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.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Career Transition Award (K99)
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Special Emphasis Panel (ZAT1-PK (16))
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Weber, Wendy J
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University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
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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; 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
Voorhees, Andrew P; DeLeon-Pennell, Kristine Y; Ma, Yonggang et al. (2015) Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction. J Mol Cell Cardiol 85:229-39
Kain, Vasundhara; Ingle, Kevin A; Colas, Romain A et al. (2015) Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. J Mol Cell Cardiol 84:24-35
Ingle, Kevin A; Kain, Vasundhara; Goel, Mehak et al. (2015) Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol 309:H1827-36
Kain, Vasundhara; Halade, Ganesh V (2015) Big eater macrophages dominate inflammation resolution following myocardial infarction. J Mol Cell Cardiol 87:225-7
de Castro BrĂ¡s, Lisandra E; Cates, Courtney A; DeLeon-Pennell, Kristine Y et al. (2014) Citrate synthase is a novel in vivo matrix metalloproteinase-9 substrate that regulates mitochondrial function in the postmyocardial infarction left ventricle. Antioxid Redox Signal 21:1974-85
Brown, Armand O; Mann, Beth; Gao, Geli et al. (2014) Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 10:e1004383
Heaberlin, James R; Ma, Yonggang; Zhang, Jianhua et al. (2013) Obese and diabetic KKAy mice show increased mortality but improved cardiac function following myocardial infarction. Cardiovasc Pathol 22:481-7

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