Candidate. The candidate, Anthony J. Donato Ph.D., is a cardiovascular physiologist in the Department of Internal Medicine at the University of Utah. Dr. Donato's research focuses on the mechanisms mediating arterial aging and the mechanisms by which caloric restriction can preserve and restore vascular health with aging. His long term goal is to direct an independent, extramurally-funded research laboratory that can integratively study vascular aging at the gene, cellular, tissue and systemic (whole-body) levels and to be recognized as an international leader in translational vascular function. The proposed K02 award will provide Dr. Donato the necessary protected career development time to achieve this goal. Career Development Plan. This award will support the further career development of Dr. Donato, allowing him to complete a well-rounded program in molecular genetics and the basic biology of aging while maintaining his training in Geriatrics. The career development plan contains several separate but coordinated efforts to enhance the expertise of the applicant including training in new experimental techniques related to endothelial activation and inducible transgenic mouse creation, didactic course work designed to facilitate better understanding of the application of molecular genetics for investigators with advanced degrees and continued attendance at regular aging and geriatric seminar series and other vascular and basic biology of aging meetings aimed to educate and encourage collaborative research between Dr. Donato and other investigators in the specialties of biology of aging and geriatric research. Research.
The aim of the research project is twofold: first, determine the modulatory influence of SIRT-1 on endothelial activation with aging and the vasoprotection induced by long term caloric restriction; second, to determine if genetically augmenting endothelial NAMPT expression/activity can ameliorate age-related endothelial dysfunction. These novel and important studies will determine if, and how, NAMPT influences sirtuins and subsequent inflammation/oxidative stress- related vascular aging. The expected results will provide clinically important information regarding the integrative physiological mechanisms by which global endothelial dysfunction is expressed with aging and if NAMPT is a potential therapeutic target.

Public Health Relevance

Advancing age is a risk factor for cardiovascular disease. This proposal aims to determine the modulatory influence of SIRT-1 on endothelial activation with aging and the vasoprotection induced by lifelong caloric restriction. Additionally, this proposal will allow for the development of skills necessary to genetically alter mice and upregulate a pathway (NAMPT), an enzyme that is believed to provide vasoprotective effects in lifelong calorically restricted animals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AG045339-04
Application #
9243203
Study Section
Biological Aging Review Committee (NIA-B)
Program Officer
Kohanski, Ronald A
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$111,653
Indirect Cost
$8,271
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Donato, Anthony J; Machin, Daniel R; Lesniewski, Lisa A (2018) Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circ Res 123:825-848
Trott, Daniel W; Henson, Grant D; Ho, Mi H T et al. (2018) Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. Exp Gerontol 109:99-107
Clifton, Heather L; Machin, Daniel R; Groot, H Jonathan et al. (2018) Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement. Exp Physiol 103:1412-1424
Machin, Daniel R; Bloom, Samuel I; Campbell, Robert A et al. (2018) Advanced age results in a diminished endothelial glycocalyx. Am J Physiol Heart Circ Physiol 315:H531-H539
Ungvari, Zoltan; Tarantini, Stefano; Donato, Anthony J et al. (2018) Mechanisms of Vascular Aging. Circ Res 123:849-867
Lesniewski, Lisa A; Seals, Douglas R; Walker, Ashley E et al. (2017) Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 16:17-26
Machin, Daniel R; Gates, Phillip E; Vink, Hans et al. (2017) Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study. J Rheumatol 44:1603-1611
Machin, Daniel R; Clifton, Heather L; Richardson, Russell S et al. (2017) Acute oral tetrahydrobiopterin administration ameliorates endothelial dysfunction in systemic sclerosis. Clin Exp Rheumatol 35 Suppl 106:167-172
Trott, Daniel W; Lesniewski, Lisa A; Donato, Anthony J (2017) Selected life-extending interventions reduce arterial CXCL10 and macrophage colony-stimulating factor in aged mouse arteries. Cytokine 96:102-106
Walker, Ashley E; Morgan, R Garrett; Ives, Stephen J et al. (2016) Age-related arterial telomere uncapping and senescence is greater in women compared with men. Exp Gerontol 73:65-71

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