Microbial Shifts and Immune Dysregulation in Hidradenitis Suppurativa Pathogenesis

化脓性汗腺炎发病机制中的微生物变化和免疫失调

• 批准号: 9980788
• 负责人: Haley Naik
• 金额: $ 17.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980788
• 关键词: 16S ribosomal RNA sequencing; Abscess; Acne; Address; Affect; Anaerobic Bacteria; Antibiotic Therapy; Biology; CCL2 gene; Cicatrix; Clinic; Clinical Trials; Complex; Cutaneous; Data; Data Set; Dermatology; Development; Disease; Drainage procedure; Environment; Flare; Foundations; Funding; Future; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Hidradenitis Suppurativa; Human; Human Microbiome; Immune; Immune System Diseases; Immune response; Immunology; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-12; Interleukin-17; Interleukin-6; Intervention; Intervention Studies; Investigation; K-Series Research Career Programs; Knowledge; Lesion; Medical; Mentors; Metagenomics; Methods; Minority; Morbidity - disease rate; Nodule; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Population; Prevalence; Process; Property; Regulation; Research; Research Design; Role; Sebaceous Glands; Sebum; Severity of illness; Signal Transduction; Site; Skin; Skin colonization; Specimen; Structure; TNF gene; Taxon; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Training Programs; Woman; Work; adalimumab; antimicrobial; base; chronic inflammatory disease; clinically relevant; commensal bacteria; cytokine; design; effective therapy; experience; functional genomics; healthy volunteer; immune activation; immunoregulation; microbial; microbial colonization; microbiota; novel therapeutic intervention; novel therapeutics; response; skin disorder; skin lesion; skin microbiome; skin microbiota; targeted agent; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; translational medicine; translational scientist; young woman

PROJECT SUMMARY Hidradenitis suppurativa (HS) is a disabling chronic inflammatory disease with few effective treatments that affects 1-4% of the Western population, predominantly women (M:F 1:3) and minorities. Despite its prevalence and morbidity, HS pathogenesis is poorly understood and this has limited the development of effective therapies. Although abnormal microbial colonization and immune dysregulation have been implicated in HS pathogenesis, neither has been rigorously studied. To address this gap, Dr. Naik’s K23 proposal will use comprehensive, systematic, unbiased approaches to investigate skin microbial perturbations and dysregulated inflammatory responses in HS. Findings from these foundational studies will guide the identification of therapeutic targets and selection of available targeted treatments for testing in future R01 studies. Dr. Naik’s goal is to become an independent R01-funded clinic-based translational investigator leading pioneering research to test novel therapies for inflammatory skin diseases and applying mechanistic studies within the context of clinical trials to deepen our understanding of disease biology. She is seeking a K23 Career Development Award to pursue focused training in mechanistic studies in human skin microbiome and cutaneous immunology research, which will be essential to achieving this goal. She has assembled an exceptional mentoring team with expertise in translational medicine (Dr. David Wofsy), human microbiome (Dr. Heidi Kong and Dr. Susan Lynch), cutaneous immunology (Dr. Michael Rosenblum), and complex medical dermatology (Dr. Kanade Shinkai). Together with her mentoring team, she has developed a rigorous training program that includes outstanding mentoring, structured tutorials, didactic coursework, and practical experience. Through the proposed research aims, she will acquire in-depth training in the concrete steps of conducting mechanistic studies in human skin microbiome and cutaneous immunology research, including study design, specimen procurement and processing methods, and computational approaches in metagenomics and functional genomics. The following research aims have been designed to align with the mentoring and didactic training proposed in this application. The rationale for this proposed research is that characterizing C. acnes perturbations over HS disease course and activation of genes in the IL-17/IL-6 immune pathway in HS may elucidate pathogenic and targetable pathways for subsequent interventional investigations. This proposal will determine how and to what extent the relative abundance of C. acnes is perturbed at HS lesional sites and sites of HS predilection over disease course (Aim 1) and whether the IL-17/IL-6 axis is a dominant immune pathway in HS lesional skin as compared with non-lesional and HV skin (Aim 2). Accomplishing these aims will provide the preliminary data needed for a competitive R01 application to select and test novel therapeutic approaches for HS.

项目概要 化脓性汗腺炎 (HS) 是一种致残性慢性炎症性疾病，有效的治疗方法很少 影响了 1-4% 的西方人口，主要是女性 (男:女 1:3) 和少数族裔。尽管其 由于 HS 的患病率和发病率较高，人们对 HS 的发病机制了解甚少，这限制了 HS 的发展 有效的疗法。尽管异常的微生物定植和免疫失调已被牵连 在 HS 发病机制中，两者都尚未得到严格研究。为了解决这一差距，Naik 博士的 K23 提案将使用 全面、系统、公正的方法来研究皮肤微生物扰动和失调 HS 中的炎症反应。这些基础研究的结果将指导识别 治疗目标和选择可用的靶向治疗以在未来的 R01 研究中进行测试。 Naik 博士的目标是成为一名独立的 R01 资助的临床转化研究者，领导 测试炎症性皮肤病新疗法和应用机制研究的开拓性研究 在临床试验的背景下加深我们对疾病生物学的理解。她正在寻找 K23 职业发展奖旨在进行人类皮肤微生物组机制研究的集中培训 皮肤免疫学研究，这对于实现这一目标至关重要。她组装了一个 杰出的指导团队，拥有转化医学（David Wofsy 博士）、人类微生物组（Dr. David Wofsy）方面的专业知识。 Heidi Kong 和 Susan Lynch 博士）、皮肤免疫学（Michael Rosenblum 博士）和复杂的医学 皮肤科（新海奏医生）。她与她的导师团队一起制定了严格的培训 计划包括出色的指导、结构化教程、教学课程和实践 经验。通过提出的研究目标，她将获得具体步骤的深入培训 进行人体皮肤微生物组和皮肤免疫学研究的机制研究，包​​括 研究设计、样本采购和处理方法以及计算方法 宏基因组学和功能基因组学。以下研究目标旨在与 本申请中提出的指导和教学培训。 这项拟议研究的基本原理是，描述痤疮丙酸杆菌对 HS 疾病的扰动特征 HS 中 IL-17/IL-6 免疫通路中基因的过程和激活可能有助于阐明 HS 的致病和 后续干预研究的目标途径。该提案将决定如何以及做什么 痤疮丙酸杆菌的相对丰度在 HS 病变部位和 HS 好发部位受到干扰的程度 病程（目标 1）以及 IL-17/IL-6 轴是否是 HS 皮损皮肤中的主要免疫通路 与非病变和 HV 皮肤相比（目标 2）。实现这些目标将提供初步数据 竞争性 R01 应用需要选择和测试 HS 的新治疗方法。