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: 10591489
• 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/10591489
• 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 Population; 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; 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-Cell Activation; T-Lymphocyte Subsets; Taiwan; Testing; Therapeutic; Topical agent; Widespread Disease; attenuation; chemokine; cytokine; ethnic difference; exome sequencing; genetic analysis; immune activation; improved; individualized medicine; innovation; keratinocyte; microbiome; molecular phenotype; new therapeutic target; novel therapeutics; personalized medicine; response; risk variant; skin barrier; skin lesion; systemic inflammatory response; 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.

项目概要 为具有不同 AD 表型（即不同种族表型和不同的 AD 患者）的患者选择治疗方法 疾病严重程度）不应通过偶然性来完成，而应以激活差异为指导 免疫回路和各自的屏障改变。我们的首要假设是不同的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。我们第一个假设的子假设 该项目认为不同种族人群中存在 AD 的离散亚型/内型。我们的第一个 该项目旨在确定来自非洲和亚洲的中度至重度 AD 患者的皮肤和血液表型， 并确定它们是否与美国的 AA 和亚洲 AD 患者相似，这意味着全球非洲人 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 被认为是整个皮肤表面的系统性疾病，免疫激活延伸至非 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 没有主要全身参与的炎症。这可能解释了系统治疗的必要性 严重患者仅用局部药物治疗病变皮肤是不够的。这项研究将定义一个 可能需要全身治疗的全身炎症的发作点。第二个项目的目标 的目的是定义与疾病严重程度增加（从轻度/有限 通过严重/广泛的疾病）。该研究将招募成年 AD 患者和 18 岁以上的对照者。 将进行 SCORAD、EASI、体表面积 (BSA)、NRS 瘙痒和睡眠不足评估。血 对于 CBC、血清（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 被绘制。将采集 PAX RNA（用于基因表达）和 PAX DNA（用于遗传分析）血液样本。 将使用基因组进行 4.5 毫米病变/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 在活检之前从相同位置进行。将进行外显子组测序来评估 每个种族/严重程度组的遗传血统。这是第一个提供系统生物学的研究 AD 方法，旨在绘制不同种族背景的 AD 分子图谱， 疾病严重程度亚组，这可能会确定专门针对疾病的新疗法 特定的种族背景或严重程度。该提案将为 AD 的个性化治疗奠定基础 与种族相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，并将促进创新途径导向治疗方法的测试和开发 针对不同的种族背景和不同的 AD 严重程度。