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

• 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
• 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

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.

这一应用，靶向皮肤伤害性感受器，以减少17型炎症 Hidradentis SupPurativa是由我提交的，Sarah Whitley，医学博士，在加州大学 匹兹堡皮肤科指导临床医生科学家职业发展 奖项(K08)。我在T辅助17(Th17)生物学方面有很强的背景，并致力于 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/翻译研究、计算生物学、神经生物学和临床研究方面的专业知识 患有破坏性且知之甚少的皮肤病汗管炎患者的护理 化妆水(Hs)。我提供的初步数据显示，皮肤的孤立激活 TRPV1-伤害性感受器通过无髓鞘感觉传入传递疼痛信号，是 足以诱导IL-1、IL-6、肿瘤坏死因子和IL-23的表达，并扩大产生IL-17的CD4+ 皮肤中的T细胞。我发现TRPV1+-神经源性神经肽CGRP和P物质 (SP)增强人皮肤树突状细胞(DC)对Toll样受体刺激的反应。 最后，我证明了用肉毒杆菌毒素阻断神经肽的释放会减少T细胞 提高HS患者皮肤密度，提高疾病控制水平。在目标1中，我提出了更多 精确描述HS皮肤中渗透毛囊皮脂腺单位的免疫细胞 高度创新的空间转录技术。目标2将检验这样的假设：抑制 肉毒杆菌毒素的神经肽活性可减少皮肤中IL-17和肿瘤坏死因子的产生。目标3将 用体外试验和组织化学方法评价SP和CGRP信号在皮肤中的功能结果 神经肽或赋形剂处理的HS皮肤组织的单细胞RNA测序分析。 总而言之，这些目标将检验我们的中心假设，即神经源性炎症加剧 CDC2对微生物产品的敏感性可引起反常的17型炎症。这是我们的 预计这些实验将在发病机制中牵涉到神经源性炎症 作为评估伤害性感受器疗效的临床试验的概念验证 抑制炎症，缓解疼痛，提高HS患者的生活质量 病人。我的工作将在我的主要导师丹尼尔博士的密切指导下进行 卡普兰，共同导师Robert Lafyatis博士，以及在关键领域拥有专业知识的科学顾问 在我之前的训练中出现了一些差距。我有一个长期得到导师支持的环境， 在翻译研究方面具有全国公认实力的部门和机构。 在该指导奖的支持下，这些研究将产生所需的初步数据 一个有竞争力的R01应用程序，并成功地开始了独立的事业。