Multi-omic Studies of Local and Systemic Immune Dysregulation in Rosacea

红斑痤疮局部和全身免疫失调的多组学研究

• 批准号: 10590784
• 负责人: Jean Suh McGee
• 金额: $ 16.99万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590784
• 关键词: Advanced Development; Affect; Atherosclerosis; Bioinformatics; Biological Assay; Biological Response Modifiers; Biometry; Blood; Blood Vessels; Cells; Circulation; Clinical Trials; Communication; Complex; Computational Biology; Core Facility; Country; Data; Development; Disease; Early Diagnosis; Educational workshop; Environment; Epidemiology; Epithelium; Etiology; Exclusion; Expression Profiling; Genetic Transcription; Goals; Grant; Health; Homeostasis; Human Subject Research; IL17 gene; Immune; Immune response; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Innate Immune System; Institution; Investigation; Israel; Kininogenase; Link; Mediating; Medical center; Mentors; Microbe; Molecular; Multiomic Data; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Physicians; Prevention; Principal Investigator; Proteome; Proteomics; Protocols documentation; Psoriasis; Public Health Schools; Regulator Genes; Research; Role; Rosacea; Scientist; Serine Protease; Serum; Shotguns; Signal Pathway; Signal Transduction; Skin; Stimulus; Systemic disease; TLR1 gene; TLR2 gene; TNF gene; Teaching Hospitals; Testing; Therapeutic; Training; Transcriptional Activation; United States; Whole Blood; Writing; burden of illness; cardiovascular risk factor; career; career development; cathelicidin; cathelicidin antimicrobial peptide; commensal microbes; comorbidity; cytokine; data integration; dysbiosis; experience; host microbiota; immune activation; improved; insight; interleukin-22; medical schools; metagenomic sequencing; microbial; microbiome; microbiota; multidisciplinary; multiple omics; new therapeutic target; novel; personalized strategies; programs; protein expression; rRNA Genes; recruit; research and development; response; skin disorder; skin microbiome; skin microbiota; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Our research proposes to elucidate local and systemic immune dysregulation in rosacea with the long-term goals of developing novel preventative and therapeutic targets and improving overall health outcomes for rosacea patients. Rosacea is a common inflammatory skin disease with unclear etiology affecting over 14 million people in the United States alone.1 Toll-like receptor 2 (TLR2) is a microbe-sensing mechanism that maintains immune homeostasis in the skin through communication with commensal microbes.2-4 Therefore, we suspect that understanding the skin microbiota-host interaction is critical to elucidating the pathogenesis of rosacea. Moreover, the immune dysregulation in rosacea does not appear to be localized to the skin. There is a growing body of epidemiological evidence demonstrating that rosacea is associated with a wide range of systemic co- morbidities.40-51 Thus, it is also important to elucidate potential systemic immune dysregulation that can explain the overall disease burden in rosacea patients. Aim 1: We aim to test the hypothesis that skin dysbiosis induces transcription and expression of the components of the innate immune response implicated in the pathogenesis of rosacea. To that end, we will perform multi-omics data integration of the microbiome, transcriptome, and proteome from rosacea skin in order to delineate the microbiota-host interaction. Aim 2: We aim to test the hypothesis that there is shared immune dysregulation between the skin and systemic circulation that can explain the burden of systemic co-morbidities in rosacea patients. To that end, we will perform multi-omics data integration of the transcriptome and proteome from the skin and blood/serum in order to characterize shared molecular pathways. Dr. McGee’s career goal is to become a physician scientist with the unique expertise to apply multi-omics, data-driven, personalized strategies to treat inflammatory skin diseases and their associated systemic co-morbidities. To achieve this goal, she will undertake a combination of formalized coursework, workshops, and hands-on training in bioinformatics, computational biology, human subjects research, and clinical trials. She will also engage in career development activities by participating in a grant writing course and a K-R transition program. Dr. McGee’s research and career development will be guided by a mentoring team with several decades of combined experience in successfully transitioning their mentees to research independence. Dr. McGee’s training will take place at two prominent academic institutions: 1) Beth Israel Deaconess Medical Center, a major teaching hospital of Harvard Medical School which supports ~250 principal investigators and offers 16 institutional and 12 departmental core facilities, and 2) Harvard T.H. Chan School of Public Health, which hosts the consistently ranked #1 biostatistics program in the country and supports computational research initiatives to answer multidisciplinary questions.

项目概要/摘要 我们的研究旨在阐明红斑痤疮的局部和全身免疫失调，并制定长期目标 开发新的预防和治疗目标并改善红斑痤疮的整体健康结果 红斑痤疮是一种常见的炎症性皮肤病，其病因尚不清楚，影响着超过 1400 万人。 仅在美国。1 Toll 样受体 2 (TLR2) 是一种维持免疫的微生物感应机制 通过与共生微生物的交流来保持皮肤的稳态。2-4 因此，我们怀疑 了解皮肤微生物群与宿主的相互作用对于阐明红斑痤疮的发病机制至关重要。 红斑痤疮的免疫失调似乎并不局限于皮肤。 流行病学证据表明红斑痤疮与多种全身性疾病有关 40-51 因此，阐明潜在的系统性免疫失调也很重要，这可以解释 目标 1：我们旨在检验皮肤生态失调引起的假设。 与发病机制有关的先天免疫反应成分的转录和表达 为此，我们将对微生物组、转录组和 目的 2：我们的目标是测试红斑痤疮皮肤的蛋白质组，以描述微生物群与宿主的相互作用。 皮肤和体循环之间存在共同的免疫失调的假设可以解释 为此，我们将进行多组学数据。 整合来自皮肤和血液/血清的转录组和蛋白质组，以表征共享的 McGee 博士的职业目标是成为一名拥有独特专业知识的医师科学家。 应用多组学、数据驱动、个性化策略来治疗炎症性皮肤病及其相关疾病 为了实现这一目标，她将结合正式的课程， 生物信息学、计算生物学、人类受试者研究等方面的研讨会和实践培训 她还将通过参加资助写作课程来从事职业发展活动和 麦吉博士的研究和职业发展将由导师团队指导。 拥有数十年成功将学员转变为研究的综合经验 McGee 博士的培训将在两个著名的学术机构进行：1) Beth Israel。 女执事医疗中心是哈佛医学院的主要教学医院，为约 250 名校长提供服务 研究者并提供 16 个机构和 12 个院系核心设施，以及 2) 哈佛大学陈曾熙学院 (Harvard T.H. Chan School of) 公共卫生部门，负责主持该国一直排名第一的生物统计项目并支持 回答多学科问题的计算研究举措。