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

 描述(由申请人提供)：本建议书详细介绍了一项为期五年的辅导性培训计划，旨在将首席调查员Annet Kirabo博士提升为独立调查员。Kirabo博士是范德比尔特大学临床药理学分部的研究讲师。她在乌干达Makerere大学获得兽医博士学位，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，并在佛罗里达大学生物医学学院生物医学跨学科项目生理学和功能基因组系获得博士学位。2011年，她以博士后身份加入大卫·哈里森博士的实验室，开始对炎症在高血压中的作用感兴趣。在K01奖项期间，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一个杰出的指导委员会的投入来扩大她的研究专长。作为博士后研究员，Kirabo博士定义了抗原提呈树突状细胞在高血压中的新角色，并表明这是由于高活性的γ-酮醛(也称为异酮类)对蛋白质的氧化修饰。异酮是通过脂质过氧化的异前列腺素途径产生的，并与蛋白质赖氨酸快速反应。Kirabo博士指出，异缩醛加合物蛋白具有免疫原性，由树突状细胞呈递，树突状细胞进而激活T细胞。在目标1中，Kirabo博士将研究钠促进树突状细胞产生免疫原性异酮的机制，并确定盐敏感葡糖激酶(SGK1)在这一过程中的作用。在目标2中，她将检测第一类主要组织相容性复合体呈递的异缩醛修饰的多肽，并确定这些多肽是否会因盐和血管紧张素II等高血压刺激而增加或改变。这些研究将对该领域具有重要意义，并将提供对高血压发病机制的更全面的理解。清除异酮类化合物可能为治疗这一重要疾病提供一种新的治疗方法。在她计划的研究中，Kirabo博士将在研究MHC生物学和生物化学的尖端方法方面积累经验。此外，Kirabo博士的培训计划包括授课课程、研讨会和参加Vanderbilt的职业发展计划，以促进初级教员的留任和终身教职。哈里森博士和Kirabo博士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员。她100%的时间将被保护用于与她的职业发展直接相关的活动，至少80%用于研究。范德比尔特的研究和学术环境对于实习生的职业发展来说是非常特殊的。(摘要结束)

 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)