This K99/R00 training application will provide training and research time for Dr. Halade's transition to independence as an NCCAM-focused investigator. The training goal of this project is to obtain additional experience in cardiac biology to allow Dr. Halade to transition to an independent career focused on using nutritional and alternative medicine approaches to improve cardiovascular health. The training plan will be carried out at the University of Texas Health Science Center at San Antonio, and includes individual and team mentoring strategies, additional coursework in cardiac physiology, and presentations at seminars and journal clubs. The principal investigator is strongly supported by his mentor and career development advisory committee that is composed of leading experts in their respective fields. The research goal of this project is to study the anti-inflammatory effect of docosahexaenoic acid (DHA) on TNF-1 signaling following myocardial infarction (MI). I will use a unique model of aging mice that have been fed an n-6 fatty acids (corn oil) diet for six months, beginning at middle-age, to induce obesity. DHA effects will be compared to a TNF-1 antagonist (etanercept). I will test the central hypothesis that DHA attenuates cardiac remodeling following MI by blunting TNF-1-mediated inflammation and extracellular matrix turnover. To test our hypotheses I will: 1) test whether DHA attenuates cardiac remodeling following MI by blunting TNF-1-mediated inflammation and extracellular matrix turnover 2) determine whether DHA attenuates fibroblast activation induced by MI 3) determine whether DHA attenuates macrophage activation induced by MI. My translational and clinically relevant hypothesis has applicability to the far-reaching epidemic of obesity, in which cardiovascular disease is a primary complication amenable to nutritional supplementation. I will use a multi-discipline approach that integrates physiology, cell biology, biochemistry, mass spectrometry, and histological approaches to unveil mechanisms on how aging and obesity influence the LV remodeling process as a function of fibroblast and macrophage activation status. The innovation of this application is that I will use: 1) components of fish oil in order to assign individual constituent functions;2) mice that are fed high n- 6 fatty acids diet beginning at middle-age, which more closely mimics what is seen in humans;and 3) state of the art approaches that will allow me to develop as an independent investigator. The results of these studies will clarify the role of DHA in post-MI remodeling in the setting of aging and obesity.

Public Health Relevance

Fish oil is the most commonly used dietary supplement and is composed of both docosahexaenoic acid (DHA) and eicosapentaenoic acid. Over 1.2 million Americans are diagnosed with a heart attack each year, and obesity is a primary risk factor for cardiovascular disease. This project will define how the individual component DHA affects, how an aging and obese mouse responds to a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Transition Award (R00)
Project #
4R00AT006704-04
Application #
8727214
Study Section
Special Emphasis Panel (ZAT1-PK (16))
Program Officer
Weber, Wendy J
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$241,736
Indirect Cost
$77,197
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Halade, Ganesh V; Black, Laurence M; Verma, Mahendra Kumar (2018) Paradigm shift - Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery. Biotechnol Adv 36:935-953
Halade, Ganesh V; Norris, Paul C; Kain, Vasundhara et al. (2018) Splenic leukocytes define the resolution of inflammation in heart failure. Sci Signal 11:
Kain, Vasundhara; Ingle, Kevin A; Kabarowski, Janusz et al. (2018) Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction. J Mol Cell Cardiol 118:70-80
Halade, Ganesh V; Kain, Vasundhara; Serhan, Charles N (2018) Immune responsive resolvin D1 programs myocardial infarction-induced cardiorenal syndrome in heart failure. FASEB J 32:3717-3729
Tourki, Bochra; Halade, Ganesh (2017) Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. FASEB J 31:4226-4239
Kain, Vasundhara; Halade, Ganesh V (2017) Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy. Front Cardiovasc Med 4:31
Halade, Ganesh V; Kain, Vasundhara (2017) Obesity and Cardiometabolic Defects in Heart Failure Pathology. Compr Physiol 7:1463-1477
Halade, Ganesh V; Kain, Vasundhara; Black, Laurence M et al. (2016) Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction. Aging (Albany NY) 8:2611-2634
DeLeon-Pennell, Kristine Y; Tian, Yuan; Zhang, Bai et al. (2016) CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling. Circ Cardiovasc Genet 9:14-25
Yabluchanskiy, Andriy; Ma, Yonggang; DeLeon-Pennell, Kristine Y et al. (2016) Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization. J Gerontol A Biol Sci Med Sci 71:475-83

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