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The Effect of IL-4 Receptor Singaling on Inflammation and Skin Barrier Function i

IL-4 受体信号传导对炎症和皮肤屏障功能的影响

基本信息

批准号：
7677678
负责人：
DOUGLAS A KUPERMAN
金额：
$ 4.85万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677678
关键词：
Albumins Alleles Allergens Allergic Atopic Dermatitis B-Lymphocytes Binding Breeding Bromodeoxyuridine Cell Surface Receptors Cells Chickens Clinical Research Contact Dermatitis Control Groups Defect Dermatitis Development Disease Disease model Environment Enzyme-Linked Immunosorbent Assay Epithelial Exons Failure Functional disorder Genes Genetic Hypersensitivity skin testing Ichthyosis Vulgaris IgE Immune Immune response Immunoblotting Immunohistochemistry In Vitro Indium Inflammation Inflammation Mediators Inflammatory Response Interleukin 4 Receptor Interleukin-13 Interleukin-4 Keratin Lead Ligation Lymphocyte Measurement Measures Modeling Mouse Strains Mus Mutant Strains Mice Pathologic Pathology Patients Proliferating Proteins Reagent Research Research Design Reverse Transcriptase Polymerase Chain Reaction Serum Signal Transduction Skin Staining method Stains Testing Th2 Cells Time Universities Urticaria Water atopy cell type cytokine egg filaggrin improved in vivo involucrin keratinocyte loricrin mouse model novel offspring promoter receptor recombinase response skin disorder

项目摘要

Atopic dermatitis occurs as a result of inappropriate immune responses to common elements in the environment. The T-helper type II (Th2) lymphocyte is a critical contributor to the pathologic inflammatory responses observed in these patients. For example, atopic dermatitis is characterized by increased levels of the Th2 cytokines, IL-4 and IL-13, in the skin. When keratinocytes are cultured with either IL-4 or IL-13 they respond by producing a variety of pro-inflammatory mediators and they lose expression of filaggrin as well as loricrin and involucrin, which are important proteins that maintain skin barrier function. However, there have been no studies performed to test the in vivo relevance of IL-4 and IL-13 acting directly on keratinocytes in the pathologies associated with atopic dermatitis. IL-4 and IL-13 signal by ligation of a common receptor, IL- 4Ra. Our hypothesis is that IL-4Ra signaling specifically in keratinocytes contributes to inflammation and failure of skin barrier function in a murine model of atopic dermatitis. The main objective is to determine the in vivo requirement for keratinocyte-specific expression of IL-4Ra in the development of skin pathologies associated with experimental atopic dermatitis. We will accomplish this objective by completing two specific aims. Specific Aim 1: To generate a mutant mouse strain that is deficient in IL-4Ra exclusively in keratinocytes. We will breed commercially available K14-Cre mice with our IL-4Ra flox/flox mice. The K14- Cre mice have expression of Cre-recombinase (Cre) only in keratinocytes. IL-4Ra flox/flox mice have Crebinding loxP sequences that flank exons 7 -9 of the IL-4Ra gene. When the two strains of mice are bred, the double mutant mice have expression of Cre only in keratinocytes causing keratinocyte-specific deletion of the IL-4Ra gene. Otherwise, these mice have normal IL-4 and IL-13 signaling in every other cell type. Specific Aim 2: To determine the in vivo requirement for keratinocyte-specific expression of IL-4Rct in the development of skin pathology associated with experimental atopic dermatitis. We anticipate that mice with keratinocyte-specific IL-4Ra deletion will be protected from inflammation and failure of skin barrier function as elicited in a well-characterized mouse model of atopic dermatitis.

特应性皮炎的发生是由于免疫系统对皮肤中常见成分的不适当反应