IMPC: Investigation into the function of pyrroline 5-carboxylate reductase 1 (PYCR1) in metabolic homeostasis

细胞的新陈代谢受到严格的控制，所以从外部吸收的营养物质只有在必要的时候才能被有效地利用。这种程度的控制需要检查和平衡不同的代谢活动，例如糖和氨基酸的代谢，以确保正常的细胞功能。对正常细胞功能至关重要的代谢的一个关键方面被称为氧化还原稳态——促氧化剂和抗氧化剂的平衡。细胞中异常的氧化还原状态可导致其功能障碍并驱动可能导致疾病的变化。已知与氧化还原稳态变化有关的一些疾病包括癌症、糖尿病和慢性炎症。我们最近发现，我们对吡咯啉5-羧酸还原酶1 （PYCR1）功能的理解可能是不正确的。这种酶负责制造一种叫做脯氨酸的氨基酸，但在这样做的过程中，它会影响细胞的氧化还原状态。虽然我们之前认为这种酶的主要功能是制造脯氨酸，但它实际上可能是对细胞氧化还原的变化做出反应，以试图保持细胞的新陈代谢健康。这一建议将提供第一个生理信息来支持我们的假设- PYCR1是响应细胞氧化还原环境变化的关键酶。这项研究得出的数据将为更大的拨款申请提供基础——包括数据和动物模型——以更充分地研究这一假设。

The metabolism of cells is tightly controlled so that nutrients taken up from the outside are used efficiently, and only when necessary. This level of control requires checks and balances that link different metabolic activities - for example the metabolism of sugars and amino acids - ensuring normal cell function. One key aspect of metabolism that is critical for normal cell function is known as redox homeostasis - the balance of pro- and anti-oxidants. An aberrant redox status in a cell can lead to its malfunction and drive changes that may result in disease. Some diseases known to be linked to changes in redox homeostasis are cancer, diabetes and chronic inflammation. We have recently discovered that our understanding of how the enzyme known as pyrroline 5-carboxylate reductase 1 (PYCR1) functions, may be incorrect. This enzyme is responsible for making an amino acid called proline, but in doing so, it influences the redox state of the cell. Although we've previously thought that the main function of this enzyme was to make proline, it may actually be to react to changes in cell redox to try and keep the metabolism of the cell healthy.This proposal will provide the first physiological information to support our hypothesis - that PYCR1 is a critical enzyme in the response to changes in the redox environment of cell. The data that comes out of this research will provide the building blocks - both data and animal model - for a bigger grant application to investigate this hypothesis more fully.