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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：
10004078
负责人：
Michelle Leigh Baack
金额：
$ 38.51万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004078
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 Preventive Intervention 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 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.

项目总结