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：
10025166
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/10025166
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.

项目摘要/摘要尽管特应性皮炎（AD）的临床和社会心理负担，有效的治疗选择有限。白介素-31（IL-31）是由皮细胞产生的炎症因子，已成为一种强大的最佳和皮疹的中介者。当给皮肤施用时，IL-31会触发皮炎并激活皮肤传入的感觉神经可以推动刮擦行为。针对IL-31的治疗抗体及其受体IL31RA在AD和慢性瘙痒的临床试验中表现出了希望。但基本问题大约IL-31生物学仍然存在。哪些细胞会产生IL-31？ IL-31在感觉传播中采取什么途径神经元？在炎症的背景下，IL-31信号如何与其他培养通路集成在一起？改进的IL-31来源，途径和效应子功能的定义将大大提高对炎症与威奇之间的联系的机械理解。 Fassett博士的长期研究目标是阐明负责的细胞和分子机制与特应相关的瘙痒。该建议的目的是使用遗传小鼠模型来解决体内通过检查内源性IL-31对皮肤炎症和瘙痒感的影响，IL-31的生物学途径。 Fassett博士的中心假设是IL-31夫妇通过其对培养基的传入途径和皮肤Th2细胞因子介导的炎症。 Fassett博士将对此进行测试假设使用三个特定目标。在AIM 1中，Fassett博士将使用新型的IL31缺陷动物和IL31-- TDTOMATO报告的动物确定多种IL-31源细胞类型在功能上如何影响皮肤TH2 体内炎症。在AIM 2中，她将阐明IL-31：IL31RA对与特应相关的贡献培养途径，包括瘙痒感和中性炎症。在AIM 3中，她将确定如何 IL-31改变了对包括Th2细胞因子在内的其他培养基的传入反应。该项目与 Niams的任务是因为它探讨了IL-31的作用机理，IL-31是潜在的生物学目标特应性皮炎和与其他炎症性皮肤疾病相关的瘙痒的治疗价值。 Fassett博士是一名受过医学博士培训的皮肤科医生，在大学担任博士后研究员加利福尼亚州，旧金山。她正在申请K08奖，以支持她成为独立的目标医师科学家。 UCSF的出色培训环境将支持她的努力。她的关键要素职业发展计划包括Cytokine Biology和Th2炎症专家Mark Ansel博士的指导；痛苦和答案专家Allan Basbaum博士的委托书；多学科咨询委员会的指导包括高级身体科学家；高级实验神经科学课程；和专业发展活动。综上所述，这项职业发展计划将为Fassett博士提供强大的在耦合和皮疹的神经免疫道路上建立她不断增长的专业知识的基础。