Skin Neuroimmune Mechanisms of Urticarial Itch

荨麻疹瘙痒的皮肤神经免疫机制

• 批准号: 10683346
• 负责人: AARON VER HEUL
• 金额: $ 14.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683346
• 关键词: Advisory Committees; Affect; Afferent Neurons; Agonist; Allergens; Allergic Disease; Allergic inflammation; Antihistamines; Atopic Dermatitis; Automobile Driving; Award; Behavior; Biological Assay; Biological Models; Biology; Biopsy; Cell physiology; Cells; Chronic; Clinical; Communities; Complement; Data; Disease; Doctor of Philosophy; Economic Burden; Epithelium; Exposure to; Family member; Funding; G-Protein-Coupled Receptors; Gene Expression; Genetic Polymorphism; Genomics; Goals; Histamine; Human; Hypersensitivity; IgE; Immune; Immune response; Immunoglobulins; Immunology; Impairment; In Vitro; Inflammatory; Interleukins; Kinetics; Knockout Mice; Laboratories; Mediating; Mediator; Mentors; Microscopy; Mus; Neuroimmunomodulation; Neurons; Neuropeptides; Neurosciences; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Play; Population; Postdoctoral Fellow; Pruritus; Publishing; Quality of life; Records; Recurrence; Research; Research Personnel; Resources; Role; Sampling; Scientist; Severities; Signal Transduction; Skin; Symptoms; Technical Expertise; Testing; Tissues; Training; Transfection; Universities; Urticaria; Variant; Virulence Factors; Vocational Guidance; Washington; Work; Writing; anti-IgE; crosslink; cytokine; disabling symptom; effective therapy; functional genomics; humanized mouse; in vitro Assay; in vivo; insight; instructor; interest; mast cell; mouse model; neuroimmunology; novel; novel therapeutics; persistent symptom; promoter; response; single-cell RNA sequencing; skills; small molecule; translational model; two photon microscopy

PROJECT SUMMARY This proposal defines a 5-year plan to prepare Aaron Ver Heul, MD, PhD, to reach his long-term goal of independence as a physician-scientist studying the neuroimmunology of allergic diseases. He is currently an Instructor in the Division of Allergy and Immunology at Washington University doing post-doctoral studies in the laboratory of Dr. Brian Kim. There, Dr. Ver Heul has studied basic mechanisms of itch to complement his clinical interest in chronic spontaneous urticaria (CSU), an itchy skin condition characterized by exaggerated mast cell (MC) responses. He has demonstrated that the cytokine interleukin (IL)-33 enhances itch in a MC-dependent manner and proposes to extend these studies to CSU. Thus, the primary scientific goal of this proposal is to understand the role of IL-33 in CSU and itch. Washington University is an ideal place to perform the proposed training and research, with outstanding resources and expertise readily available. Dr. Brian Kim, the primary mentor, is an expert in neuroimmunology, atopic dermatitis, and itch. Dr. Steve Brody, the co-mentor, is an expert in translational models of epithelial biology. Both have strong records of continuous funding and training successful scientists. Dr. Ver Heul has also assembled an advisory committee with expertise in immunology, neuroscience, functional genomics, and in vivo microscopy, who will provide crucial scientific training and career guidance. He will take didactics in genomics, microscopy, and scientific writing. He will have multiple opportunities to present his work locally and to the larger scientific community. Dr. Ver Heul’s immediate objectives during the award period are to acquire requisite skills to complete the proposed research, publish the results, and successfully obtain independent funding. IL-33 is increased in a variety of allergic diseases including CSU, which affects 1% of the population. MCs are highly responsive to IL-33, and exaggerated MC activation is a major contributor to CSU pathogenesis. Recently, two distinct pathways by which MCs can be activated to cause itch were identified. One responds to allergens, while the other responds to a variety of small molecules including neuropeptides and many common drugs (known as basic secretagogues). Taken together with the demonstration that IL-33 enhances histaminergic itch, Dr. Ver Heul now proposes to test the hypothesis that IL-33 broadly amplifies different forms of MC-mediated itch responses. By completing the proposed aims, Dr. Ver Heul will define 1) how IL-33 enhances allergen- mediated itch and 2) how IL-33 enhances basic secretagogue-mediated itch. The proposed studies determine mechanisms of IL-33-enhanced MC activation in vitro and in mouse models of itch and extend these findings to analyses of CSU patient samples. Fulfilling the aims will provide new insight into mechanisms of CSU and itch and establish Dr. Ver Heul as an independent investigator in allergy and immunology.

项目总结

项目成果

Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis.

在特应性皮炎小鼠模型中，Difelikefalin 可抑制瘙痒并减少抓挠，而与炎症无关。

• DOI: 10.1016/j.jaci.2023.06.022
• 发表时间: 2023
• 期刊: The Journal of allergy and clinical immunology
• 作者: Tamari,Masato;Zamidar,Lydia;VerHeul,AaronM;Nograles,Kristine;Goncalves,Joana;Guttman-Yassky,Emma;Lebwohl,Mark;Kim,BrianS
• 通讯作者: Kim,BrianS