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

描述(由申请人提供)：该项目的重点是预防糖尿病母亲(ODM)子女的心血管疾病。妊娠期糖尿病的患病率正在上升，糖尿病母亲(IDM)所生婴儿中有三分之一在出生时心脏肥大。尽管有健康的生活方式，IDM仍有患心血管疾病的风险 成年期，通过燃料介导的胎儿编程而提出。目前的预防措施侧重于血糖控制，但血糖正常的女性可能会影响婴儿，这涉及到其他由燃料介导的违规者，包括血脂。过多的循环血脂在心脏病的发展规划中的相对贡献还没有得到很好的认识或研究。为了更好地理解这一点，我们的研究计划利用妊娠晚期糖尿病的啮齿动物模型，通过对照或高脂饮食来模拟IDM经历的心脏病。使用这个模型，我们模拟了人类母体-胎盘-胎儿的相互作用，复制了母体高血糖、高脂血症和胎儿高胰岛素血症的三联体。在这种情况下，新生儿会受到心肌肥厚的影响，收缩功能较差，类似于IDM。出乎意料的是，我们证明了母亲的高脂肪饮食，而不是糖尿病，显著增加了新生儿的围产期死亡率。死亡的后代心脏增大，有明显的脂滴积累。阵列分析指出，调控心脏能量代谢的基因表达发生了变化。这些初步发现促使了燃料介导的发育编程的生物能量假说的产生。由于心脏对能量的需求非常高，它可以快速地运输、储存和利用不同的底物来获得能量。正常情况下，新生儿心脏在糖酵解方面是有效的，但成人心脏更喜欢脂肪酸氧化作为一种更有效的来源 三磷酸腺苷。我们认为，将发育中的心脏暴露于过量的循环燃料中，会重新编程底物代谢和能量生产效率，而且，这种重新编程会在一生中导致持续的心脏风险。我的实验室已经验证了所有提出的方法，收集了越来越多的初步数据来支持我们的假设，现在准备进一步确定母体糖尿病和高脂肪饮食对发育中的心脏的潜在机制和长期后果。我们的目标是通过评估子代在整个成熟过程中心脏健康的结构、功能、组织病理学、心血管风险和生物能量标记物来实现这一点。我的长期职业目标是了解母亲或新生儿血脂紊乱的发育后果，并确定预防策略，以改善高危婴儿的长期结局。本申请的目的是利用指导临床科学家计划建立一个独立资助的基础科学计划，以研究与高脂肪摄入和糖尿病怀孕相关的过量循环血脂在子代心脏病发育规划中的贡献。作为候选人，我能够建立坚实的基础和临床研究基础，加上一年的临床经验，使我成为一名理想的临床科学家，将科学发现从工作台带到床边。我的科学基础迅速发展，从一项评估母乳样本中脂肪酸水平的翻译研究，到同时实施一项随机临床试验，并建立一个研究脂质介导的发育编程的基础科学实验室。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。为实现这一目标，制定了一项职业发展计划，以帮助实现流畅的独立调查，采用结构化的、以目标为导向的、提交报告、出版和赠款的时间表。该计划利用承诺的资源、丰富和协作的机构环境以及跨学科指导团队的指导。两位非常合适的共同导师的独特作用确保了基础科学和临床研究的日常指导很容易从当地著名的导师大卫·皮尔斯博士和威廉·哈里斯博士那里获得。科学监督通过包括诺里斯博士和西格博士在内的季度咨询委员会会议得到加强，这两位临床科学家在他们的脂质生物化学和心血管疾病发展规划领域被证明是成功的。尤金·霍伊梅博士是咨询委员会的第三名成员，他通过咨询委员会和每月的儿科指导计划会议增加领导力和专业发展指导。(见Mentor和Biosketches的声明)真正的翻译候选人、忠诚的培养机构、定制的指导团队和具有重要意义的创新研究计划的结合，为您的项目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和高脂肪饮食相关的母亲血脂异常对发育中的胎儿心脏的有害影响，并有望在心血管疾病开始之前就预防它。

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.