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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757736
• 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，构成线粒体的内层，线粒体被认为是细胞的“动力室”。心磷脂存在于每个器官中，但在不同器官中有不同形式的心磷脂。由于不同的地方需要特定形式的心磷脂，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，并在需要时产生更多。心磷脂的这种“重塑”对健康很重要。当身体不能产生足够的心磷脂时，或者当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，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。还有一些遗传性疾病，儿童出生时重塑心磷脂的能力很差，这可能会导致严重的后果，如心力衰竭。 我们发现了一种重塑心磷脂的新酶。我们对此感到非常兴奋，因为这是近10年来的首次新发现。我们也很兴奋，因为之前的一些发现是由加拿大人发现的，这意味着我们可以帮助加拿大成为这一领域的全球领导者。大脑中有很多这种酶，心脏和肌肉中也有很多这种酶，这些都是非常有活力的组织，需要产生大量的能量。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。为了进一步了解这种酶是如何工作的，以及它在体内的作用，我们将在细胞中研究它，并将其分离纯化。这让我们可以测试它的工作效果如何，它制造了哪些特定类型的心磷脂，以及改变这些形式如何改变细胞产生能量的工作方式。这将告诉我们很多关于这种新酶的信息，也告诉我们细胞是如何工作的。我们还将研究它在体内的作用。正常情况下，人类和小鼠有两个DNA拷贝，其中包含制造这种酶的蓝图。我们制造了一种特殊的老鼠，它们缺少其中一个拷贝。我们将把这些老鼠放在一起繁殖，这样我们就可以制造出没有任何拷贝的老鼠。我们有很多测试老鼠正常功能和疾病的经验。我们将研究这些特殊的老鼠，看看失去这种酶对它们的影响有多大。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的问题。我们还将研究他们的肌肉和脂肪，看看它是否会改变他们的工作方式。这些信息将帮助我们了解人类的功能，这对健康和疾病很重要。