Role of Salt, Isoketal-modified Proteins and Dendritic Cells in Hypertension

盐、异缩酮修饰蛋白和树突状细胞在高血压中的作用

• 批准号: 9014703
• 负责人: Annet Kirabo
• 金额: $ 3.96万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014703
• 关键词: Angiotensin II; Antigens; Biochemistry; Biology; Cardiovascular Diseases; Cardiovascular system; Career Mobility; Cause of Death; Cells; Cellular biology; Clinical; Clinical Pharmacology; Complex; Data; Dendritic Cells; Development; Disease; Doctor of Philosophy; Doctor of Veterinary Medicine; Environment; Ethers; Etiology; Excess Dietary Salt; Faculty; Florida; Free Radicals; Funding; Glucokinase; Histocompatibility; Hypertension; IL6 gene; Immunology; Inflammation; Interleukin-1 beta; Interleukin-17; Investigation; Isoprostanes; Journals; Laboratories; Lead; Lipid Peroxidation; Lysine; Major Histocompatibility Complex; Master of Science; Mediating; Medicine; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Mining; Minnesota; Molecular Biology; Mus; NADP; NADPH Oxidase; Oxidases; Pathogenesis; Pathway interactions; Peptides; Physiology; Positioning Attribute; Post-Translational Protein Processing; Postdoctoral Fellow; Process; Production; Proliferating; Proteins; Research; Research Personnel; Risk; Risk Factors; Role; Science; Signal Transduction; Sodium; Sodium Chloride; Stimulus; Superoxides; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Time; Training; Training Activity; Training Programs; Uganda; Universities; Vent; Veterinary Medicine; Work; abstracting; adduct; base; career development; college; cytokine; experience; functional genomics; immunogenic; instructor; interest; ketoaldehyde; member; novel; novel therapeutic intervention; programs; response; salt intake; salt sensitive hypertension; tenure track

 DESCRIPTION (provided by applicant): This proposal details a five-year mentored training program for career development and advancement of Dr. Annet Kirabo, D.V.M., M.Sc., Ph.D., the principle investigator, into an independent investigator. Dr. Kirabo is a Research Instructor i the Division of Clinical Pharmacology at Vanderbilt University. She obtained a Doctorate of Veterinary Medicine from Makerere University, Uganda, A Master of Science in Cell and Molecular Biology from St. Cloud State University, Minnesota, and a Ph.D. from the University of Florida, College of Medicine Interdisciplinary Program in Biomedical Sciences, Department of Physiology and Functional Genomics. In 2011, she joined Dr. David Harrison's laboratory as a Post-Doctoral Fellow and became interested in the role of inflammation in hypertension. During her K01 award, she will continue to work with Dr. Harrison, but will expand her research expertise via co-mentorship from Dr. Sebastian Joyce and input from an outstanding mentoring committee. As a postdoctoral fellow, Dr. Kirabo defined a novel role of antigen presenting dendritic cells in hypertension and showed that this is due to oxidative protein modifications by highly reactive γ-ketoaldehydes, also known as isoketals. Isoketals are produced via the isoprostane pathway of lipid peroxidation and rapidly react with protein lysines. Dr. Kirabo showed that isoketal-adducted proteins are immunogenic, and are presented by dendritic cells, which in turn activate T cells. In aim 1, Dr. Kirabo will examine mechanisms by which sodium promotes production of immunogenic isoketals in dendritic cells and determine the role of the salt-sensing glucokinase (SGK1) in this process. In aim 2, she will detect isoketal-modified peptides presented by class one major histocompatibility complexes, and determine if these are increased or altered in response to hypertensive stimuli such as salt and angiotensin II. These studies will have significant implications for the field, and will provide a more comprehensive understanding of the pathogenesis of hypertension. Scavenging of isoketals may provide a new therapeutic approach for treatment of this important disease. During her planned research, Dr. Kirabo will become experienced with cutting edge approaches to study MHC biology and biochemistry. In addition, Dr. Kirabo's training plan includes didactic courses, seminars, and participation in career development programs at Vanderbilt that promote the retention and tenure of junior faculty members. Drs. Harrison and Kirabo have developed a time line for her career development and training activities that will enable her to compete for funding and develop into an independent investigator in the field of inflammation and hypertension. 100% of her time will be protected for activities directly related to her career development with at least 80% for research. The Vanderbilt research and academic environment is highly exceptional for trainee career development. (End of Abstract)

 描述（由申请人提供）：本提案详细介绍了一个为期五年的指导培训计划，用于Annet Kirabo博士的职业发展和晋升，D.V.M.，理学硕士，哲学博士、从首席调查员变成独立调查员Kirabo博士是范德比尔特大学临床药理学系的研究导师。她在乌干达马凯雷雷大学获得兽医学博士学位，在明尼苏达州圣克劳德州立大学获得细胞和分子生物学理学硕士学位，并在美国明尼苏达州获得博士学位。来自佛罗里达大学医学院生物医学科学跨学科项目，生理学和功能基因组学系。2011年，她加入了大卫哈里森博士的实验室，担任博士后研究员，并对炎症在高血压中的作用产生了兴趣。在她的K 01奖，她将继续与哈里森博士，但将扩大她的研究专业知识，通过共同指导博士塞巴斯蒂安乔伊斯和输入从一个优秀的指导委员会。作为博士后研究员，Kirabo博士定义了抗原呈递树突状细胞在高血压中的新作用，并表明这是由于高反应性γ-酮醛（也称为异酮醛）对氧化蛋白质的修饰。异缩酮通过脂质过氧化的异前列烷途径产生，并与蛋白质赖氨酸快速反应。Kirabo博士表明，异缩酮加合蛋白具有免疫原性，并由树突状细胞呈递，树突状细胞反过来激活T细胞。在目标1中，Kirabo博士将研究钠促进树突状细胞中免疫原性异缩酮产生的机制，并确定盐敏感葡萄糖激酶（SGK 1）在这一过程中的作用。在目标2中，她将检测由第一类主要组织相容性复合物呈递的异缩酮修饰的肽，并确定这些肽是否在对高血压刺激（如作为盐和血管紧张素II）的反应中增加或改变。这些研究将对该领域具有重要意义，并将为高血压的发病机制提供更全面的了解。清除异缩酮可能为治疗这一重要疾病提供新的治疗方法。Kirabo博士将在研究MHC生物学和生物化学的前沿方法方面积累经验。此外，Kirabo博士的培训计划包括教学课程、研讨会和参与范德比尔特的职业发展计划，这些计划旨在促进初级教师的留任和终身任职。Harrison和Kirabo博士为她的职业发展和培训活动制定了一个时间表，这将使她能够竞争资金，并发展成为炎症和高血压领域的独立研究者。100%的时间将被用于与其职业发展直接相关的活动，至少80%的时间用于研究。范德比尔特大学的研究和学术环境对于学员的职业发展来说是非常特殊的。(End摘要）