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

项目摘要 儿科研究中心旨在了解发育起源中细胞柔韧性的调节因子 健康与疾病（DOHaD）项目3将确定线粒体和细胞代谢在 心肌细胞命运作为糖尿病妊娠后出生的后代心脏病的关键介质。婴儿 患有糖尿病或肥胖症的母亲所生的孩子在出生时和成年后患心脏病的风险更高， 据称是通过对发育中的心脏的燃料介导的影响。然而，预防和治疗 缺乏干预措施，因为根本的机制仍然不明。 Baack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基础上， 特别是高脂肪饮食，会引起线粒体功能障碍，改变细胞生物能量学， 在发育中的后代的心脏心肌病。此外，糖尿病妊娠暴露足以 将这些心脏代谢的后果延续到成年期。 拟议的项目建立在这一发现的基础上，使用Baack实验室的良好表征和生理学 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测定，以及 来自暴露于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 怀孕所提出的方法将揭示发病机制，并将发现转化为人类 同时回答两个悬而未决的问题 1)糖尿病妊娠是如何引起线粒体功能障碍和改变细胞生物能量学的？ 发育中的后代的心脏 2)对细胞柔顺性，特别是心肌细胞增殖、分化的下游影响是什么？ 以及衰老与发育性程序性心脏病的关系？ 与儿科研究中心一起，项目3将展示线粒体的作用， 代谢可塑性的干细胞调节，并建立了坚实的基础，需要发展产前和产后 在这个不断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.