮脂细胞）。最后，我们将检验以下假设该患者中I型干扰素签名的增加是由于对皮肤细胞的直接影响或间接影响皮脂腺活性改变对皮肤菌群的影响。拟议的研究将使我们能够特征是一种新型自身炎性皮肤疾病和与减少有关的第一种人类疾病皮脂腺功能；他们还可以提供有关改善该患者皮肤疾病的治疗的见解。此外，我们将获得有关皮肤及其附属物（例如皮脂腺）界面的新知识与环境，免疫系统和共同体一起提供复杂的屏障免疫。