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

这项应用，靶向皮肤伤害感受器，以减少17型炎症， Hidradenitis Suppurativa，是由我，莎拉惠特利，医学博士，博士，在大学 匹兹堡皮肤科指导临床医生科学家职业发展 奖项（K 08）。我在T辅助细胞17（Th 17）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，我将获得和扩展 在临床/转化研究，计算生物学，神经生物学和临床 护理患有毁灭性和知之甚少的皮肤病Hidradenitis的患者 化脓性（HS）。我目前的初步数据表明，孤立的激活皮肤 TRPV 1-伤害感受器，通过无髓鞘感觉传入传递疼痛信号， 足以诱导IL-1、IL-6、TNF α和IL-23表达并扩增产生IL-17的CD 4 + 皮肤中的T细胞我发现TRPV 1+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样受体刺激的反应性。 最后，我证明了用肉毒杆菌毒素阻断神经肽的释放可以减少T细胞 HS患者的皮肤中的密度，以改善疾病控制。在目标1中，我建议 精确地表征免疫细胞浸润的毛囊皮脂腺单位在HS皮肤使用 高度创新的空间转录组技术目标2将检验抑制 神经肽活性与肉毒杆菌毒素一起降低皮肤中IL-17和TNF α的产生。目标3将 使用体外测定评估皮肤中SP和CGRP信号传导的功能结果， 用神经肽或载体处理的HS皮肤外植体的单细胞RNA测序分析。 总之，这些目标将检验我们的核心假设，即神经源性炎症加剧 cDC 2对微生物产物的敏感性诱导异常的17型炎症。是我们 预期这些实验将暗示发病机制中的神经源性炎症 并作为临床试验的概念验证，评估伤害感受器的疗效 抑制炎症减轻，缓解疼痛，改善HS的生活质量 患者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 Kaplan，共同导师Robert Lafyatis博士，以及在填补关键领域的专业知识的科学顾问 我以前的训练中的差距。我有一个从我的导师那里得到持久支持的环境， 系和机构，具有全国公认的实力，在转化研究。 在这个指导奖的支持下，这些研究将产生所需的初步数据， 一个有竞争力的R 01应用程序，并成功地启动一个独立的职业生涯。

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.