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)