Structural and Biochemical Basis of the Vitamin K cycle

描述（由申请人提供）：哮喘是一种慢性肺部炎症性疾病，被认为完全由Th2细胞的产物介导。初步证据表明，对过敏原诱导的气道高反应性（AHR）的遗传易感性是由于上皮细胞对吸入过敏原的不同反应。在易感动物中，上皮细胞来源的因子选择性地增强了肺髓树突状细胞（mDC）对th17倾斜细胞因子的激活和产生。然而，目前尚不清楚上皮如何增强mDC能力以促进Th17反应，或者Th17和Th2细胞如何协同加剧哮喘。目的是：1)确定负责促进肺部mDCs激活的上皮细胞因子，2)确定Th17反应在加剧th2相关病理中的作用，以及3)使用一种新的工具-来自协作交叉的重组近交系小鼠菌株-确定新的哮喘易感基因。本提案中概述的研究和职业发展活动将使候选人实现其长期职业目标，成为一名独立研究者，专注于解剖遗传差异如何影响上皮细胞调节树突状细胞活性的能力，并促进Th17 T细胞反应。为了获得必要的技能，候选人的K99研究将在哮喘遗传学和肺上皮培养技术领域的专家Marsha Wills-Karp的实验室进行，在那里他将获得培养和操作的专业知识

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the lung thought to be mediated exclusively by the products of Th2 cells. Preliminary evidence suggests that genetic susceptibility to allergen-induced airway hyperresponsiveness (AHR) results from differential epithelial cell responsiveness to inhaled allergen. In susceptible animals, epithelial cell-derived factors selectively enhance the activation, and production of Th17-skewing cytokines by pulmonary myeloid dendritic cells (mDC). However, it is unclear how the epithelium enhances mDC capacity to promote Th17 responses, or how Th17 and Th2 cells collaborate to exacerbate asthma. The aims are: 1) to identify the epithelial cell factors responsible for promoting the activation of pulmonary mDCs, 2) identify the role of Th17 responses in exacerbating the Th2-associated pathology, and 3) identify novel asthma susceptibility genes using a novel tool, recombinant inbred mouse strains from the Collaborative Cross. The studies and career development activities outlined in this proposal will allow the candidate to achieve his long term career goal of becoming an independent investigator with a focus on dissecting how genetic differences influence the ability of epithelial cells to regulate dendritic cell activity, and promote Th17 T cell responses. To acquire the necessary skill set, the candidate's K99 research will take place in the lab of Marsha Wills-Karp, an expert in the field of asthma genetics, and pulmonary epithelial culture techniques, where he will acquire expertise in the culture and manipulation of murine pulmonary epithelium. Moreover, during the mentored phase, the candidate will acquire expertise in the use of genetic and bioinformatics approaches to identify novel asthma susceptibility genes, through advanced training at the University of Cincinnati, and Jackson Laboratories. This training will be essential for completing the research proposed for the independent phase of this award. Subsequent studies to dissect the function of identified asthma susceptibility genes in murine and human populations will form the basis of future R01 applications, assisting in the transition to scientific independence.