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
• 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
• 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

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.

项目总结/文摘