Oxidative metabolism in heart regeneration: friend or foe?

心血管疾病是世界范围内导致死亡的主要原因。这可以部分归因于人类心脏无法再生失去的心脏组织。在心肌梗塞时，数十亿心肌细胞死亡，坏死组织随后被不可收缩的纤维化疤痕所取代，最终导致心力衰竭和死亡。因此，确定能够导致成功的心脏再生的途径具有巨大的治疗潜力。与人类和一般成年哺乳动物相比，斑马鱼在整个成年期都保持着再生失去的心脏组织的能力。因此，这是一个很好的模型来识别驱动心脏再生的途径。然而，几种野生型斑马鱼株的再生能力是高度可变的。在我的博士学位期间，我将利用这些物种内的差异来确定成功的心脏再生的新途径。通过这种比较方法，我已经确定了以前未被重视的氧化代谢在再生过程中的作用。与之前认为的相反，成功的心脏再生似乎依赖于氧化代谢基因在其后期的上调。这一过程似乎与胚胎肌球蛋白标记物的表达有关。通过我的博士学位，我打算通过RNAseq，蛋白质组学和代谢组学进一步了解代谢，基因表达和心肌细胞再分化之间的相互作用。此外，对再生表面鱼和非再生洞穴鱼（Astyanax mexicanus）的比较将揭示斑马鱼中发现的机制是否通过其他物种的进化而得到保护。此外，通过P1和P7新生小鼠心脏再生的比较，我将验证氧化磷酸化在再生P1心脏中的表达，并表征其在心肌细胞再分化中的作用。此外，我打算药理学上调节成年小鼠的氧化代谢，以探索这些代谢途径诱导哺乳动物心脏再生的任何治疗潜力。总之，该项目旨在表征氧化磷酸化作为促进心脏再生的一个因素。

Cardiovascular disease is the leading cause of death worldwide. This can be partially attributed to the inability of the human heart to regenerate lost cardiac tissue. Upon myocardial infarction billions of cardiomyocytes die and the necrotic tissue is then replaced by a non-contractile fibrotic scar which will eventually lead to the development of heart failure and death. Consequently, identifying pathways which can lead to successful heart regeneration has immense therapeutic potential.In contrast to humans, and adult mammals in general, zebrafish maintain the ability to regenerate lost cardiac tissue throughout their adult life. As a result, the are an excellent model to identify pathways which drive cardiac regeneration. Nevertheless, the regenerative capacity of several wild type zebrafish strains is highly variable. During my DPhil I will be exploiting those intra-species differences to identify novel pathways which are responsible for successful heart regeneration.Through this comparative approach I have identified a previously underappreciated role of oxidative metabolism in the regenerative process. Contrary to what was previously believed, successful heart regeneration appears to be dependent on an upregulation of oxidative metabolism genes during its late stages. This process seems to be linked to the expression of embryonic myosin markers. Through my DPhil I intend to further understand the interplay between metabolism, gene expression and cardiomyocyte re-differentiation through the use of RNAseq, proteomics and metabolomics. Additionally, comparison between the regenerative surface fish and non-regenerative cavefish (Astyanax mexicanus) will reveal whether the mechanisms identified in zebrafish are conserved through evolution in other species.Furthermore, through comparison of P1 to P7 neonatal mice heart regeneration I will validate the expression of oxidative phosphorylation in the regenerating P1 heart and characterise its role in the context of cardiomyocyte re-differentiation. Additionally, I intend to pharmacologically modulate oxidative metabolism in adult mice to explore any therapeutic potential of these metabolic pathways to induce heart regeneration in the mammalian heart.In conclusion, this project aims at the characterisation of oxidative phosphorylation as a factor which promotes heart regeneration.