Paraoxonase-2 S311C Polymorphism Alters Glycosylation and Lactonase Activity

Paraoxonase-2 S311C 多态性改变糖基化和内酯酶活性

• 批准号: 7919812
• 负责人: DAVID A STOLTZ
• 金额: $ 5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919812
• 关键词: Advisory Committees; Affect; Amino Acids; Bacterial Genes; Bronchiectasis; Cause of Death; Cellular biology; Cessation of life; Chemicals; Chronic; Chronic lung disease; Clinical; Commit; Communication; Critical Care; Cysteine; Cystic Fibrosis; Data; Defect; Detection; Development; Development Plans; Disease; Disease Progression; Doctor of Philosophy; Ensure; Enzymes; Epithelial Cells; Faculty; Failure; Family; Fellowship; Fostering; Gene Expression; Gene Family; Genetic; Genetic Polymorphism; Gluconolactonase; Golgi Apparatus; Human; Human Genetics; Immunocompromised Host; Infection; Inherited; Iowa; Laboratory Study; Link; Lung; Mentors; Microbial Biofilms; Modification; Molecular and Cellular Biology; Mus; Nosocomial Infections; Oligosaccharides; Paraoxonase-2; Pathogenesis; Patients; Pattern; Physicians; Play; Positioning Attribute; Predisposition; Process; Production; Pseudomonas aeruginosa; Public Health; Regulation; Research; Research Personnel; Role; Scientist; Serine; Signal Transduction; Site; Symptoms; Testing; Training; United States; Universities; Variant; Virulence; airway epithelium; airway inflammation; body system; career development; design; experience; glycosylation; homoserine lactone; human PON2 protein; interest; member; novel therapeutics; programs; quorum sensing; respiratory; response; success; trafficking

DESCRIPTION (provided by applicant): This application is to provide support for a supervised research career development experience for Dr. David Stoltz in the field of airway cell biology. Dr. Stoltz has completed a combined M.D./Ph.D. program and is currently in the Pulmonary/Critical Care fellowship at the University of Iowa. His training plans include further didactic studies and laboratory training in cell and molecular biology and human genetics. These experiences will foster the development of Dr. Stoltz into an independent researcher and outstanding physician-scientist. Drs. Joseph Zabner, as primary mentor, and Michael Welsh, as co-mentor, will be responsible for ensuring the success of the career development plan. An advisory committee composed of experts in fields related to the proposed project will provide ongoing critical review and scientific as well as professional guidance. The proposed research will focus on regulation of Pseudomonas aeruginosa quorum sensing, an important determinant of bacterial virulence and biofilm formation, by paraoxonase-2 (PON2) in airway epithelial cells. We have recently shown that PON2 inactivates the P. aeruginosa quorum-sensing molecule, 3OC12-HSL and, of clinical interest, a common polymorphism in PON2 (Ser311Cys) impairs this response. My preliminary data suggest that differential glycosylation occurs between the PON2 variants. I hypothesize that the PON2 Ser311 Cys polymorphism results in impaired lactonase activity due to altered glycosylation and/or a PON2 trafficking/localization defect. The Specific Aims designed to test this hypothesis include: 1) Investigating which PON2 glycosylation sites undergo core glycosylation and modification, 2) Evaluating if the altered glycosylation pattern in the PON2 variants represents altered PON2 trafficking/localization, and 3) Determining if glycosylation is important for PON2 lactonase activity. Both the mentors and the University of Iowa are highly committed to Dr. Stoltz's academic success and development into an independent researcher. As a sign of this commitment, he will join the faculty of the Division of Pulmonary/Critical Care in July 2007. Dr Stoltz's research plan has great relevance to public health as P. aeruginosa is a common cause of infection and death in hospital acquired infections and cystic fibrosis, the most common inherited, lethal disorder in the United States. Findings from the proposed project will hopefully uncover new therapeutic options for P. aeruginosa infections.

描述(申请人提供)：本申请旨在为David Stoltz博士在呼吸道细胞生物学领域的指导研究生涯发展经验提供支持。斯托尔茨博士完成了医学博士和博士学位的结合项目，目前在爱荷华大学接受肺/重症监护研究。他的培训计划包括进一步的教学研究和实验室培训，内容包括细胞和分子生物学以及人类遗传学。这些经历将把斯托尔茨博士培养成一名独立的研究员和杰出的内科科学家。约瑟夫·扎布纳博士作为主要导师，迈克尔·威尔什作为共同导师，将负责确保职业发展计划的成功。一个由与拟议项目有关的领域的专家组成的咨询委员会将提供持续的批判性审查以及科学和专业指导。拟议的研究将集中在呼吸道上皮细胞中对氧磷酶-2(PON2)对铜绿假单胞菌群体感应的调控，对铜绿假单胞菌群体感应是细菌毒力和生物膜形成的重要决定因素。我们最近发现PON_2使铜绿假单胞菌群体感应分子3OC12-HSL失活，临床上，PON_2的一个常见的多态(Ser311Cys)会削弱这种反应。我的初步数据表明，PON2变异体之间发生了差异糖基化。我推测PON2Ser311 Cys多态可能是由于糖基化改变和/或PON2运移/定位缺陷而导致的乳糖酶活性降低。旨在验证这一假说的具体目的包括：1)调查PON2糖基化位点进行核心糖基化和修饰，2)评估PON2变异体中改变的糖基化模式是否代表PON2运输/定位的改变，以及3)确定糖基化对PON2内酯酶活性是否重要。导师和爱荷华大学都高度致力于斯托尔茨博士的学术成功和发展成为一名独立的研究人员。作为这一承诺的标志，他将于2007年7月加入肺/重症监护科教员。斯托尔茨博士的研究计划与公共卫生密切相关，因为铜绿假单胞菌是医院获得性感染和囊性纤维化的常见感染和死亡原因，囊性纤维化是美国最常见的遗传性致命疾病。拟议项目的研究结果有望为铜绿假单胞菌感染找到新的治疗选择。