Probing the interplay of substrate and lipid interactions in the mechanism of a transporter family linked to age-related metabolic diseases and cancer

医疗保健实践和技术的进步延长了人类的寿命，但寿命的延长与年龄相关疾病的增加有关，包括糖尿病，肥胖和癌症。这些慢性疾病改变了病人的生活，也给我们的卫生服务带来了巨大的负担。上述与癌症有关的疾病与细胞代谢密切相关。事实上，症状通常可以通过减少饮食中消耗的卡路里数量来缓解（称为卡路里限制）。热量限制已被证明可以逆转与年龄有关的疾病，延长许多不同物种的寿命，包括灵长类动物，这表明这些好处也可以扩展到人类。对于人体来说，从饮食中摄取营养素，营养素必须从血液中运输到细胞中，在那里它们被加工用于能量生产和细胞成分的合成。营养物质的吸收是由存在于细胞膜中的称为转运蛋白的蛋白质进行的，细胞膜是细胞内部和环境之间的油脂状屏障。转运蛋白是微型分子机器，它利用细胞提供的能源将化学物质“泵送”穿过细胞膜。与任何泵一样，切断它的能量来源或堵塞其机制将使其停止运作。柠檬酸盐是人类正常代谢和脂肪产生的关键营养素，并通过一种名为INDY的蛋白质运输到细胞中，这代表我还没有死，因为INDY功能的中断会使果蝇的寿命延长一倍。在小鼠中，干扰INDY可以保护它们免受糖尿病和肥胖的影响。因此，阻止人类INDY转运蛋白正常发挥功能的药物可用于治疗与年龄相关的代谢性疾病，促进健康衰老。本研究的目的是了解INDY转运蛋白如何识别不同的化合物，以及它们如何利用能量源为这些化学物质穿过细胞膜提供动力。在了解它们如何工作的过程中，我们可以设计化学抑制剂，可以切断能量供应，或者在这些分子机器的工作中充当分子抑制剂。为了开发针对INDY蛋白的药物，我们需要知道这些蛋白质的样子，它们如何识别它们运输的营养物质，如何利用能量来源，以及自然环境，即油样膜，如何影响这些转运蛋白的活性。使用各种各样的互补实验方法，我们将解决我们知识中的这些空白，这将使我们深刻理解这些蛋白质如何在基础水平上发挥作用，并为未来开发INDY特异性药物奠定基础。

Advances in healthcare practices and technology have increased human lifespan, but increased longevity correlates with an increase in age-related diseases, including diabetes, obesity and cancer. These chronic diseases have life-changing effects on patients and are an enormous burden on our health services.Age-related diseases such as those named above are closely linked with cellular metabolism. In fact, symptoms can often be alleviated by reducing the number of calories consumed in the diet (termed caloric restriction). Caloric restriction has been shown to reverse age-related diseases and prolong the life of many different species, including primates, suggesting these benefits could also be extended to humans. For the human body to use nutrients from the diet, the nutrients have to be transported from the bloodstream into cells, where they are processed for energy production and the synthesis of cellular components. Nutrient uptake is performed by proteins called transporters that exist in the cell membrane, which is the greasy, oil-like barrier between the inside of the cell and the environment. Transporters are miniature molecular machines that "pump" chemicals across the cell membrane using an energy source provided by the cell. As with any pump, cutting it off from its energy source or jamming up the mechanism will stop it from functioning.Citrate is a key nutrient for normal metabolism and fat production in humans, and is transported into cells by a protein called INDY, which stands for I'm not dead yet because disruption of INDY function in fruitflies doubles their lifespan. In mice, disrupting INDY protects them from diabetes and obesity. Therefore, drugs that stop human INDY transporter proteins from functioning properly could be used to treat age-related metabolic diseases and promote healthy ageing.The aim of this study is to understand how INDY transporters are able recognise different chemical compounds, and how they harness an energy source to power movement of these chemicals across the cell membrane. In understanding how they work, we can design chemical inhibitors that could cut off the energy supply or act as molecular spanners in the works of these molecular machines. To develop drugs that target INDY proteins we need to know what these proteins look like, how they recognise the nutrients they transport, how the energy source is harnessed, and how the natural environment, i.e. the oil-like membrane, influences the activity of these transporters. Using a wide variety of complementary experimental approaches, we will address these gaps in our knowledge, which will give us a profound understanding of how these proteins work at a fundamental level, and will lay the foundation for the development of INDY specific drugs in the future.