Epithelial Genes in Allergic Inflammation

过敏性炎症中的上皮基因

• 批准号: 9304955
• 负责人: Gurjit K. Khurana Hershey
• 金额: $ 137.63万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304955
• 关键词: Adhesions; Adhesives; Administrative Supplement; Affect; Allergic inflammation; Allergic rhinitis; Antibiotic Resistance; Asthma; Atopic Dermatitis; Bacteria; Behavior; Biochemical; Cell Wall; Cells; Characteristics; Child; Childhood Asthma; Chronic; Clinical; Code; Collection; Crystallization; DNA; Data; Dermatologic; Dermatology; Desmosomes; Disease; Dominant-Negative Mutation; Duct (organ) structure; Epidermis; Epithelial; Equilibrium; Event; Exhibits; Filament; Food Hypersensitivity; Fostering; Functional disorder; Genes; Genus staphylococcus; Gills; Growth; Human; Image; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Ions; Journals; Knock-out; Lesion; Link; Measures; Mediating; Membrane Proteins; Metals; Methods; Microbial Biofilms; Molecular; Nature; Nose; Pathogenesis; Patients; Peptide Hydrolases; Polysaccharides; Prevalence; Process; Protease Inhibitor; Proteins; Pruritus; PubMed; Recombinants; Relapse; Risk; Role; Sampling; Severities; Skin; Staphylococcus aureus; Staphylococcus epidermidis; Statistical Data Interpretation; Structure; Surface; Surveys; Sweat; Symbiosis; TLR2 gene; Taiwan; Testing; Thermodynamics; Toxin; Translational Research; Variant; Zinc; allergic response; antimicrobial; antimicrobial peptide; base; cohort; commensal microbes; cytokine; eccrine; experimental study; extracellular; keratinocyte; keratinocyte differentiation; mechanical properties; microbial; microbial colonization; microorganism interaction; nanoscale; next generation sequencing; parent grant; poly-N-acetyl glucosamine; response; skin barrier; skin disorder; skin lesion; skin microbiome; staphylococcal protease; success; synergism; translational medicine; ward

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that affects 15-20% of children worldwide. In addition to the characteristic lesions accompanied by intense itching, AD increases the risk of microbial colonization and allergic responses including food allergy, allergic rhinitis, and asthma, in a process referred to as the atopic march. It was noted over 40 years ago that AD lesions were frequently colonized by Staphylococcus aureus. Recently, lesions from AD patients were discovered to be colonized by both S. aureus and S. epidermidis strains that formed biofilms, which are adhesive surface-attached colonies that become highly resistant to antibiotics and immune responses. S. epidermidis is a normal skin commensal that in some contexts can antagonize S. aureus biofilm growth. However, we have found that S. aureus and S. epidermidis are capable of forming synergistic mixed biofilms when co-cultured, which is consistent with recent skin microbiome surveys showing increased prevalence of both S. aureus and S. epidermidis on AD lesional skin. Data from our lab and others has shown that staphylococcal biofilm growth is dependent on intercellular adhesion events mediated by the Aap and SasG proteins expressed on the surfaces of S. epidermidis and S. aureus, respectively. It has recently been shown that Aap and SasG can mediate heterophilic adhesion events between S. epidermidis and S. aureus cells. Our central hypothesis is that such heterophilic protein adhesion events facilitate the growth of strong mixed-species staphylococcal biofilms on AD lesional skin, which promote inflammation, compromise skin barrier function, and result in more severe AD and progression to asthma. Through the proposed aims, we will 1) test whether heterophilic protein interactions between Aap and SasG allow synergistic growth of mixed-species biofilms between Staphylococcus spp colonizing AD but not normal skin; 2) delineate the mechanistic basis by which mixed biofilms promote disease; and 3) test whether synergistic staphylococcal strains that make the strongest mixed biofilms are associated with AD severity, barrier dysfunction, and progression to asthma in M-PAACH children.

特应性皮炎（AD）是一种慢性复发性炎症性皮肤疾病，影响了全球15-20％的儿童。除了伴有强烈瘙痒的特征性病变外，AD还增加了微生物定植和过敏反应的风险，包括食物过敏，过敏性鼻炎和哮喘，在所谓的特征游行中。值得注意的是，多40年前，AD病变经常被金黄色葡萄球菌定植。最近，发现AD患者的病变被形成生物膜的金黄色葡萄球菌和表皮链球菌菌株殖民，它们是粘附性表面连接的菌落，它们对抗生素和免疫反应具有高度抗性。表皮链球菌是一种正常的皮肤，在某些情况下可以拮抗金黄色葡萄球菌生物生长。然而，我们发现，在共培养时，金黄色葡萄球菌和表皮链球菌能够形成协同的混合生物膜，这与最近的皮肤微生物组调查表明，在皮肤上的皮肤链球菌和表皮链球菌的患病率都增加。我们实验室和其他人的数据表明，葡萄球菌生物膜的生长分别取决于由AAP和SASG蛋白介导的细胞间粘附事件，分别在表皮链球菌和金黄色葡萄球菌的表面上表达。最近已经显示，AAP和SASG可以介导表皮链球菌和金黄色葡萄球菌细胞之间的异质粘附事件。我们的核心假设是，这种异质蛋白粘附事件有助于促进炎症，损害皮肤屏障功能的强大混合物种葡萄球菌生物膜的生长，并导致更严重的AD和对哮喘的进展。 通过拟议的目的，我们将测试AAP和SASG之间的异质蛋白相互作用是否可以使混合物种生物膜在葡萄球菌spp spp中的AD结肠aD中的生物膜协同生长，但不是正常的皮肤； 2）描述混合生物膜促进疾病的机械基础； 3）测试使混合生物膜最强的葡萄球菌菌株是否与M-Paach儿童的AD严重程度，屏障功能障碍以及向哮喘的进展有关。