Structural and Biochemical Basis of the Vitamin K cycle

维生素 K 循环的结构和生化基础

基本信息

批准号：
7714059
负责人：
Weikai Li
金额：
$ 9万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7714059
关键词：
Acids Address Allergens Amino Acids Animals Anticoagulants Area Asthma Award Binding Biochemical Bioinformatics Biological Assay Blood Coagulation Factor Blood Vessels Breathing Calcium ion Catalysis Chronic Complex Coumarins Coupled Couples Culture Techniques Cysteine Deep Vein Thrombosis Dendritic Cells Disease Electron Transport Electrons Enzymes Epithelial Epithelial Cells Epithelium Future Genetic Genetic Predisposition to Disease Goals Hemorrhage High Pressure Liquid Chromatography Homologous Gene Human Hydroquinones Inbred Strains Mice Inflammatory Laboratories Lead Lung Lung diseases Maps Mediating Medical Membrane Membrane Proteins Mentors Methods Modeling Molecular Conformation Mus Mutagenesis Mutation Myelogenous Myocardial Infarction Oral Pancreatic ribonuclease Pathology Pathway interactions Peptides Periplasmic Proteins Pharmaceutical Preparations Phase Population Principal Investigator Production Protein Disulfide Isomerase Protein translocation Proteins Publishing Pulmonary Embolism Quinones Reaction Recombinants Research Research Personnel Resolution Role Scientist Series Staging Stroke Structure Surface Susceptibility Gene Synechococcus T-Lymphocyte Th2 Cells Therapeutic Thioredoxin Thrombosis Training Universities Vitamin K Vitamins Warfarin Work airway hyperresponsiveness alpha benzopyrone base carboxylation career career development cofactor cytokine density design drug mechanism electron density electron donor epoxidase gamma-glutamyl carboxylase high risk hydroquinone improved inhibitor/antagonist mutant novel periplasm prevent reduced vitamin K research study resistance mutation response sample fixation skills tool vitamin K epoxide reductase vitamin K1 oxide

项目摘要

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.

描述（由申请人提供）：哮喘是一种肺部慢性炎症性疾病，被认为仅由 Th2 细胞产物介导。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性所致。在易感动物中，上皮细胞衍生因子选择性增强肺髓树突状细胞 (mDC) 的激活和 Th17 偏向细胞因子的产生。然而，尚不清楚上皮如何增强 mDC 促进 Th17 反应的能力，或者 Th17 和 Th2 细胞如何协作加剧哮喘。目的是：1）确定负责促进肺 mDC 活化的上皮细胞因子，2）确定 Th17 反应在加剧 Th2 相关病理学中的作用，以及 3）使用新工具确定新的哮喘易感基因，来自 Collaborative Cross 的重组近交小鼠品系。该提案中概述的研究和职业发展活动将使候选人能够实现其成为独立研究者的长期职业目标，重点是剖析遗传差异如何影响上皮细胞调节树突状细胞活性和促进 Th17 T 的能力细胞反应。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肺上皮细胞的专业知识。小鼠肺上皮。此外，在指导阶段，候选人将通过辛辛那提大学和杰克逊实验室的高级培训，获得使用遗传和生物信息学方法来识别新型哮喘易感基因的专业知识。该培训对于完成该奖项独立阶段提出的研究至关重要。随后对小鼠和人类群体中已确定的哮喘易感基因功能进行剖析的研究将构成未来 R01 应用的基础，有助于向科学独立的过渡。