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:10470809
- 负责人:
- 金额:$ 17.75万
- 依托单位:
- 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:
- 关键词:AblationAddressAdultAdvisory CommitteesAffectAfferent NeuronsAfferent PathwaysAllelesAllergensAlopeciaAnimalsAtopic DermatitisAwardBehaviorBiologicalBiological ProductsBiologyCD4 Positive T LymphocytesCaliforniaCellsChildChloroquineClinicalClinical TrialsCommunicationCouplesCutaneousDataDermatitisDermatologistDevelopmentDevelopment PlansDoctor of PhilosophyElementsEngineeringEnvironmentExanthemaExcoriationFoundationsFunctional disorderFutureGeneticGenetic EpistasisGoalsHTR2A geneHematopoieticHistamineImmuneImmune responseImmune systemInflammationInflammation MediatorsInflammatoryInterleukin-13Interleukin-4InterleukinsKnock-inLinkMapsMediatingMediator of activation proteinMentorshipMissionModelingMolecularMouse StrainsMusNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNerveNervous system structureNeurogenic InflammationNeuroimmuneNeuronsNeurosciencesPAR-2 ReceptorPainPathway interactionsPatient CarePatientsPatternPeptide HydrolasesPeripheralPhysiciansPopulationPostdoctoral FellowProductionPruritusRecombinant InterleukinsReporterResearchResourcesSan FranciscoScientistSensorySignal TransductionSkinSourceT-LymphocyteTRPV1 geneTestingTherapeuticTherapeutic antibodiesTissuesTrainingTransgenic AnimalsTransgenic OrganismsUniversitiesafferent nerveatopybehavior influencebehavioral responsecareer developmentcell typechronic inflammatory skinchronic itchcytokineeffective therapyeffector T celleosinophilexperimental studyimprovedin vivomast cellmouse geneticsmouse modelmultidisciplinaryneurotoxicnoveloverexpressionpsychosocialreceptorresponseskin disordertool
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)瘙痒症的临床症状和心理社会负担较低,但仍有有效的治疗方法和选择。
白介素31(IL-31)是一种由皮肤和T细胞产生的致炎因子,已成为一种强大的免疫球蛋白。
中介人认为皮肤既有瘙痒,又有皮疹。当给皮肤用药时,IL-31可能会引发皮炎,并激活皮肤。
传入感觉神经驱动抓挠行为。治疗性免疫抗体针对IL-31及其受体。
受体IL31RA已经在治疗阿尔茨海默病和慢性皮肤瘙痒的临床试验中显示出了希望。但还没有基本的临床问题。
关于IL-31的生物学仍将存在。哪些细胞可以产生IL-31?IL-31是通过什么途径在感觉传入中激活的。
神经元?在慢性炎症的背景下,IL-31信号如何与其他促瘙痒信号通路整合?
改进对IL-31的主要来源、途径、细胞和效应器功能的定义将大大促进这一进程。
对炎症和瘙痒之间的联系的机械性理解。
*法西特博士的长期研究和目标是为了阐明细胞和分子生物学机制对癌症的责任。
特应性-相关的皮肤瘙痒。这项新提案的主要目标是在体内使用基因突变的小鼠模型来解决这一问题。
IL-31的生物学研究是通过研究内源性IL-31对皮肤炎症和感觉瘙痒的影响来实现的。
路径。法西特博士的核心假设是,IL-31可通过其综合效应影响患者的皮肤瘙痒和皮疹。
瘙痒感受性传入神经通路和皮肤Th2细胞因子介导的炎症。Fassett博士将对此进行测试。
假设使用了三个特定的目标。在目标1中,法西特博士将不会使用新的IL31缺乏的动物,而将使用IL31-
TdTomato的记者试图通过动物来确定多种来源的IL-31来源的细胞类型在功能上如何影响皮肤Th2细胞。
炎症存在于体内。在Aim 2中,她将进一步阐明IL-31:IL31RA对特应性疾病的主要贡献。
瘙痒感受性通路包括瘙痒、感觉和神经源性炎症。在目标3中,她不会决定如何治疗。
IL-31可以改变对其他皮肤瘙痒原的传入反应,包括Th2细胞因子。这一项目的实施与治疗无关。
NIAMS的使命是因为它探索了IL-31的作用机制,成为潜在的伟大的生物和靶向基因。
特应性皮炎的治疗价值很高,瘙痒和其他炎症性皮肤疾病的治疗价值也很高。
Fassett博士是一名医学博士和博士学位的皮肤科医生,目前在北京大学从事博士后医学研究和研究员工作。
她正在申请一项K08大奖,以进一步支持她成为一名独立候选人的目标。
她是一名医生和科学家。加州大学旧金山分校独特的环境培训将继续支持她的努力。这是她成功的关键要素
职业发展计划将包括博士的指导,他是细胞因子和生物学方面的专家,也是Th2炎症方面的专家;;。
共同指导由美国疼痛和瘙痒方面的专家Allan和Basbaum博士提供;;由一个多学科的医疗咨询委员会提供指导。
包括高级内科医生兼科学家;;和高级实验神经科学的课程工作;;专家和专业人员。
发展与活动。综合来看,这份新的职业发展计划将为法西特博士提供一个强大的团队。
基金会致力于帮助她在治疗瘙痒和皮疹的主要神经免疫途径方面积累越来越多的专业知识。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marlys S Fassett其他文献
Marlys S Fassett的其他文献
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{{ truncateString('Marlys S Fassett', 18)}}的其他基金
Illuminating IL-31-producing cells in allergic skin disease
照亮过敏性皮肤病中产生 IL-31 的细胞
- 批准号:
10729476 - 财政年份:2023
- 资助金额:
$ 17.75万 - 项目类别:
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
- 批准号:
10240316 - 财政年份:2019
- 资助金额:
$ 17.75万 - 项目类别:
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
- 批准号:
10684666 - 财政年份:2019
- 资助金额:
$ 17.75万 - 项目类别:
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
- 批准号:
10025166 - 财政年份:2019
- 资助金额:
$ 17.75万 - 项目类别:
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