Interleukin-31 at the neuroimmune interface of pruritus and dermatitis

白介素 31 在瘙痒和皮炎神经免疫界面的作用

基本信息

批准号：
10240316
负责人：
Marlys S Fassett
金额：
$ 17.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240316
关键词：
Ablation Address Adult Advisory Committees Affect Afferent Neurons Afferent Pathways Alleles Allergens Alopecia Animals Atopic Dermatitis Award Behavior Biological Biology CD4 Positive T Lymphocytes California Cells Child Chloroquine Clinical Clinical Trials Communication Couples Cutaneous Data Dermatitis Dermatologist Development Development Plans Doctor of Philosophy Elements Engineering Environment Exanthema Excoriation Foundations Functional disorder Future Genetic Genetic Epistasis Goals HTR2A gene Hematopoietic Histamine Immune Immune response Immune system Inflammation Inflammation Mediators Inflammatory Interleukin-13 Interleukin-4 Interleukins Knock-in Link Maps Mediating Mediator of activation protein Mentorship Mission Modeling Molecular Mouse Strains Mus National Institute of Arthritis and Musculoskeletal and Skin Diseases Nerve Nervous system structure Neurogenic Inflammation Neuroimmune Neurons Neurosciences PAR-2 Receptor Pain Pathway interactions Patient Care Patients Pattern Peptide Hydrolases Peripheral Physicians Population Postdoctoral Fellow Production Pruritus Recombinant Interleukins Reporter Research Resources San Francisco Scientist Sensory Signal Transduction Skin Source T-Lymphocyte TRPV1 gene Testing Therapeutic Therapeutic antibodies Tissues Training Transgenic Animals Transgenic Organisms Universities afferent nerve atopy behavior influence behavioral response career development cell type chronic inflammatory skin chronic itch cytokine effective therapy effector T cell eosinophil experimental study improved in vivo mast cell mouse genetics mouse model multidisciplinary neurotoxic novel overexpression psychosocial receptor response skin disorder tool

项目摘要

PROJECT SUMMARY/ABSTRACT Despite the clinical and psychosocial burden of itch in atopic dermatitis (AD), effective treatment options are limited. Interleukin-31 (IL-31), an inflammatory factor produced by skin T cells, has emerged as a powerful mediator of both itch and rash. When administered to skin, IL-31 can trigger dermatitis and activate cutaneous afferent sensory nerves to drive scratching behavior. Therapeutic antibodies directed against IL-31 and its receptor, IL31RA, have shown promise in clinical trials for AD and chronic pruritus. Yet fundamental questions about IL-31 biology remain. Which cells make IL-31? What pathways does IL-31 actuate in sensory afferent neurons? How do IL-31 signals integrate with other pruritogenic pathways in the context of inflammation? Improved definitions of the sources, pathways, and effector functions of IL-31 will substantially advance mechanistic understanding of the links between inflammation and itch. Dr. Fassett’s long-term research goal is to elucidate cellular and molecular mechanisms responsible for atopy-associated pruritus. The objective of this proposal is to use genetic mouse models to address the in vivo biology of IL-31 by examining the effects of endogenous IL-31 on cutaneous inflammation and pruritus sensory pathways. Dr. Fassett’s central hypothesis is that IL-31 couples itch and rash via its combined effects on pruritoceptive afferent pathways and cutaneous Th2 cytokine-mediated inflammation. Dr. Fassett will test this hypothesis using three specific aims. In Aim 1, Dr. Fassett will use novel IL31-deficient animals and IL31- tdTomato reporter animals to determine how multiple IL-31 source cell types functionally impact cutaneous Th2 inflammation in vivo. In Aim 2, she will elucidate the contribution of IL-31:IL31RA to atopy-associated pruritoceptive pathways including itch sensation and neurogenic inflammation. In Aim 3, she will determine how IL-31 alters afferent responses to other pruritogens, including Th2 cytokines. This project is relevant to the mission of NIAMS because it explores the mechanism of action of IL-31, a biologic target of potentially great therapeutic value for atopic dermatitis and for pruritus associated with other inflammatory skin diseases. Dr. Fassett is an MD PhD-trained Dermatologist working as a post-doctoral research fellow at the University of California, San Francisco. She is applying for a K08 Award to support her goal of becoming an independent physician scientist. UCSF’s exceptional training environment will support her efforts. Critical elements of her career development plan include mentorship by Dr. Mark Ansel, expert in cytokine biology and Th2 inflammation;; co-mentorship by Dr. Allan Basbaum, expert in pain and itch;; guidance by a multidisciplinary advisory committee including senior physician-scientists;; coursework in advanced experimental neuroscience;; and professional development activities. Taken together, this career development plan will provide Dr. Fassett with a strong foundation on which to build her growing expertise in the neuroimmune pathways that couple itch and rash.

项目概要/摘要尽管特应性皮炎（AD）瘙痒会带来临床和社会心理负担，但有效的治疗选择白细胞介素 31 (IL-31) 是一种由皮肤 T 细胞产生的炎症因子，现已成为一种强大的药物。 IL-31 是瘙痒和皮疹的介质。当施用到皮肤上时，IL-31 可以引发皮炎并激活皮肤。传入感觉神经驱动针对 IL-31 及其抓挠行为的治疗性抗体。受体 IL31RA 在治疗 AD 和慢性瘙痒症的临床试验中显示出了前景。关于 IL-31 的生物学特性。哪些细胞会产生 IL-31？IL-31 在感觉传入中激活哪些途径？在炎症情况下，IL-31 信号如何与其他致痒途径整合？ IL-31 的来源、途径和效应子功能的定义的改进将大大推进对炎症和瘙痒之间联系的机制理解。法塞特博士的长期研究目标是阐明负责的细胞和分子机制该提案的目的是使用遗传小鼠模型来解决体内的问题。通过检查内源性 IL-31 对皮肤炎症和瘙痒感觉的影响来研究 IL-31 的生物学 Fassett 博士的中心假设是 IL-31 通过其对瘙痒和皮疹的综合作用。 Fassett 博士将测试瘙痒传入通路和皮肤 Th2 细胞因子介导的炎症。使用三个特定目标的假设在目标 1 中，Fassett 博士将使用新型 IL31 缺陷动物和 IL31- tdTomato 报告动物确定多种 IL-31 源细胞类型如何在功能上影响皮肤 Th2 在目标 2 中，她将阐明 IL-31:IL31RA 对特应性相关的作用。在目标 3 中，她将确定瘙痒感受途径，包括瘙痒感和神经源性炎症。 IL-31 改变对其他瘙痒原（包括 Th2 细胞因子）的传入反应。 NIAMS 的使命是因为它探索了 IL-31 的作用机制，IL-31 是一个具有潜在巨大潜力的生物靶标。对特应性皮炎和与其他炎症性皮肤病相关的瘙痒具有治疗价值。 Fassett 博士是一位医学博士训练有素的皮肤科医生，在该大学担任博士后研究员她正在申请 K08 奖，以支持她成为独立人士的目标。加州大学旧金山分校卓越的培训环境将支持她的努力。职业发展计划包括细胞因子生物学和 Th2 炎症专家 Mark Ansel 博士的指导；由疼痛和瘙痒专家 Allan Basbaum 博士共同指导；由多学科咨询委员会提供指导；包括高级医师科学家；；以及高级实验神经科学课程；总而言之，该职业发展计划将为法塞特博士提供强大的支持。在此基础上，她在瘙痒和皮疹相关的神经免疫途径方面不断积累专业知识。