A Rodent Model to Study Links Among Diet, Visceral Adipose and Cardiomyopathy

研究饮食、内脏脂肪和心肌病之间联系的啮齿动物模型

• 批准号: 8662827
• 负责人: Melinda Ann Frye
• 金额: $ 3.95万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662827
• 关键词: Achievement; Adipose tissue; Adult; Advanced Development; Affect; American Heart Association; Animal Model; Animals; Aptitude; Area; Award; Biological Markers; Biology; Biomedical Research; Body fat; Caliber; Carbohydrates; Cardiomyopathies; Cardiovascular system; Cell physiology; Chronic; Clinical; Clinical Research; Collaborations; Complex; Controlled Study; Critical Thinking; Data; Data Collection; Development; Diet; Dietary Intervention; Disease; Disease Attributes; Doctor of Philosophy; Doctor of Veterinary Medicine; Echocardiography; Electron Microscopy; Ensure; Equipment; Ethics; Experimental Designs; Extracellular Matrix; Fatty acid glycerol esters; Fostering; Foundations; Functional disorder; Funding; Generations; Genomics; Goals; Grant; Health; Health Care Costs; Heart; Heart Transplantation; Heart failure; High Pressure Liquid Chromatography; Human; Hypertension; Hypertrophy; Immunohistochemistry; Individual; Inflammatory; Institution; Interdisciplinary Study; Internal Medicine; Investigation; Knowledge; Laboratories; Left Ventricular Hypertrophy; Link; Lipids; Macronutrients Nutrition; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentors; Metabolism; Methods; Modeling; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardial tissue; Myocardium; National Center for Research Resources; Nonesterified Fatty Acids; Obesity; Organ; Overweight; Pathology; Pathway interactions; Physiology; Prevalence; Prevention; Production; Publications; Rat Strains; Relaxation; Research; Resources; Risk Factors; Rodent; Rodent Model; Role; Scientist; Solid; Sprague-Dawley Rats; Staging; Strategic Planning; Structure; Study of magnetics; System; TNF gene; Techniques; Thick; Time; Training; Translational Research; Tumor Necrosis Factor-alpha; United States; United States National Institutes of Health; Universities; Validation; Ventricular Remodeling; Veterinary Medicine; Visceral; Wistar Rats; Work; Writing; career; cellular pathology; clinically relevant; cytokine; design; dietary control; experience; feeding; field study; high risk; improved; in vivo; in vivo Model; innovation; interest; liquid chromatography mass spectrometry; polyunsaturated fat; prevent; programs; response; saturated fat; skills; sound; statistics; teacher; tool; translational study

DESCRIPTION (provided by applicant): Project Summary: 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.

描述（由申请人提供）：项目摘要：肥胖症的患病率在全球增加。即使没有高血压或缺血性疾病，肥胖个体也有较高的心肌病和心力衰竭的风险。在我们对肥胖介导的心肌病（OC）的理解中，存在两个原则差距。首先，缺乏对OC的细胞病理学知识。其次，饮食中大营养素对OC的贡献以及内脏脂肪在建立这种联系中的作用是未知的。我们对OC的了解将通过饮食肥胖的体内啮齿动物模型提高，以便研究心肌功能和结构变化与潜在细胞病理学的研究同时研究。受控的饮食研究将提高我们对大量营养素在OC进展中的作用以及内脏脂肪在介导这些作用中的作用的理解。具体目的1：开发饮食肥胖的啮齿动物模型，以表征心肌和内脏脂肪对饮食大量营养素的反应。在这里，将研究大鼠菌株和饮食的相互作用，以优化OC的啮齿动物模型，通过体内研究细胞过程的心肌结构的超声心动图测量和功能。磁共振成像（MRI）将用于定量内脏脂肪质量，并将使用高性能液相色谱法（HPLC）测量饮食诱导的心肌和脂肪脂质谱的变化。特定目的2：确定OC发展是否需要增加内脏脂肪质量。使用在AIM 1中优化的模型，将使用配对设计来限制在促进OC的饮食中限制内脏脂肪质量。除了AIM 1技术外，还将根据脂肪质量和心肌病理学来测量内脏脂肪的秘密。该项目将通过促进对能源作为脂肪存储的途径的理解，促进对OC生物标志物的识别并实现旨在防止肥胖相关并发症的策略的发现，从而促进NIH肥胖研究战略计划的实现。该项目与NCRR战略计划相关，将促进动物模型的开发和验证OC研究。作为P.I.是D.V.M.，该项目还将促进与NIH和NCRR相关的跨学科和翻译研究。 Frye博士是该奖项机会的强大而独特的候选人，因为她在人类和兽医医学方面的背景。这为她提供了独特的观点，使她能够将创新的方法应用于临床问题，并轻松弥合田野之间的差距，以促进多学科和转化研究。 Frye博士在内科医学方面的高级培训为她提供了对临床问题和系统生理学的扩展知识。此外，弗莱博士对心血管系统的临床和研究兴趣是长期存在的，她的研究重点是肥胖归因于疾病，这表明了对这一研究领域的承诺。弗莱博士的荣誉是她认识到培训中的差距，并积极努力获得所需的技能。她的博士学位经验并不常见，但弗莱博士在通过美国心脏协会获得资金，产生复杂的体内模型并寻求指导的指导方面表现出了毅力和创新。 Frye博士感谢她为自己的领域做出显着贡献的能力将得到该奖项提供的保护时间的加强，以接受实验设计，统计分析，实验室管理，赠款写作和方法对回答她的研究问题至关重要的方法。 Frye博士与整个大学的许多部门的个人都享受着合作的专业关系。她还与其他机构和当地心脏病专家建立了与科学家建立关系，证明了进行转化研究的潜力。 Frye博士的实验室配备了体内和体内研究的削减，并配备了用于通用实验室技术的工具，包括肌细胞隔离，以及用于进行超声心动图的设备。其他资源将允许HPLC，质谱法，电子显微镜，基因组分析，晚期免疫组织化学研究和MRI。博士。 Pagliassotti和Orton作为她的指导团队，将在代谢，肥胖和心肌病的领域提供合理的指导。除了理论贡献外，两位导师还将为严格的方法和高级技术培训做出贡献。 Frye博士凭借她的指导团队制定了一项计划，该计划将高级统计，赠款写作和道德规范的正式培训纳入头两年，同时与实验设计，批判性思维和方法进行了广泛的培训。凭借这一扎实的基础，弗莱博士将致力于实现既定目标，发展高级技能，促进协作，出版和过渡到生成R01提案的实现。短期职业目标包括：完成当前项目和发现的发布；提高了基础技能的能力，包括道德，批判性思维，实验设计，统计和实验室管理；对肥胖，代谢和心肌病的了解增加；提高生物医学研究中提出和回答问题所需的技术技能。长期目标包括：协作关系的持续发展促进转化研究；生产一系列严格的研究，这些研究证明了OC领域的专业知识；制定强大的外部资助研究计划；实现任期，以确保作为兽医科学家，教师和导师的进步。