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Overall Atopic Dermatitis Research Network

整体特应性皮炎研究网络

基本信息

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
项目类别：
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

项目摘要

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.