Innate Signaling, Cysteinyl Leukotrienes, and Asthma Elicited by House Dust Mite

描述(由申请者提供)：本建议书详细介绍了一项为期5年的培训计划，旨在发展哮喘和过敏性炎症的学术生涯。PI将专注于获得分子生物学和哮喘小鼠模型方面的关键技能，以成为一名独立的研究人员。PI在布里格姆妇女医院完成了肺部、过敏和免疫学方面的奖学金，包括为期两年的关于半胱氨酰白三烯(Cys-LTs)作为强大的促炎介质的作用的研究。她现在是一名医学讲师，计划在弗兰克·奥斯汀博士(导师)和金冈博士(共同导师)的指导下继续进行基础科学研究。 尘螨是世界范围内最重要的过敏原之一，与哮喘的发病机制有关。奥斯汀博士的实验室最近的工作表明，屋尘螨提取物中的葡聚糖能诱导大量产生Cys-LTs，而且髓系C型凝集素受体Dectin-2介导了这一过程。这项工作描述了一种新的过敏原促进炎症的机制，并确定了这种新描述的模式识别受体的重要功能。在拟议的计划中，我们将研究Dectin-2信号和随后产生的Cys-LT在树突状细胞激活(AIM 1)和对尘螨反应的先天和获得性肺部炎症(AIM 2)中的作用。 这位导师是该领域的一位杰出的科学家，有50多名受训人员，完全专注于他目前的实验室计划。共同导师是一位资深的分子生物学家，他将直接指导学员。此外，一个咨询小组还包括模式识别受体(小林博士)和二十烷类生物学(博伊斯博士)方面的专家。兰布雷希特博士是研究哮喘中树突状细胞功能的小鼠模型的专家，他将提供咨询。这项研究将在高度合作的炎症和过敏性疾病研究科进行，这是额外支持的来源。最后，该机构致力于提供必要的资源和培训，帮助首席调查员建立独立的职业生涯。 相关性(见说明)：屋尘螨是全世界最重要的过敏原因之一，这种过敏是哮喘发生的风险因素。确定这种室内尘螨具有如此高的免疫原性的研究将有助于设计新的哮喘预防和治疗方法。

DESCRIPTION (provided by applicant): This proposal details a 5-year training program for the development of an academic career in the pathogenesis of asthma and allergic inflammation. The PI will focus her efforts on acquiring critical skills in molecular biology and mouse models of asthma to become an independent investigator. The PI completed fellowships in Pulmonary and in Allergy and Immunology at Brigham and Women's Hospital, including two years of research on the role of cysteinyl leukotrienes (cys-LTs) as powerful pro-inflammatory mediators. She is now an Instructor in Medicine with plans to continue basic science research under the direction of Dr. Frank Austen (mentor) and Dr. Yoshihide Kanaoka (co-mentor). Dust mite is one of the most significant allergens world-wide and has been linked to asthma pathogenesis. Recent work in Dr. Austen's lab shows that glycans in house dust mite extract elicit robust production of cys-LTs, and that the myeloid C-type lectin receptor, Dectin-2, mediates this process. This work describes a novel mechanism by which allergens can promote inflammation and identifies an important function for this newly-described pattern-recognition receptor. In the proposed plan, we will investigate the role of Dectin-2 signaling, and the subsequent cys-LTs produced, in dendritic cell activation (Aim 1) and in the generation of innate and adaptive pulmonary inflammation (Aim 2) in response to dust mite. The mentor is an eminent scientist in the field with over 50 established trainees and is fully focused on his current laboratory program. The co-mentor is an established molecular biologist who will directly supervise the trainee. In addition, an advisory group includes experts in pattern recognition receptors (Dr. Kobayashi) and eicosanoid biology (Dr. Boyce). Dr. Lambrecht, an expert in mouse models of dendritic cell function in asthma, will consult. The research will take place within the highly collaborative Inflammation and Allergic Diseases Research Section, a source of additional support. Lastly, the institution is committed to providing the necessary resources and training to help the primary investigator establish an independent career. RELEVANCE (See instructions): House dust mite is one of the most significant causes of allergy worldwide, and this allergy is a risk factor for the development of asthma. Studies to determine why this house dust mite is so immunogenic will be helpful to design new therapies for asthma prevention and treatment.