Overall Atopic Dermatitis Research Network

整体特应性皮炎研究网络

• 批准号: 9256409
• 负责人: DONALD YM LEUNG
• 金额: $ 600万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256409
• 关键词: Adult; Animals; Atopic Dermatitis; Bacteria; Bacterial Infections; Biological Markers; Cells; Child; Clinical; Clinical Research; Clinical Trials; Coagulase; Cutaneous; Defect; Disease; Doctor of Philosophy; Dose; Eczema Herpeticum; Elements; Epidermis; Epigenetic Process; Ethnic group; Etiology; Fluzone; Funding; Gene Expression Profile; Genes; Genetic; Genome; Genus staphylococcus; Goals; Herpesvirus 1; Host Defense; Host Defense Mechanism; Human; Immune; Immune Targeting; Immune response; Immunization; Infection; Infectious Skin Diseases; Inflammation; Innate Immune System; Interleukin-13; Interleukin-4; Intervention; Intervention Studies; Lesion; Link; Measures; Microbe; Molecular; Pathway interactions; Patients; Phenotype; Protocols documentation; Quantitative Trait Loci; Race; Randomized; Recurrence; Research; Role; Route; Severity of illness; Skin; Staphylococcus aureus; Symbiosis; Systems Biology; TSLP gene; Testing; Topical application; Translating; Transplantation; Vaccination; Viral; Virus Diseases; Work; adaptive immune response; allergic response; base; biobank; commensal microbes; cytokine; design; genetic profiling; genome wide association study; genomic data; high throughput screening; immunogenicity; immunoregulation; improved; insight; killings; microbiome; microbiota transplantation; molecular marker; mouse model; next generation; novel; novel strategies; pathogenic bacteria; personalized medicine; public health relevance; response; skin barrier; skin disorder; skin microbiome; targeted treatment; trait; transcriptome sequencing

 DESCRIPTION (provided by applicant): The primary objective of the studies in this ADRN application is to improve our understanding of mechanisms underlying cutaneous host defense, by determining the cause of different phenotypes of atopic dermatitis (AD) including Staphylococcus aureus (S. aureus) colonization, eczema herpeticum (EH) and severe AD. These studies will include assessment of skin barrier, and adaptive/innate immune system responses to viral and bacterial infections, as well as genetic and epigenetic studies. Three Interventional Clinical Trials Projects with accompanying mechanistic studies are proposed. The first intervention will be aimed at modulating bacterial colonization of the skin and improving the skin host defense by microbiome transplant. The other 2 interventions will assess the effects of Th2/TSLP cytokine blockade in human AD on S. aureus colonization and vaccination responses in different skin compartments (intradermal and transcutaneous). Three Clinical Mechanistic Studies will be aimed at delineating cellular and molecular mechanisms of severe AD phenotypes, and AD subsets prone to recurrent EH, and S. aureus colonization and/or infection. Two animal protocols are also proposed to directly support clinical studies by providing a mechanistic understanding of skin host defense to alterations in microbiome, and comparing cutaneous versus non-cutaneous vaccination immune responses. The proposed protocols are as follows: 1) Targeted Microbiome Transplant in AD; 2) Effect of Dupilumab(r) (anti-IL4Ra) on the Host-Microbe Interface in AD; 3) Randomized Study of Fluzone(r) Immunogenicity after Transcutaneous Vaccination in AD; 4) A Systems Biology Approach to Identify Determinants of S. aureus Colonization in AD; 5) Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum; 6) Defining the Determinants of Disease Severity in AD of Different Races and Ethnic Groups; 7) Modulation of the Immune Response to Cutaneous Immunization in a Mouse Model of AD by S. aureus; 8) Control of Microbiome Function by the Barrier in a Mouse Model of AD. Successful completion of these 6 interrelated clinical projects, and 2 animal protocols which directly support the human research, will create a paradigm shift in our understanding of genetics, skin barrier function, microbiome, innate and adaptive immune response underlying host defense mechanisms in the skin of distinct but associated AD phenotypes. At the end of this funding period, these cutting edge mechanistic studies will be translated into new treatment approaches in AD, a disease that remains difficult to treat and that has eluded molecular characterization.

 描述（由申请人提供）：本 ADRN 申请中研究的主要目的是通过确定包括金黄色葡萄球菌（S. aureus）在内的特应性皮炎（AD）不同表型的原因，提高我们对皮肤宿主防御机制的理解。这些研究将包括评估皮肤屏障、适应性/先天免疫系统对病毒和细菌感染的反应，以及遗传和细菌感染。提出了三个干预性临床试验项目以及相应的机制研究。第一个干预措施旨在调节皮肤的细菌定植并改善皮肤的细菌定植。 其他 2 项干预措施将评估人类 AD 中 Th2/TSLP 细胞因子阻断对金黄色葡萄球菌在不同皮肤区室（皮内和经皮）定植和疫苗接种反应的影响。还提出了两种动物方案，以描述严重 AD 表型和易于复发 EH 的 AD 亚型以及金黄色葡萄球菌定植和/或感染的细胞和分子机制，以通过提供直接支持临床研究。了解皮肤宿主对微生物组变化的防御机制，并比较皮肤与非皮肤疫苗接种免疫反应。 拟议方案如下：1) AD 中的靶向微生物组移植；2) Dupilumab(r)（抗 IL4Ra）的效果。 AD 中宿主-微生物界面的研究；3) AD 经皮疫苗接种后 Fluzone(r) 免疫原性的随机研究；4) 识别 AD 决定因素的系统生物学方法； AD 中金黄色葡萄球菌的定植；5) 综合极端性状分析，了解疱疹性湿疹的病因；6) 确定不同种族和民族群体 AD 疾病严重程度的决定因素；7) 皮肤免疫反应的调节金黄色葡萄球菌建立的 AD 小鼠模型；8) AD 小鼠模型中屏障对微生物组功能的控制。成功完成这 6 个相互关联的临床项目和 2 个直接支持人类研究的动物方案，将在我们对皮肤宿主防御机制的遗传学、皮肤屏障功能、微生物组、先天性和适应性免疫反应的理解上产生范式转变。在此资助期结束时，这些前沿的机制研究将转化为 AD 的新治疗方法，AD 是一种仍然难以治疗且无法进行分子表征的疾病。