Targeting cutaneous nociceptors to reduce Type-17 inflammation in hidradenitis suppurativa

靶向皮肤伤害感受器减少化脓性汗腺炎的 17 型炎症

基本信息

批准号：
10590050
负责人：
Sarah Kern Whitley
金额：
$ 16.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2023-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10590050
关键词：
Abscess Affect Anatomy Apocrine Glands Area Award Axilla Biological Products Biology Botulinum Toxins CCL2 gene CD4 Positive T Lymphocytes Candida albicans Cell Density Cells Characteristics Cicatrix Clinical Clinical Trials Computational Biology Cutaneous Data Dendritic Cells Dermatology Development Disease Disease remission Doctor of Philosophy Dose Environment FDA approved Fistula Gene Expression Profiling Genomics Hair follicle structure Health Health Care Costs Healthcare Hidradenitis Suppurativa Human IL17 gene Immune Immune System Diseases Immune response Immunology In Vitro Infection Inflammation Inflammatory Innate Immune System Institution Interferon Type I Interleukin-1 Interleukin-6 K-Series Research Career Programs Lesion Ligands Link MAP Kinase Gene Macrophage Measures Mediating Memory Mental Depression Mentors Messenger RNA Methods Microbe Minority Nerve Neurobiology Neurogenic Inflammation Neuropeptide Receptor Neuropeptides Nociceptors Pain Pathogenesis Pathologic Patient Care Patients Population Production Proteins Quality of life Randomized, Controlled Trials Receptor Signaling Research Scientist Sensory Signal Transduction Sinus Skin Stimulus Substance P T cell response T-Lymphocyte TACR1 gene TLR2 gene TNF gene TRPV1 gene Technology Testing Tissues Toll-like receptors Training Translational Research Universities Woman Work antagonist antimicrobial botulinum toxin treatment career chronic inflammatory disease clinical care cutaneous sensory nerve cytokine disorder control dysbiosis economic impact effective therapy efficacy evaluation expectation experience experimental study functional outcomes immune cell infiltrate improved in vitro Assay inhibitor innate immune mechanisms innovation interleukin-23 lipoteichoic acid mast cell microbial colonization microbial products neurotransmitter antagonist next generation sequencing novel pain relief pain signal protein expression randomized controlled design receptor expression response single-cell RNA sequencing skin disorder skin microbiota targeted agent transcriptomics

项目摘要

This application, Targeting cutaneous nociceptors to reduce Type-17 inflammation in Hidradenitis Suppurativa, is submitted by me, Sarah Whitley, MD, PhD, in the University of Pittsburgh Department of Dermatology for a Mentored Clinician Scientist Career Development Award (K08). I have a strong background in T helper 17 (Th17) biology and a commitment to research in cutaneous immunology. To complete my research objectives, I will gain and extend expertise in clinical/translational research, computational biology, neurobiology, and the clinical care of patients afflicted by the devastating and poorly understood skin disease Hidradenitis Suppurativa (HS). I present preliminary data showing that isolated activation of cutaneous TRPV1-nociceptors, which transduce pain signals through unmyelinated sensory afferents, is sufficient to induce expression of IL-1, IL-6, TNF, and IL-23 and expand IL-17-producing CD4+ T cells in skin. I show that the TRPV1+-nerve-derived neuropeptides CGRP and Substance P (SP) enhance human skin dendritic cell (DC) responsiveness to toll-like receptor stimulation. Finally, I demonstrate that blockade of neuropeptide release with botulinum toxin reduces T cell density in the skin of HS patients to improve disease control. In Aim 1, I propose to more precisely characterize the immune cells infiltrating the pilosebaceous unit in HS skin using a highly innovative spatial transcriptomic technology. Aim 2 will test the hypothesis that inhibiting neuropeptide activity with botulinum toxin reduces IL-17 and TNF production in skin. Aim 3 will evaluate the functional outcome of SP and CGRP signaling in skin using in vitro assays and single cell RNA-sequencing analyses of HS skin explants treated with neuropeptide or vehicle. Together, these aims will test our central hypothesis that neurogenic inflammation heightens cDC2 sensitivity to microbial products to induce aberrant Type-17 inflammation. It is our expectation that these experiments will implicate neurogenic inflammation in the pathogenesis of HS and serve as proof-of-concept for clinical trials evaluating the efficacy of nociceptor inhibition in reduction of inflammation, relief of pain, and improvement in quality of life for HS patients. My work will proceed under close advisement from my primary mentor, Dr. Daniel Kaplan, co-mentor Dr. Robert Lafyatis, and scientific advisors with expertise in areas that fill key gaps in my previous training. I have an environment of enduring support from my mentors, department, and institution which has nationally recognized strength in translational research. With support from this mentored award, these studies will yield the preliminary data needed for a competitive R01 application and successfully launch an independent career.

该应用针对皮肤伤害感受器来减少 17 型炎症化脓性汗腺炎，由我，Sarah Whitley，MD，PhD，大学提交匹兹堡皮肤科指导临床科学家职业发展奖 (K08) 我在 T 辅助细胞 17 (Th17) 生物学方面拥有深厚的背景并致力于研究为了完成我的研究目标，我将获得并扩展皮肤免疫学的研究。临床/转化研究、计算生物学、神经生物学和临床领域的专业知识护理受破坏性且人们知之甚少的皮肤病汗腺炎影响的患者我提供的初步数据显示皮肤的孤立激活。 TRPV1-伤害感受器通过无髓鞘感觉传入传导疼痛信号，足以诱导 IL-1、IL-6、TNFα 和 IL-23 的表达并扩大产生 IL-17 的 CD4+ 皮肤中的 T 细胞显示 TRPV1+-神经源性神经肽 CGRP 和 P 物质。 (SP) 增强人类皮肤树突状细胞 (DC) 对 Toll 样受体刺激的反应。最后，我证明用肉毒杆菌毒素阻断神经肽释放会减少 T 细胞在目标 1 中，我建议采取更多措施。使用高度创新的空间转录组技术将检验抑制的假设。肉毒杆菌毒素的神经肽活性会减少皮肤中 IL-17 和 TNFα 的产生。使用体外测定评估皮肤中 SP 和 CGRP 信号传导的功能结果对经神经肽或媒介物处理的 HS 皮肤外植体进行单细胞 RNA 测序分析。总之，这些目标将检验我们的中心假设，即神经源性炎症会加剧 cDC2 对微生物产物的敏感性会诱发异常的 17 型炎症。期望这些实验将在发病机制中暗示神经源性炎症 HS 并作为评估伤害感受器功效的临床试验的概念验证抑制减少炎症、缓解疼痛并改善 HS 的生活质量我的工作将在我的主要导师丹尼尔博士的密切建议下进行。 Kaplan、联合导师 Robert Lafyatis 博士以及在关键领域拥有专业知识的科学顾问我之前的训练中的差距，我有一个来自导师持久支持的环境，具有全国公认的转化研究实力的部门和机构。在这个指导奖项的支持下，这些研究将产生所需的初步数据具有竞争力的 R01 申请并成功开展独立职业生涯。