Microbial Shifts and Immune Dysregulation in Hidradenitis Suppurativa Pathogenesis

项目总结 化脓性汗腺炎(HS)是一种慢性致残性炎症性疾病，治疗效果不佳。 这影响了1-4%的西方人口，主要是女性(M：F 1：3)和少数族裔。尽管它的 HS的发病率和发病机制尚不清楚，这限制了HS的发展。 有效的治疗方法。尽管异常的微生物定植和免疫失调被牵连 在HS的发病机制中，两者都没有得到严格的研究。为了解决这一差距，奈克博士的K23提案将使用 全面、系统、不偏不倚的方法调查皮肤微生物扰动和失调 HS的炎症反应。这些基础性研究的发现将指导识别 治疗目标和可用靶向治疗的选择，以便在未来的R01研究中进行测试。 奈克博士的目标是成为一家由R01资助的独立诊所转译研究员，领导 测试炎症性皮肤病新疗法的开创性研究和应用机制研究 在临床试验的背景下，加深我们对疾病生物学的理解。她正在寻找一辆K23 职业发展奖，致力于人类皮肤微生物组和 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 在转化医学(David Wofsy博士)、人类微生物群(Dr.David Wofsy)(Dr. 海蒂·孔和苏珊·林奇博士)、皮肤免疫学(迈克尔·罗森布鲁姆博士)和复杂医学 皮肤科(Kanade Shinkai医生)。与她的指导团队一起，她发展了一种严格的训练 该计划包括出色的指导、结构化的教程、教学课程和实践 经验。通过提出的研究目标，她将在以下具体步骤中获得深入的培训 进行人体皮肤微生物组的机制研究和皮肤免疫学研究，包括 研究设计、样本采购和处理方法以及计算方法 元基因组学和功能基因组学。以下研究目标旨在与 在本申请中建议进行辅导和授课培训。 这项拟议研究的基本原理是，表征痤疮念珠菌对HS疾病的扰动 IL-17/IL-6免疫通路中的基因在HS中的进程和激活可能阐明HS的致病和 为后续干预性调查提供有针对性的途径。这项提案将决定如何以及针对什么 粉刺念珠菌的相对丰度在HS皮损部位和HS偏好部位的扰动程度高于 病程(目标1)和IL-17/IL-6轴是否是HS皮损AS的主要免疫途径 与非皮损和高压皮肤对照(目标2)。实现这些目标将提供初步数据 用于竞争性的R01应用程序，以选择和测试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.