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）：该提案详细介绍了一项为期五年的指导培训计划，旨在将主要研究者 Annet Kirabo 博士（D.V.M.、M.Sc.、Ph.D.）职业发展和晋升为独立研究者。 Kirabo 博士是范德比尔特大学临床药理学部的研究讲师。她在乌干达麦克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圣克劳德州立大学获得细胞和分子生物学理学硕士学位。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，她作为博士后加入 David Harrison 博士的实验室，并对炎症在高血压中的作用产生了兴趣。在获得 K01 奖期间，她将继续与哈里森博士合作，但将通过塞巴斯蒂安·乔伊斯博士的共同指导和杰出指导委员会的投入来扩展她的研究专业知识。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）对氧化蛋白的修饰所致。异酮缩醇是通过脂质过氧化的异前列烷途径产生的，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，由树突状细胞呈递，进而激活 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 (SGK1) 在此过程中的作用。在目标 2 中，她将检测由一类主要组织相容性复合物呈现的异缩酮修饰肽，并确定这些肽是否因盐和血管紧张素 II 等高血压刺激而增加或改变。这些研究将对该领域产生重大影响，并将提供对高血压发病机制的更全面的了解。异缩酮的清除可能为治疗这一重要疾病提供新的治疗方法。在她计划的研究期间，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、研讨会以及参与范德比尔特大学的职业发展计划，以促进初级教员的保留和终身任职。博士。哈里森和基拉博为她的职业发展和培训活动制定了时间表，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。她 100% 的时间将用于与职业发展直接相关的活动，其中至少 80% 用于研究。范德堡大学的研究和学术环境对于实习生的职业发展来说非常特殊。 （摘要完）