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

项目总结 儿科研究中心旨在了解发育起源中细胞柔韧性的调节因素 健康与疾病(DOHAD)。项目3将确定线粒体和细胞新陈代谢在 心肌细胞命运是糖尿病妊娠后出生的后代心脏病的关键调节因素。婴儿 患有糖尿病或肥胖症的母亲所生的孩子在出生和成年时患心脏病的风险更高， 据称是通过燃料对发育中的心脏产生影响。然而，预防和治疗 由于根本机制尚不清楚，因此缺乏干预措施。 巴克实验室已经做好了解决这个问题的准备，因为它建立在他们最近发现的产妇糖尿病的基础上， 尤其是在高脂肪饮食的情况下，会刺激线粒体功能障碍，改变细胞生物能量学和 发育中的子代心脏中的心肌病。此外，糖尿病孕妇的风险暴露足以 将这些心脏新陈代谢的后果延长到成年。 拟议的项目建立在这一发现的基础上，利用Baack实验室良好的特征和生理 相关的大鼠模型，先进的系统生物学工具，最先进的活细胞代谢分析，以及 人脐带间充质干细胞来源的心脏祖细胞暴露于正常或糖尿病 怀孕了。建议的方法将揭示发病机制，并将研究结果转化为人类。 在回答两个悬而未决的问题时： 1)糖尿病妊娠是如何导致线粒体功能障碍和细胞生物能量学改变的 发育中的后代的心脏？ 2)下游对细胞柔韧性，特别是对心肌细胞的增殖、分化有什么影响 以及衰老与发育性程序性心脏病有关？ 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，并为出生前和出生后的发育奠定坚实的基础 在日益增长的高危人群中预防心脏病的干预措施。

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.