The prevalence of obesity is increasing globally. Obese individuals are at higher risk for cardiomyopathy and heart failure, even in the absence of hypertension or ischemic disease. Two principle gaps in our understanding of obesity-mediated cardiomyopathy (OC) exist. First, knowledge of cellular pathology underlying OC is lacking. Second, the contribution of dietary macronutrients to OC, and the role of visceral adipose in establishing this link, is unknown. Our knowledge of OC would be advanced by an in vivo rodent model of dietary obesity, in order to study myocardial functional and structural changes concomitantly with studies of underlying cellular pathology. Controlled dietary studies would improve our understanding of the role of macronutrients in progression of OC, and of the visceral adipose in mediating these effects.
Specific Aim 1 : To develop rodent models of dietary obesity, in order to characterize myocardial and visceral adipose responses to dietary macronutrients. Here, interactions of rat strain and diet will be studied to optimize rodent models of OC, paring echocardiographic measures of myocardial structure and function with ex vivo studies of cellular processes. Magnetic resonance imaging (MRI) will be used to quantitate visceral adipose mass, and diet- induced changes in the myocardial and adipose lipid profile will be measured using high performance liquid chromatography (HPLC).
Specific Aim 2 : To determine whether increased visceral adipose mass is required for the development of OC. Using the model optimized in Aim 1, a pair-feeding design will be used to restrict visceral adipose mass in the context of a diet that promotes OC. In addition to Aim 1 techniques, visceral adipose secretogues will be measured in relation to adipose mass and myocardial pathology. This project will promote actualization of the NIH Obesity Research Strategic Plan by advancing understanding of pathways regulating the storage of energy as fat, promoting identification of OC biomarkers and enabling the discovery of strategies aimed at preventing obesity-related complications. Relevant to the NCRR Strategic Plan, this project will promote the development and validation of animal models for the study of OC. As the P.I. is a D.V.M., this project will also promote interdisciplinary and translational research, relevant to both the NIH and NCRR. Dr. Frye is a strong and unique Candidate for this award opportunity due to her background in both human and veterinary medicine. This affords her a distinct perspective, equipping her to apply innovative approaches to clinical problems, and easily bridge the gap between fields to facilitate multidisciplinary and translational research. Dr. Frye's advanced training in internal medicine provides her with expanded knowledge of clinical problems and systems physiology. Additionally, Dr. Frye's clinical and research interest in the cardiovascular system is longstanding, and her investigations focused on disease attributed to obesity demonstrate a commitment to this field of study. It is to Dr. Frye's credit that she recognizes gaps in her training and actively works to gain needed skills. Her PhD experience was not conventional, yet Dr. Frye demonstrated perseverance and innovation in procuring funding through the American Heart Association, generating a complex in vivo model, and seeking mentors for guidance. Dr Frye appreciates that her ability to contribute remarkably to her field would be strengthened by protected time provided by this award, to receive training in experimental design, statistical analysis, laboratory management, grant writing and methods critical to answering her research questions. Dr. Frye enjoys collegial professional relationships with individuals from many departments throughout the university. She has also established relationships with scientists at other institutions and with local cardiologists, attesting to potential for enacting translational studies. Dr. Frye's laboratory is equipped for paring in vivo and ex vivo studies, with tools for general laboratory techniques, including myocyte isolation, along with equipment for performing echocardiography. Additional resources will allow HPLC, mass spectrometry, electron microscopy, genomic analyses, advanced immunohistochemistry studies and MRI. Drs. Pagliassotti and Orton, as her mentoring team, will provide sound guidance in the areas of metabolism, obesity and cardiomyopathy. In addition to theoretical contributions, both mentors will contribute to training in rigorous methods and advanced techniques. With her mentoring team, Dr. Frye has developed a plan incorporating formal training in advanced statistics, grant writing and ethics into the first 2 years, concomitantly with extensive training in experimental design, critical thinking and methods. With this solid foundation, Dr. Frye would devote the latter 3 years to achievement of stated aims, development of advanced skills, fostering collaboration, publication, and transition to generation of an R01 proposal. Short term career goals include: completion of current projects and publication of findings;increased aptitude in foundational skills including ethics, critical thinking, experimental design, statistics and laboratory management;increased knowledge of obesity, metabolism and cardiomyopathy;advancing technical skills needed to ask and answer questions in biomedical research. Long term goals include: continued advancement of collaborative relationships fostering translational research;production of a body of rigorous research demonstrating expertise in the field of OC;development of a robust extramurally funded research program;achievement of tenure to ensure progress as a veterinary scientist, teacher and mentor.
Project Narrative: In the United States alone, the prevalence of overweight and obese adult's averages 26%, having increased by nearly 20% over the last 3 decades. The aims of this project are directed at mitigating the human toll and health care costs associated with heart failure in obese individuals.
|Jeckel, Kimberly M; Bouma, Gerrit J; Hess, Ann M et al. (2014) Dietary fatty acids alter left ventricular myocardial gene expression in Wistar rats. Nutr Res 34:694-706|
|Mehlman, E; Bright, J M; Jeckel, K et al. (2013) Echocardiographic evidence of left ventricular hypertrophy in obese dogs. J Vet Intern Med 27:62-8|
|Nivala, Angela M; Reese, Lauren; Frye, Melinda et al. (2013) Fatty acid-mediated endoplasmic reticulum stress in vivo: differential response to the infusion of Soybean and Lard Oil in rats. Metabolism 62:753-60|
|Jeckel, Kimberly M; Veeramachaneni, D N Rao; Chicco, Adam J et al. (2012) Docosahexaenoic acid supplementation does not improve Western diet-induced cardiomyopathy in rats. PLoS One 7:e51994|
|Jeckel, Kimberly M; Miller, Kelsey E; Chicco, Adam J et al. (2011) The role of dietary fatty acids in predicting myocardial structure in fat-fed rats. Lipids Health Dis 10:92|
|Gentile, Christopher L; Frye, Melinda A; Pagliassotti, Michael J (2011) Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease. Biofactors 37:8-16|