Manipulating Neuropeptide Receptors in Mast Cells for Atopic Dermatitis Treatment

 描述(由申请人提供)：这是匹兹堡大学医学院皮肤科研究讲师蒂娜·L·桑普特博士的导师科学家职业发展奖申请书。桑普特博士之前的培训重点是同种异体系统中诱导对非自身抗原耐受的潜在分子机制。在被任命为皮肤科医生后，桑普特博士研究了皮肤炎症的机制，以及肥大细胞(MCs)的神经免疫调节作用。她专注于与过敏反应和特应性皮炎(AD)相关的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功能方面的额外培训，以及翻译研究和管理、领导力和资质方面的培训。对于桑普特博士转变为一名研究皮肤过敏性炎症的独立研究员来说，这种培训是必要的。这项应用将进一步分析MC激活的机制，特别是在AD中，AD是一种常见的、令人衰弱的皮肤病，代表着严重的健康问题。我们将描述IgE-Ag激活的MC引起的致病T细胞应答和局部组织损伤的始动机制。AD与促炎神经肽的分泌增加相关，我们将分析它们在疾病发生和维持中的作用。具体地说，我们将分析MC表达的神经激肽-1和-2受体(分别为NK1R和NK2R)的激动剂P物质(SP)和/或血激素-1(HK-1)激活MC后的分子通路。事实上，NK1R和NK2R影响MC功能，通过这些受体进行的神经免疫调节是AD病理免疫反应的中心。这一提议将检验这样一种假设，即干扰神经免疫MC激活将使AD的免疫成分最小化。我们的假设将在三个目标上得到检验。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NK2R在体内外肥大细胞功能中的作用。目标3，使用两个活体AD模型将描述其作用 NKR在与AD相关的细胞和分子级联中的表达。此外，它还将评估NK受体操作在AD中的治疗潜力。这项申请的主要目的是为桑普特博士提供必要的额外培训，使她成为转化皮肤生物学领域的独立研究人员，并为推出临床批准的NK受体抑制剂来治疗AD患者的复发提供理论依据。

 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.