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.

项目摘要/摘要 我们的研究建议阐明酒渣鼻的局部和全身免疫失调，并具有长期目标 开发新颖的预防和治疗靶标，并改善酒渣鼻的整体健康状况 患者。酒渣鼻是一种常见的炎症性皮肤疾病，病因不清楚，超过1400万人 仅在美国。1收费受体2（TLR2）是一种保持免疫的微生物感应机制 通过与共生微生物进行交流，皮肤中的稳态。2-4因此，我们怀疑 了解皮肤菌群宿主相互作用对于阐明酒渣鼻的发病机理至关重要。而且， 酒渣鼻中的免疫失调似乎并未定位在皮肤上。越来越多的身体 流行病学证据表明酒渣鼻与广泛的全身共同体有关 40-51，这也重要的是阐明可以解释的潜在系统性免疫失调 酒渣鼻患者的总体疾病伯嫩。目标1：我们旨在检验皮肤营养不良诱导的假设 在发病机理中实施的先天免疫反应的成分的转录和表达 酒渣鼻。为此，我们将执行微生物组，转录组和 从酒渣鼻皮肤上蛋白质组，以描绘微生物群 - 宿主相互作用。目标2：我们旨在测试 假设皮肤和全身循环之间存在共同的免疫失调，可以解释 酒渣鼻患者的全身合并症的伯恩（Burnen）。为此，我们将执行多论数据 从皮肤和血液/血清的转录组和蛋白质组整合以表征共享 分子途径。 McGee博士的职业目标是成为具有独特专业知识的物理科学家 采用多媒体，数据驱动的个性化策略来治疗炎症性皮肤疾病及其相关性 系统性合并症。为了实现这一目标，她将进行正式课程的结合， 研讨会和生物信息学，计算生物学，人类学科研究和实践培训 临床试验。她还将通过参加赠款写作课程，从事职业发展活动 K-R过渡计划。麦吉博士的研究和职业发展将由一个心理团队指导 拥有数十年的综合经验，可以成功地将其梅内斯过渡到研究 独立。麦吉博士的培训将在两个著名的学术机构举行：1）贝丝以色列 女执事医疗中心，哈佛医学院的一家大型教学医院，支持约250名校长 调查人员并提供16个机构和12个部门核心设施，以及2）哈佛T.H.陈学校 公共卫生，该公共卫生在该国举办了一贯排名第一的生物统计学计划，并支持 计算研究计划以回答多学科问题。