A new enzyme in cardiolipin synthesis

心磷脂合成中的新酶

• 批准号: RGPIN-2019-05642
• 负责人: Duncan, Robin
• 金额: $ 3.64万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738423
• 关键词: new; enzyme; cardiolipin; synthesis

Cardiolipin is a special type of fat that makes up the inside lining of the mitochondria, which are considered the `powerhouses' of the cell. Cardiolipin is found in every organ, but there are different forms of cardiolipin in different organs. Because specific forms of cardiolipin are needed in different places, different organs have special little machines, called enzymes, that they use to convert cardiolipin from one form to another, and to make more when it is needed. This `remodeling' of cardiolipin is important for health. When the body doesn't make enough cardiolipin, or when the body doesn't make the right types of cardiolipin, diseases can result. In fact, changes in cardiolipin amount and type commonly occur in aging, and also in many different diseases, such as Alzheimer's and Parkinson's diseases, heart disease and stroke, cardiovascular disease, and diabetes. There are also genetic diseases, where children are born with a poor ability to remodel cardiolipin, and it can cause serious consequences like heart failure. We have discovered a new enzyme that remodels cardiolipin. We are very excited about this, since it is the first new discovery of its kind in almost 10 years. We are also excited because some of the previous discoveries have been by Canadians, which means that we can help to make Canada a global leader in this field. There is a lot of this enzyme in the brain, and also in the heart and muscle which are all very energetic tissues that need to make a lot of power. There is also some in the fat, which is exciting, because changes in energy production in fat can affect weight gain. To find out more about how this enzyme works, and what it does in the body, we are going to study it in cells, and also make it in an isolated, purified form. This lets us let test how well it works, what specific types of cardiolipin it makes, and how changing those forms changes how well cells can work to make energy. This will tells us a lot about this new enzyme, but also about how cells work. We are also going to study what it does in the body. Normally, humans and mice have two copies of DNA that contains the blueprint for making this enzyme. We have made special mice that are missing one of those copies. We are going to breed the mice together, so that we make mice that don't have any copies. We have a lot of experience testing mice for normal function, and for disease. We are going to study these special mice to see how much they are affected by losing this enzyme. We are going to study their brains, to see if they have memory problems, and problems with the cells and molecules that control learning. We will also study their muscle and fat, to see if it changes how well they work. This information will help us to understand how humans function, which is important for health and disease.

心磷脂是一种特殊类型的脂肪，构成线粒体的内壁，线粒体被认为是细胞的“发电站”。心磷脂存在于每个器官中，但不同器官中有不同形式的心磷脂。因为不同的地方需要特定形式的心磷脂，所以不同的器官有特殊的小机器，称为酶，它们用来将心磷脂从一种形式转化为另一种形式，并在需要时制造更多。心磷脂的这种“重塑”对于健康很重要。当身体不能产生足够的心磷脂，或者身体不能产生正确类型的心磷脂时，就会导致疾病。事实上，心磷脂含量和类型的变化通常发生在衰老过程中，也发生在许多不同的疾病中，例如阿尔茨海默病和帕金森病、心脏病和中风、心血管疾病和糖尿病。还有遗传性疾病，孩子出生时重塑心磷脂的能力很差，这会导致心力衰竭等严重后果。 我们发现了一种可以重塑心磷脂的新酶。我们对此感到非常兴奋，因为这是近 10 年来的第一个此类新发现。我们也很兴奋，因为之前的一些发现是加拿大人的，这意味着我们可以帮助加拿大成为该领域的全球领导者。大脑、心脏和肌肉中都含有大量这种酶，这些都是非常活跃的组织，需要产生大量能量。脂肪中也有一些，这是令人兴奋的，因为脂肪中能量产生的变化会影响体重增加。为了更多地了解这种酶的工作原理以及它在体内的作用，我们将在细胞中研究它，并将其制成分离、纯化的形式。这让我们可以测试它的工作效果如何，它产生什么特定类型的心磷脂，以及改变这些形式如何改变细胞产生能量的能力。这将告诉我们很多关于这种新酶的信息，同时也告诉我们细胞如何工作。我们还将研究它在体内的作用。通常，人类和小鼠都有两份 DNA，其中包含制造这种酶的蓝图。我们制作了一种特殊的小鼠，它缺少其中一个副本。我们将把老鼠放在一起繁殖，这样我们就能培育出没有任何副本的老鼠。我们在测试小鼠的正常功能和疾病方面拥有丰富的经验。我们将研究这些特殊的小鼠，看看它们因失去这种酶而受到多大的影响。我们将研究他们的大脑，看看他们是否有记忆问题，以及控制学习的细胞和分子是否有问题。我们还将研究他们的肌肉和脂肪，看看这是否会改变他们的工作能力。这些信息将帮助我们了解人类如何运作，这对于健康和疾病很重要。