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 ?-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.

Public Health Relevance

Inflammation contributes to the genesis of hypertension, which is a major risk factor for cardiovascular disease. There is overwhelming evidence that high salt intake contributes to inflammation and hypertension but the mechanisms are not clear. By defining the mechanisms by which salt contributes to inflammation and hypertension, this project may provide novel targets for treatment of this important disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZHL1)
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Lidman, Karin Fredriksson
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Vanderbilt University Medical Center
United States
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McDonnell, Wyatt J; Koethe, John R; Mallal, Simon A et al. (2018) High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity. Diabetes 67:2361-2376
Xiao, Liang; Patrick, David M; Aden, Luul A et al. (2018) Mechanisms of isolevuglandin-protein adduct formation in inflammation and hypertension. Prostaglandins Other Lipid Mediat 139:48-53
Kirabo, Annet (2017) A new paradigm of sodium regulation in inflammation and hypertension. Am J Physiol Regul Integr Comp Physiol 313:R706-R710
Dixon, Kala B; Davies, Sean S; Kirabo, Annet (2017) Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension. Am J Physiol Heart Circ Physiol 312:H368-H374
Barbaro, Natalia R; Foss, Jason D; Kryshtal, Dmytro O et al. (2017) Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension. Cell Rep 21:1009-1020
Kirabo, Annet; Ryzhov, Sergey; Gupte, Manisha et al. (2017) Neuregulin-1? induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts. J Mol Cell Cardiol 105:59-69
Barbaro, Natalia R; Kirabo, Annet; Harrison, David G (2017) A New Role of Mister (MR) T in Hypertension: Mineralocorticoid Receptor, Immune System, and Hypertension. Circ Res 120:1527-1529
Foss, Jason D; Kirabo, Annet; Harrison, David G (2017) Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol 312:R1-R4
Itani, Hana A; Xiao, Liang; Saleh, Mohamed A et al. (2016) CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli. Circ Res 118:1233-43
Wu, Jing; Saleh, Mohamed A; Kirabo, Annet et al. (2016) Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest 126:1607

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