Mitochondria, metabolic plasticity and cell fate in the developmental origin of fuel-mediated cardiomyopathy

燃料介导的心肌病发育起源中的线粒体、代谢可塑性和细胞命运

基本信息

批准号：
10259825
负责人：
Michelle Leigh Baack
金额：
$ 44.86万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2022-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259825
关键词：
AKT Signaling Pathway Adult Adult Children Bioenergetics Biogenesis Biological Assay Birth Cardiac Cardiac Myocytes Cardiac development Cardiac health Cardiomyopathies Carnitine Palmitoyltransferase I Cell Death Cell Proliferation Cell physiology Cells Complex Development Diabetes Mellitus Diabetic mother Disease Enzymes Exposure to Failure Fatty Acids Fetal Development Foundations Future Genes Glycolysis Health Heart Heart Diseases High Fat Diet Human Impairment Infant Insulin Intervention Life Mediating Mediator of activation protein Mesenchymal Stem Cells Metabolic Metabolic Pathway Metabolism Methods Mitochondria Modeling Mothers Newborn Infant Obesity Organ Organogenesis Oxidative Phosphorylation Oxidative Stress Pathogenesis Pediatric Research Physiological Populations at Risk Positioning Attribute Pregnancy Problem Solving Proto-Oncogene Proteins c-akt Pyruvate Kinase Rattus Regulation Research Project Grants Respiration Risk Role Stress Systems Biology Therapeutic Intervention Therapeutic Studies Time Translating Umbilical cord structure advanced system anaerobic glycolysis cardiogenesis cardiometabolism diabetic exposed human population fatty acid oxidation healthy lifestyle heart disease risk heart metabolism high risk human model improved in utero in vitro Model interest maternal diabetes migration mitochondrial dysfunction neonatal exposure offspring prenatal prevent preventive intervention progenitor respiratory senescence stem cell division stem cell fate stem cells tool

项目摘要

PROJECT SUMMARY The Center for Pediatric Research aims to understand regulators of cellular pliancy in the developmental origin of health and disease (DOHaD). Project 3 will determine the role of mitochondria and cellular metabolism in cardiomyocyte fate as a key mediator of heart disease in offspring born following a diabetic pregnancy. Infants who are born to mothers with diabetes or obesity are at higher risk of heart disease at birth and in adulthood, purportedly through fuel-mediated influences on the developing heart. However, preventative and therapeutic interventions are lacking because the underlying mechanism remains unknown. The Baack Lab is well poised to solve this problem as it builds upon their recent discovery that maternal diabetes, especially with a high-fat diet, incites mitochondrial dysfunction, altered cellular bioenergetics and cardiomyopathy in the developing offspring's heart. Moreover, exposure to diabetic pregnancy was sufficient to extend these cardiometabolic consequences into adulthood. The proposed project builds upon this discovery using The Baack Lab's well-characterized and physiologically relevant rat model, advanced systems biology tools, state-of-the-art live-cell metabolic assays, and mesenchymal stem cell derived cardiac progenitors from human umbilical cords exposed to normal or diabetic pregnancy. The proposed methods will uncover mechanisms of pathogenesis and translate findings to humans while answering two unresolved questions: 1) How does diabetic pregnancy cause mitochondrial dysfunction and altered cellular bioenergetics in the developing offspring's heart? 2) What are the downstream effects on cell pliancy, specifically cardiomyocyte proliferation, differentiation and senescence as it relates to developmentally programmed heart disease? Together with the Center for Pediatric Research, Project 3 will demonstrate the role of mitochondria and metabolic plasticity in stem cell regulation and set a firm foundation needed to develop pre- and post-natal interventions to prevent heart disease in this growing at-risk population.

项目摘要小儿研究中心旨在了解发育起源中细胞质量的调节剂健康与疾病（DOHAD）。项目3将确定线粒体和细胞代谢在心肌细胞命运是糖尿病怀孕后出生后代的心脏病的关键介体。婴儿患有糖尿病或肥胖母亲的母亲出生时，出生时和成年后患心脏病的风险更高，据称通过燃料介导的对发展心脏的影响。但是，预防性和治疗性缺乏干预措施，因为基本机制仍然未知。 Baack Lab已准备好解决这个问题，因为它最近发现了母体糖尿病，特别是使用高脂饮食，促进线粒体功能障碍，细胞生物能量改变和发展后代心脏的心肌病。此外，暴露于糖尿病妊娠足以将这些心脏代谢后果扩展到成年。拟议的项目使用Baack Lab的表征和生理学良好的发现建立在这一发现的基础上相关的大鼠模型，高级系统生物学工具，最先进的实时代谢分析和来自正常或糖尿病的人脐带的间充质干细胞衍生的心脏祖细胞怀孕。提出的方法将发现发病机理的机制，并将发现转化为人类在回答两个未解决的问题的同时： 1）糖尿病妊娠如何引起线粒体功能障碍和细胞生物能的改变发展后代的心？ 2）下游对细胞质量的影响是什么，特别是心肌细胞增殖，分化和衰老与发育编程的心脏病有关吗？与儿科研究中心一起，项目3将展示线粒体和干细胞调节中的代谢可塑性，并为产后和产后发展所需的牢固基础在这种不断增长的高危人群中，采取了预防心脏病的干预措施。