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.

该应用程序针对皮肤伤害感受器，以减少17型炎症 Hidradenitis Purpurativa，由Me，Me，Sarah Whitley，医学博士提交匹兹堡皮肤科系的指导临床医生职业发展奖项（K08）。我在T Helper 17（Th17）生物学方面有很强的背景皮肤免疫学研究。为了完成我的研究目标，我将获得并扩展临床/转化研究，计算生物学，神经生物学和临床方面的专业知识护理受到毁灭性和不良皮肤疾病的患者的护理修剪（HS）。我提供了初步数据，表明皮肤的孤立激活 TRPV1不感染者通过无髓的感觉传入传递疼痛信号，是足以诱导IL-1，IL-6，TNF和IL-23的表达并扩展IL-17产生的CD4+ 皮肤中的T细胞。我表明TRPV1+-NENVE衍生的神经肽CGRP和物质P （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，我证明了用肉毒杆菌毒素释放神经肽的块 HS患者皮肤的密度改善疾病控制。在AIM 1中，我建议更多精确地表征了使用A 高度创新的空间转录组技术。 AIM 2将检验抑制的假设肉毒杆菌毒素的神经肽活性降低了皮肤中IL-17和TNF的产生。目标3意志使用体外测定和用神经肽或媒介物处理的HS皮肤外植体的单细胞RNA测序分析。这些目的共同测试了我们的中心假设，即神经源性感染会增强 CDC2对微生物产物的敏感性诱导异常17型注射。这是我们的期望这些实验会隐含发病机理中的中性炎症 HS的临床试验概念证明，评估伤害感受器的效率抑制减少感染，缓解疼痛和改善HS生活质量的抑制作用患者。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。卡普兰（Kaplan），罗伯特·拉菲蒂斯（Robert Lafyatis）博士和科学顾问在填补关键领域的专业知识我以前的培训中的差距。我有一个持久的导师支持的环境，部门和机构在转化研究中具有全国认可的力量。在此事项奖的支持下，这些研究将产生所需的初步数据具有竞争力的R01应用程序，并成功启动了独立职业。