Developing a Molecular Map of Atopic Dermatitis Across Ethnicity and Severity Subtypes.

开发跨种族和严重程度亚型的特应性皮炎分子图谱。

• 批准号: 10379345
• 负责人: Emma Guttman
• 金额: $ 22.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-13 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379345
• 关键词: 18 year old; Adult; Affect; Africa; African; African American; American; Asia; Asian; Asian Americans; Asian population; Atopic Dermatitis; Biological Markers; Biopsy; Blood; Blood specimen; Body Surface; Body Surface Area; Characteristics; China; Clinical; Cytokine Activation; DNA; Data; Defect; Development; Disease; Disease Progression; Enrollment; Epithelial Cell Aggregation and Separation; Ethnic Origin; Ethnic group; European; Flow Cytometry; Gene Expression; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Healthcare; Hyperplasia; IgE; Immune; Immune Targeting; Immunohistochemistry; Immunologic Markers; Inflammation; Interleukin-13; Interleukin-4; Investigation; Japan; Korea; Lesion; Location; Maps; Modality; Modeling; Molecular; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Prevalence; Pruritus; Psoriasis; Punch Biopsy; Quality of life; Quantitative Reverse Transcriptase PCR; RNA; Reporting; Resistance; Serum; Severities; Severity of illness; Skin; Sleep Deprivation; Sleep disturbances; Subgroup; Surface; Swab; Systemic disease; Systems Biology; T-Lymphocyte Subsets; Taiwan; Testing; Therapeutic; Topical agent; Widespread Disease; attenuation; base; chemokine; cytokine; ethnic difference; exome sequencing; genetic analysis; immune activation; improved; individualized medicine; innovation; interleukin-22; keratinocyte; microbiome; molecular phenotype; new therapeutic target; novel therapeutics; personalized medicine; response; risk variant; skin barrier; skin lesion; systemic inflammatory response; therapy development; transcriptome sequencing

Project Summary Selection of therapeutics for patients with different AD phenotypes (i.e differing ethnic phenotypes and varying disease severity) should not be done by serendipity, but should be guided by differences in activation of immune circuits, and respective barrier alterations. Our overarching hypothesis is that different AD endotypes (based on ethnicity and severity) have different molecular phenotypes in skin and blood that may require use of different therapeutic approaches. The sub-hypothesis underlying our first project is that discrete subtypes/endotypes of AD exist within different ethnic populations. Our first project aims to define the skin and blood phenotypes of moderate-to-severe AD patients from Africa and Asia, and determine whether they are similar to those of AA and Asian AD patients in the US, implying global African and Asian AD phenotypes. The sub-hypothesis underlying our second project is that severe AD may be considered a systemic disease of the entire skin surface with immune activation extending to non- lesional skin and circulating cytokines, while mild disease may reflect only focal lesional skin inflammation without major systemic involvement. This may explain the need for systemic treatments and the inadequacy of treating only lesional skin with topical agents in severe patients. This study will define an onset point for systemic inflammation that may necessitate systemic treatments. The aim of the second project is to define the skin and blood biomarkers associated with increasing disease severity (from mild/limited through severe/extensive disease). The study will enroll adult AD patients and controls above 18 years old. SCORAD, EASI, body surface area (BSA), NRS pruritus and sleep loss assessments will be performed. Blood for CBC, serum (for circulating cytokines and chemokines, IgE and specific IgE levels), and flow cytometry, will be drawn. PAX RNA (for gene expression) and PAX DNA (for genetic analyses) blood samples will be taken. 4.5 mm lesional/LS and non-lesional/NL punch biopsies will be performed for skin profiling using genomic (RNAseq and qRT-PCR) and immunohistochemistry approaches. TEWL and swabs for microbiome will be performed from the same locations prior to biopsies. Exome sequencing will be performed to assess for genetic ancestry of each ethnicity/severity group. This is the first investigation that provides a system biology approach for AD, aiming to produce a molecular map of AD across its different ethnic backgrounds and disease severity sub-groups, which can possibly identify new therapeutics specifically geared towards a particular ethnic background, or severity. The proposal will set the stage for personalized therapy for AD based on skin and blood biomarkers (barrier, immune activation, microbiome, genetic risk alleles) related to ethnicity and severity, and will promote testing and development of innovative pathway-directed therapeutic approaches for the different ethnic backgrounds and varying AD severity.

项目总结