Microbial Shifts and Immune Dysregulation in Hidradenitis Suppurativa Pathogenesis

项目摘要 化脓性汗腺炎（HS）是一种致残性慢性炎症性疾病，治疗效果不佳 这影响到1-4%的西方人口，主要是妇女（男：女1：3）和少数民族。尽管 尽管HS的发病率和发病率很高，但HS的发病机制尚不清楚，这限制了HS的发展。 有效的治疗。尽管异常的微生物定植和免疫失调与 在HS发病机制中，两者都没有被严格研究。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的炎症反应。这些基础研究的结果将指导识别 治疗靶点和选择可用的靶向治疗，用于在未来的R 01研究中进行测试。 Naik博士的目标是成为一名独立的R 01资助的基于临床的翻译研究者， 开拓性研究，测试炎症性皮肤病的新疗法，并应用机制研究 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，在人体皮肤微生物组的机制研究中进行重点培训， 皮肤免疫学研究，这将是实现这一目标的关键。她已经组装了一个 杰出的指导团队，具有转化医学（大卫沃夫西博士），人类微生物组（博士。 Heidi Kong和Susan Lynch博士）、皮肤免疫学（Michael Rosenblum博士）和复杂医学 皮肤科（Kanade Shinkai博士）。她和她的指导团队一起， 计划，包括优秀的指导，结构化教程，教学课程，和实践 体验.通过拟议的研究目标，她将获得深入的培训，具体步骤， 在人体皮肤微生物组和皮肤免疫学研究中进行机制研究，包括 研究设计、标本获取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。 这项研究的基本原理是，C。痤疮对HS疾病的干扰 HS中IL-17/IL-6免疫途径中基因的过程和激活可以阐明HS的致病性和 为后续干预性研究提供有针对性的途径。这份提案将决定如何以及向什么 扩大了C.痤疮在HS病变部位和HS好发部位受到干扰， 病程（目的1）和IL-17/IL-6轴是否是HS皮损皮肤中的主要免疫途径， 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 R 01的竞争性应用需要选择和测试HS的新治疗方法。

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.