Manipulating Neuropeptide Receptors in Mast Cells for Atopic Dermatitis Treatment

 描述（由申请人提供）：这是一个指导科学家职业发展奖申请博士。匹兹堡大学医学院皮肤病学系研究讲师Sumpter说。Sumpter博士之前的培训集中在同种异体系统中非自身抗原耐受诱导的潜在分子机制。在皮肤科任职后，Sumpter博士研究了皮肤炎症的机制以及肥大细胞（MC）的神经免疫调节作用。她专注于启动和维持IgE介导的MC激活相关的过敏反应和特应性皮炎（AD）。该奖项将支持皮肤生物学，免疫学和MC功能方面的额外培训，以及转化研究和管理，领导力和granitarian。这项培训对于Sumpter博士转变为研究皮肤过敏性炎症的独立研究者是必要的。 本申请将进一步分析MC激活的机制，特别是在AD，一种常见的，使人衰弱的皮肤病，代表了一个严重的健康问题。我们将描述致病性T细胞反应的启动和局部组织损伤加重的IgE抗原激活的MC。AD与促炎性神经肽分泌增加相关，我们将分析它们在疾病发生和维持中的作用。具体而言，我们将分析MC激活后的分子途径，P物质（SP）和/或hemokinin-1（HK-1），神经激肽-1和-2受体（分别为NK 1 R和NK 2 R）的激动剂在MC中表达。事实上，NK 1 R和NK 2 R影响MC功能，并且通过这些受体的神经免疫调节在AD的病理性免疫应答中是中心的。该提议将检验干扰神经免疫MC活化将使AD的免疫组分最小化的假设。我们的假设将在三个目标中得到检验。目的1分析神经肽启动的细胞内通路在肥大细胞活化中的作用。目的2阐明NK 2 R在肥大细胞功能中的作用。目的3、利用两种体内AD模型来阐明 在与AD相关的细胞和分子级联中的NKR。此外，它将评估NK受体操纵在AD中的治疗潜力。本申请的总体目标是为Sumpter博士提供必要的额外培训，使其成为转化皮肤生物学的独立研究者，并为引入临床批准的NK受体抑制剂治疗AD患者复发提供依据。

 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.