Dietary interventions to modulate heart health in offspring born to diabetic mothers and the subsequent generation.

通过饮食干预来调节糖尿病母亲所生的后代及其后代的心脏健康。

基本信息

批准号：
10548852
负责人：
Michelle Leigh Baack
金额：
$ 41.5万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548852
关键词：
Address Adult Aging Antioxidants Birth Breeding Calories Cardiac Cardiac Myocytes Cardiac health Cardiomyopathies Cardiovascular Diseases Cell Death Coenzyme Q10 Counseling DNA Damage DNA Repair Deoxyguanosine Development Diabetes Mellitus Diabetic mother Diet Modification Dietary Fats Dietary Intervention Dietary Supplementation Disease Family Family Planning Fatty Acids Fatty acid glycerol esters Female Fertilization Fetus Generations Genomic Instability Genomic approach Genomics Gestational Diabetes Goals Heart Heart Diseases High Fat Diet Human Hyperglycemia Hyperlipidemia Impairment Inflammation Inheritance Patterns Inherited Intake Intervention Lesion Life Link Mediating Metabolic Diseases Metabolic stress Metabolism Mitochondria Modeling Mothers Mutation Myocardial dysfunction Newborn Infant Obesity Outcome Ovary Overnutrition Ovulation Oxidative Stress Pattern Phenotype Play Population Predisposition Pregnancy Pregnancy Trimesters Prevention Rattus Reactive Oxygen Species Risk Role Shapes Supplementation Testing Third Pregnancy Trimester Time Ubiquinone Work blastocyst cardiovascular disorder risk clinical application clinical effect clinical practice clinically relevant diabetic dietary dietary antioxidant effective intervention efficacy testing fetal genome-wide genomic profiles glycemic control heart disease risk heart function high risk implantation improved innovation maternal diabetes maternal obesity mitochondrial dysfunction mortality mother nutrition next generation offspring oxidative DNA damage oxidative damage prevent programs risk mitigation screening transcriptome transcriptomics whole genome

项目摘要

Gestational diabetes and obesity expose the fetus to overnutrition during critical windows of development. Evidence shows that fetal overnutrition increases the risk of heart disease at birth and later in life. What’s more, programmed risk can be passed on to the next generation. The goal of our lab is to develop effective interventions that improve heart health in this readily identifiable population, lessening the burden of heart disease over time. To understand the role of maternal diet in developmentally programmed heart disease, we developed a rat model that compared outcomes of control, diabetes-, high-fat diet-, and combination-exposed offspring. We found that, just like in humans, fetal overnutrition in rats causes cardiac dysfunction at birth and again in adulthood. We also demonstrated that cardiac consequences are due to mitochondrial dysfunction, impaired cardiomyocyte metabolism, and faster cell death following metabolic stress. Importantly, we found that a maternal high-fat diet exaggerates mitochondrial and cardiac dysfunction to increase mortality in offspring born to diabetic mothers (ODM), specifically by increasing fetal overnutrition and programming the cardiac transcriptome to be more susceptible to oxidative damage. While our work highlights the role of maternal dietary fat intake, key questions about programming remain: 1. Does oxidative DNA damage contribute to programmed heart disease in ODM and the next generation? 2. Will limiting fat intake during the last trimester of pregnancy mitigate risks? 3. Can the dietary antioxidant Coenzyme Q (CoQ10) prevent programmed heart disease in ODM and their progeny? Aim 1 will use innovative genomic approaches paired with cardiac phenotyping across generations to establish whether oxidative DNA damage contributes to programmed heart disease following fetal overnutrition. As primary producers of ROS, dysfunctional mitochondria can cause oxidative DNA damage in the form of 8-oxo- 7,8-dihydro-2’-deoxyguanosine (8-oxodG), a mutagenic lesion prone to misrepair and genome instability. Genomic perturbations from 8-oxodG have been linked to metabolic disease, early ageing, and inflammation; moreover, they may be inheritable. We will determine whether 8-oxodG contributes to programmed heart disease in our model by comparing whole genome levels and downstream genomic perturbations using oxiDIP-seq. We will also use scRNA-sequencing of blastocysts from F0 females and their F1 and F2 offspring to delineate the timing of newly acquired mutations and whether there is compounding or dilution from DNA repair mechanisms across generations. Aims 2 and 3 will determine whether dietary interventions including limiting dietary fat intake in the last third of pregnancy or supplementing high-risk females with dietary CoQ10 during ovulation and fertilization will decrease the risk of developmentally programmed heart disease in ODM and their progeny. Findings are needed to understand mechanisms, inheritance patterns, and the effects of clinically applicable interventions such as expanding diabetic screening and dietary counseling to include management of maternal hyperlipidemia as well as hyperglycemia or offering preventative dietary supplementation during family planning.

妊娠糖尿病和肥胖使胎儿在关键的发育窗口中暴露于营养不良。有证据表明，胎儿的营养营养成分会增加出生时心脏病的风险。此外，可以将编程风险传递给下一代。我们实验室的目的是制定有效的干预措施，以改善这种易于识别的人群的心脏健康，从而减少心脏病的燃烧。为了了解孕产妇饮食在发育编程的心脏病中的作用，我们开发了一种大鼠模型，比较了对照，糖尿病，高脂饮食和结合暴露后代的结果。我们发现，就像在人类中一样，大鼠的胎儿营养不良会在出生时和成年后再次引起心脏功能障碍。我们还证明了心脏后果是由于线粒体功能障碍，心肌细胞代谢应激受损和代谢应激后更快的细胞死亡引起的。重要的是，我们发现，主要的高脂饮食夸大了线粒体和心脏功能障碍，从而增加了糖尿病母亲（ODM）的后代死亡率（ODM），尤其是通过增加胎儿营养和对心脏转录组进行编程，使其更容易受到氧化损害的影响。虽然我们的工作突出了Matal饮食脂肪摄入的作用，但有关编程的关键问题仍然存在：1。氧化DNA损伤是否有助于ODM和下一代中编程的心脏病？ 2。在怀孕的最后三个月减轻风险会限制脂肪摄入吗？ 3。饮食中的抗氧化剂辅酶Q（COQ10）可以防止ODM中编程的心脏病及其进度吗？ AIM 1将使用与世代相传的心脏表型配对的创新基因组方法，以确定氧化性DNA损伤是否有助于胎儿营养不良后编程的心脏病。作为ROS的主要生产国，功能障碍的线粒体会以8-氧基7,8-二氢-2'-脱氧瓜烷氨酸（8-氧化物）的形式引起氧化物DNA损伤，这是一种诱变的病变，容易发生虚假和基因组不稳定性。来自8-oxoDG的基因组扰动与代谢疾病，早衰症和炎症有关。而且，它们可能是可以继承的。我们将通过使用氧化和氧化seq比较整个基因组水平和下游基因组扰动来确定8-OXODG是否在模型中促进了程序性心脏病。我们还将使用来自F0女性及其F1和F2后代的胚泡的SCRNA序列来描述新获得的突变的时机，以及是否有复合或稀释世代的DNA修复机制。目标2和3将决定饮食干预措施，包括限制怀孕的最后三分之一饮食脂肪的摄入，还是补充排卵和施肥期间饮食中的COQ10的高风险女性，会降低ODM中发展为ODM及其进步的心脏病的风险。需要发现来了解机制，遗传模式以及临床适用的干预措施的影响，例如扩大糖尿病筛查和饮食咨询，包括治疗母体高脂血症以及高血糖或在计划生育过程中提供预防性饮食补充。