Manipulating Neuropeptide Receptors in Mast Cells for Atopic Dermatitis Treatment

操纵肥大细胞中的神经肽受体治疗特应性皮炎

• 批准号: 8967414
• 负责人: Tina L Sumpter
• 金额: $ 8.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967414
• 关键词: Accounting; Adult; Affect; Affinity; Agonist; Allergic inflammation; Allogenic; Anaphylaxis; Antigens; Appointment; Asthma; Atopic Dermatitis; Award; Binding; Biology; Blocking Antibodies; Cell physiology; Child; Complex; Cromoglicic Acid; Cutaneous; Dendritic Cells; Dendritic cell activation; Dermal; Dermatologist; Dermatology; Development; Disease; Equilibrium; Evolution; Family member; Fiber; Food Hypersensitivity; Genetic; Genetic Transcription; Health; Histamine; IL4 gene; IgE; Immune; Immune response; Immunology; Immunosuppression; Immunotherapy; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-13; Interleukin-5; Interleukin-6; Intervention; K-Series Research Career Programs; Leadership; Leukocytes; Maintenance; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular; Mus; Neurokinin A; Neuropeptide Receptor; Neuropeptides; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phase; Prevention; Production; Publishing; Receptor Signaling; Regulation; Relapse; Research; Research Personnel; Risk Factors; Role; Scientist; Signal Transduction; Skin; Substance P; Substance P Receptor; System; T cell response; Tachykinin; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Translational Research; Tumor Necrosis Factor-alpha; Universities; Visit; anti-IgE; antigen binding; base; cost; cost effective; cytokine; desensitization; immune activation; immunopathology; in vivo; inhibitor/antagonist; innovation; instructor; mast cell; medical schools; novel therapeutics; public health relevance; receptor; receptor expression; response; skin disorder; socioeconomics; transcription factor

 DESCRIPTION (provided by applicant): This is a Mentored Scientist Career Development Award application for Dr. Tina L. Sumpter, Research Instructor in the Department of Dermatology, School of Medicine, at the University of Pittsburgh. Dr. Sumpter's prior training focused on the underlying molecular mechanisms of tolerance induction to non-self-antigens in the allogeneic system. Following, her appointment in the Department of Dermatology, Dr. Sumpter studied the mechanisms of cutaneous inflammation, and the role of neuro-immune regulation of mast cell (MCs). She focused on initiation and maintenance of IgE-mediated MC activation relevant for anaphylaxis and atopic dermatitis (AD). This award will support additional training in facets of skin biology, immunology and MC function, and translational research and in management, leadership and grantsmanship. This training is necessary for Dr. Sumpter's transition to an independent investigator studying allergic inflammation in the skin. This application will further analyze the mechanisms of MC activation specifically in AD, a common, debilitating skin disease that represents a serious health problem. We will delineate the initiatio of pathogenic T cell responses and local tissue damage aggravated by IgE-Ag activated MCs. AD correlates with increased secretion of pro-inflammatory neuropeptides and we will analyze their role in the initiation and maintenance of disease. Specifically, we will analyze the molecula pathways following MC activation by substance P, (SP) and/or hemokinin-1 (HK-1), both agonists of the neurokinin-1 and -2 receptors (NK1R and NK2R, respectively) expressed in MC. Indeed, NK1R and NK2R affect MC function, and neuro-immune regulation via these receptors is central in the pathologic immune responses of AD. This proposal will test the hypothesis that interfering with neuro-immune MC activation will minimize the immune component of AD. Our hypothesis will be tested in three aims. Aim 1 will analyze the role of intracellular pathways initiated by neuropeptides in mast cell activation. Aim 2 delineates the function of the NK2R in mast cell function in vitro and in vivo. Aim 3, using two in vivo AD models will delineate the role of NKR in the cellular and molecular cascades relevant for AD. Furthermore, it will assess the therapeutic potential of NK receptor manipulation in AD. The overarching objectives of this application are to provide additional training necessary for Dr. Sumpter to establish herself as an independent researcher in translational cutaneous biology and to provide rationale for the introduction of clinically approved NK receptor inhibitors to treat relapses in AD patients.

 描述（由应用程序提供）：这是匹兹堡大学医学院皮肤病学研究讲师Tina L. Sumpter博士的指导科学家职业发展奖。 Sumpter博士先前的培训集中在同种异体系统中对非抗原抗原的耐受性诱导的基本分子机制。随后，她在皮肤病学系任命，Sumpter博士研究了皮肤注射的机制，以及肥大细胞（MCS）的神经免疫调节的作用。她专注于与过敏反应和特应性皮炎有关的IgE介导的MC激活的启动和维持。该奖项将支持在皮肤生物学，免疫学和MC功能以及转化研究以及管理，领导力和赠款技巧方面的额外培训。这项训练对于Sumpter博士向研究皮肤过敏性注射的独立研究人员的过渡是必要的。该应用将进一步分析AD中MC激活的机制，AD是一种常见的，使人衰弱的皮肤病，代表了严重的健康问题。我们将描述病原T细胞反应和IgE-AG激活MC汇总的局部组织损伤的倡议。 AD与促炎性神经肽的分泌增加相关，我们将分析它们在疾病主动和维持中的作用。具体而言，我们将通过MC中表达的Neurokinin-1和-2受体（NK1R和NK2R）的激动剂（分别为NK1R和NK2R）分析MC激活后MC激活后的分子途径。实际上，NK1R和NK2R会影响MC功能，而通过这些受体进行神经免疫调节是AD的病理免疫反应中的核心。该提案将检验以下假设：干扰神经免疫MC激活将最大程度地减少AD的免疫成分。我们的假设将以三个目标进行检验。 AIM 1将分析神经肽在肥大细胞激活中引发的细胞内途径的作用。 AIM 2描述了NK2R在体外和体内肥大细胞功能中的功能。 AIM 3，使用两个体内广告模型将描述角色 与AD相关的细胞和分子级联反应中的NKR。此外，它将评估AD中NK受体操纵的治疗潜力。本应用程序的总体目标是为Sumpter博士提供所需的额外培训，以使自己成为转化皮肤生物学领域的独立研究人员，并为引入临床认可的NK受体抑制剂的引入以治疗AD患者的继承提供理由。