Lipotoxic Effects of Maternal Diabetes and High Fat Diet on the Developing Heart

母亲糖尿病和高脂肪饮食对发育中的心脏的脂毒性影响

基本信息

批准号：
9518996
负责人：
Michelle Leigh Baack
金额：
$ 11.97万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9518996
关键词：
Adult Adult Children Advisory Committees Affect Aldosterone Basic Science Bioenergetics Birth Blood Blood Pressure Monitors C-Peptide Cardiac Cardiac Myocytes Cardiac development Cardiac health Cardiomegaly Cardiovascular Diseases Cardiovascular system Childhood Clinical Clinical Research Committee Members Custom Data Deposition Development Development Plans Diabetes Mellitus Diabetic mother Dietary Fats Dietary Intervention Disease Dyslipidemias Echocardiography Energy Metabolism Energy-Generating Resources Ensure Environment Evaluation Exposure to Extracellular Matrix Fatty Acids Fatty acid glycerol esters Fetal Growth Fetal Heart Fostering Foundations Funding Generations Genes Gestational Diabetes Glucose Glycolysis Goals Grant Growth Health Heart Heart Diseases Heart Hypertrophy Heart Rate High Fat Diet Human Human Milk Hyperinsulinism Hyperlipidemia Hypertrophy Impairment Incidence Infant Inflammatory Institution Insulin Intake Intervention Investigation Knowledge Laboratory Study Leadership Leptin Life Lipid Biochemistry Lipids Measurement Mechanics Mediating Mentor&apos s Statement Mentors Metabolic Metabolism Methods Mitochondria Modeling Molecular Morbidity - disease rate Neonatal Newborn Infant Obesity Outcome Oxygen Consumption Palmitates Pathway interactions Perinatal mortality demographics Physiological Play Population Population Decreases Populations at Risk Pregnancy Pregnancy in Diabetics Prevalence Prevention strategy Preventive measure Production Publications Pyruvate Randomized Clinical Trials Renin Research Resources Rest Risk Rodent Model Role Sampling Scientist Solid Source Structure Testing Time TimeLine Triad Acrylic Resin Weaning Woman Work base bench to bedside blood glucose regulation cardiovascular disorder risk cardiovascular health cardiovascular risk factor career career development diabetic experience extracellular fatty acid oxidation fetal fetal programming healthy lifestyle heart disease risk heart function hemodynamics high risk high risk infant improved innovation maternal diabetes maternal hyperglycemia meetings novel offender offspring polypeptide C prevent programs public health relevance screening success translational study

项目摘要

DESCRIPTION (provided by applicant): This project is focused on preventing cardiovascular disease in offspring of diabetic mothers (ODMs). The prevalence of diabetes during pregnancy is escalating, and one third of all infants born to diabetic mothers (IDMs) have cardiac hypertrophy at birth. Despite a healthy lifestyle, IDMs carry a risk of cardiovascular disease into adulthood, proposedly through fuel mediated fetal programming. Current preventative measures focus on glucose control, but normoglycemic women can have affected infants, implicating additional fuel- mediated offenders, including lipids. The relative contribution of excess circulating lipids in developmental programming of cardiac disease is not well recognized, or studied. To better understand this, our research plan utilizes a rodent model of late-gestation diabetes, with a control- or high-fat diet, to simulate cardiac disease experienced by IDMs. Using this model, we mimicked human maternal-placental-fetal interactions, reproducing a triad of maternal hyperglycemia, hyperlipidemia, and fetal hyperinsulinemia. Under these conditions, newborn offspring were affected by cardiac hypertrophy, poor systolic function similar to IDMs. Unexpectedly, we demonstrated that a maternal high-fat diet, not diabetes, markedly increased perinatal mortality in newborns. Offspring that died had enlarged hearts with marked lipid droplet accumulation. Array analysis pointed to altered expression in genes regulating cardiac energy metabolism. These preliminary findings prompted generation of a bioenergetic hypothesis of fuel-mediated developmental programming. Due to its very high energy needs, the heart can rapidly transport, store, and utilize different substrates for energy. Normally, neonatal hearts ar efficient at glycolysis, but adult hearts prefer fatty acid oxidation as a more efficient source of ATP. We propose that exposing the developing heart to excess circulating fuels reprograms substrate metabolism and energy production efficiency, and furthermore, this reprogramming contributes to ongoing cardiac risk throughout life. My lab has validated all proposed methods, collected mounting preliminary data to support our hypothesis, and is now poised to further determine the underlying mechanisms and long-term consequences of maternal diabetes and high-fat diet on the developing heart. We aim to do this through evaluation of structural, functional, histopathologic, cardiovascular risk and bioenergetic markers of cardiac health in our offspring throughout their maturation. My long-term career goal is to understand developmental consequences of maternal or neonatal lipid disturbances, and identify preventative strategies to improve long-term outcomes of high-risk infants. The objective of this application is to utilize th mentored clinical scientist program to establish an independently funded basic science program to study the contribution of excess circulating lipid associated with high-fat intake and diabetic pregnancy in the developmental programming of cardiac disease in offspring. As the candidate, my ability to establish a solid foundation of both basic and clinical research, in addition to year of clinical experience, make me an ideal clinical scientist to take scientific discovery from the bench to the bedside. My scientific foundation has grown rapidly from one translational study evaluating fatty acid levels in human milk samples to the simultaneous implementation of a randomized clinical trial and the development of a basic science laboratory studying lipid-mediated developmental programming. Establishing independently funded research will require that scientific findings reach significance in the field. To accomplish this, a career development plan was established to aid in growth towards fluent independent investigation using a structured, goal-oriented, timeline of presentation, publication and grant submissions. The plan utilizes committed resources, a rich and collaborative institutional environment, and guidance of a trans- disciplinary mentoring team. The unique role of two well-suited co-mentors ensures that day-to-day guidance of both basic science and clinical research is readily available from well established local mentors, Dr. David Pearce and Dr. William Harris. Scientific oversight is enhanced through quarterly advisory committee meetings that include Dr. Norris and Dr. Segar, clinical scientists with proven success in their fields of lipid biochemistry and developmental programming of cardiovascular disease. Dr. Eugene Hoyme, a third advisory committee member, adds leadership and professional development guidance through the advisory committee and monthly Pediatric Mentoring Program meetings. (See Statement by Mentor and Biosketches) The combination of a truly translational candidate, a committed and fostering institution, a customized mentoring team and an innovative research plan with high significance provide the perfect arrangement for a successful clinical scientist in your program. We predict that completion of this project will substantiate the harmful effects of maternal dyslipidemia associated with diabetes and a high-fat diet on the developing fetal heart and promises hope of preventing cardiovascular disease even before it begins.

描述（由申请人提供）：该项目的重点是预防糖尿病母亲（ODM）的后代心血管疾病。怀孕期间糖尿病的患病率正在升级，糖尿病母亲（IDMS）出生的所有婴儿中有三分之一在出生时患有心脏肥大。尽管有健康的生活方式，IDM仍会冒患心血管疾病的风险成年，通过燃料介导的胎儿编程提出。当前的预防措施集中在葡萄糖控制上，但是正常血糖妇女可能会影响婴儿，这意味着包括脂质在内的其他燃料介导的罪犯。过多的循环脂质在心脏病的发展编程中的相对贡献尚未得到很好的认可或研究。为了更好地理解这一点，我们的研究计划利用了妊娠后期糖尿病的啮齿动物模型，并采用控制或高脂饮食来模拟IDM所经历的心脏病。使用此模型，我们模仿了人类植物 - 狂热相互作用，再现了母体高血糖，高脂血症和胎儿高胰岛素血症的三合会。在这些条件下，新生儿后代受心脏肥大的影响，收缩功能较差，类似于IDM。出乎意料的是，我们证明了母体高脂饮食，而不是糖尿病，显着增加了新生儿的围产期死亡率。死亡的后代随着脂质液滴积累的明显增大心脏。阵列分析指出，调节心脏能量代谢的基因表达改变。这些初步发现促使产生了燃料介导的发育节目的生物能假设。由于其能量非常高，心脏可以迅速运输，存储和利用不同的基材来获得能量。通常，新生儿心脏在糖酵解方面有效，但成人心脏更喜欢脂肪酸氧化是更有效的来源 ATP。我们建议，将发展心脏的心脏暴露于过量的循环燃料中，可以重新编程底物代谢和能源生产效率，此外，这种重编程有助于一生中持续的心脏风险。我的实验室验证了所有提出的方法，收集了安装初步数据以支持我们的假设，现在有望进一步确定母体糖尿病的基本机制和长期后果以及对发育中心的心脏饮食的高脂饮食。我们的目的是通过评估结构，功能，组织病理学，心血管风险和心脏健康的生物能标记在我们的后代的整个成熟过程中。我的长期职业目标是了解孕产妇或新生儿脂质障碍的发育后果，并确定预防策略以改善高风险婴儿的长期结果。该应用的目的是利用指导的临床科学家计划来建立一个独立的基础科学计划，以研究与高脂摄入量和糖尿病妊娠相关的过量循环脂质在后代心脏病的发展计划中的贡献。作为候选人，除了临床经验的年份外，我还可以为基础研究和临床研究建立坚实的基础，这使我成为从长凳到床边进行科学发现的理想临床科学家。我的科学基础从评估人乳样品中的脂肪酸水平的一项翻译研究迅速发展，到同时实施一项随机临床试验以及研究脂质介导的发育计划的基础科学实验室的发展。建立独立资助的研究将要求科学发现在该领域具有重要意义。为此，制定了一项职业发展计划，以帮助使用结构化的，面向目标的，演示，出版和赠款提交的时间表来实现流利的独立调查。该计划利用了实体资源，丰富而协作的机构环境以及跨学科指导团队的指导。两位合适的副委员的独特作用确保了基础科学和临床研究的日常指导，可以从良好的当地导师David David David和William Harris博士那里获得。通过季度咨询委员会会议，包括诺里斯博士和塞加尔博士，临床科学家在脂质生物化学和心血管疾病的发展计划中取得了成功，可以增强科学监督。第三个咨询委员会成员Eugene Hoyme博士通过咨询委员会和每月的儿科指导计划会议增加了领导力和专业发展指导。（请参阅Mentor and Biosketches的声明）真正的转化候选人，致力于和培养机构，定制的指导团队以及具有很高意义的创新研究计划的结合，为您计划中成功的临床科学家提供了完美的安排。我们预测，该项目的完成将证实与糖尿病有关的母体血脂异常的有害影响，以及对发育中的胎儿心脏的高脂饮食，并希望甚至在开始之前预防心血管疾病的希望。