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.

项目摘要 选择用于具有不同AD表型（即不同种族表型和不同 疾病严重程度）不应该由偶然发现来完成，而应该由激活的差异来指导。 免疫回路和各自的屏障改变。我们的总体假设是，不同的AD 内型（基于种族和严重程度）在皮肤和血液中具有不同的分子表型 这可能需要使用不同的治疗方法。我们第一个假设背后的子假设 AD的离散亚型/内型存在于不同种族人群中。我们的第一 该项目旨在确定来自非洲和亚洲的中重度AD患者的皮肤和血液表型， 并确定它们是否与美国AA和亚洲AD患者相似，这意味着全球非洲 和亚洲AD表型。我们第二个项目的子假设是，严重的AD可能是 被认为是一种全身性疾病的整个皮肤表面的免疫激活延伸到非 病变皮肤和循环细胞因子，而轻度疾病可能仅反映局灶性病变皮肤 炎症，无主要全身受累。这可能解释了需要系统治疗， 在严重患者中仅用局部药物治疗病变皮肤的不足。这项研究将确定一个 可能需要全身治疗的全身性炎症的发作点。第二个项目的目的是 是定义与疾病严重程度增加（从轻度/限制性）相关的皮肤和血液生物标志物， 严重/广泛的疾病）。该研究将招募18岁以上的成人AD患者和对照。 将进行SCORAD、EASI、体表面积（BSA）、NRS瘙痒和睡眠丧失评估。血液 对于CBC、血清（用于循环细胞因子和趋化因子、IgE和特异性IgE水平）和流式细胞术，将 被吸引。将采集PAX RNA（用于基因表达）和PAX DNA（用于基因分析）血样。 4.5将使用基因组技术进行mm病变/LS和非病变/NL穿刺活检，以进行皮肤分析 （RNAseq和qRT-PCR）和免疫组织化学方法。TEWL和微生物组拭子将 在活检之前从相同的位置进行。将进行外显子组测序，以评估 每个种族/严重程度组的遗传祖先。这是第一次提供系统生物学的研究， AD的方法，旨在产生不同种族背景的AD分子图谱， 疾病严重程度亚组，这可能会发现新的治疗方法，特别是针对 特殊的种族背景或严重性。该提案将为基于AD的个性化治疗奠定基础 与种族有关的皮肤和血液生物标志物（屏障、免疫激活、微生物组、遗传风险等位基因） 和严重程度，并将促进测试和开发创新的路径导向的治疗方法 不同的种族背景和不同的AD严重程度。