MICA: Deciphering the mechanism of action of miR-125b in beta cells and its therapeutic potential in Diabetes

MICA：破译 miR-125b 在 β 细胞中的作用机制及其治疗糖尿病的潜力

基本信息

批准号：
MR/X009912/1
负责人：
Aida Martinez-Sanchez
金额：
$ 78.61万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX009912%2F1
关键词：
MICA Deciphering mechanism action miR

项目摘要

Over 8.5% of the world's adult population suffer diabetes. If poorly treated, diabetes leads to very high blood sugar levels which worsen the disease and lead to complications such as kidney failure and blindness, shortening life expectancy by 10 years in the case of type 2 diabetes (T2D). Pancreatic beta cells are in charge of secreting insulin in response to rises in blood sugar. Failure of beta cells to secrete enough insulin contributes to the development of diabetes. Importantly, the prevalence of high-blood sugar accelerates beta cell failure and contributes to beta cell loss by mechanisms which are not yet clear. A better understanding of the process leading to beta cell failure is vital for the development of drugs capable of stopping the development of T2D. MiRNAs are small RNA molecules that do not produce proteins themselves but are capable to reduce the rate at which other proteins (their "targets") are produced. MicroRNAs exist in beta cells that regulate important functions such as their capacity to produce and secrete insulin. Also, changes in the levels of certain miRNAs in beta cells are associated with the development of T2D.We have recently made three important findings. Firstly, when mouse and human beta cells are exposed to high levels of glucose, their levels of the miRNA miR-125b (miR-125b-5p) go up. Secondly, the introduction of additional miR-125b in the beta cells of mice causes them to produce and secrete less insulin and develop diabetes. We have also observed that reducing the amount of miR-125b in human beta cells in culture improves their capacity to secrete insulin in response to glucose. Accordingly, we hypothesize that beta cell selective inhibition of miR-125b has the potential to protect beta cell function from hyperglycaemia. Thirdly, we have seen that high levels of miR-125b lead to the appearance of enlarged lysosomes while low levels of miR-125b lead to changes in mitochondria morphology and in the content of genes related to mitochondrial function. Lysosomes and mitochondria are subcellular organelles very important for the recycling of cellular components and waste and for energy production, respectively. Thus, we hypothesize that miR-125b regulates beta cell function by modulating lysosomal and/or mitochondrial function. Both processes are essential for adequate beta cell function and are altered in diabetes.Additionally, we have demonstrated that miR-125b targets the cation-dependent lysosomal mannose-6-phosphate receptor (M6PR) which transports lysosomal enzymes to lysosomes for their adequate functioning. Nevertheless, the role of M6PR for lysosomal and secretory function in beta cells hasn't been studied.Thus, the specific aims of this proposal are to determine:1. Whether and how selective elimination/reduction of miR-125b in beta cells prevents T2D progression2. The role of miR-125b in lysosomal and mitochondrial function3. The function of M6PR in beta cellsTo achieve these aims we will use a combination of- Mice deleted for/overexpressing miR-125b selectively in beta cells. The use of mice is necessary since maintenance of glucose homeostasis requires interplay between all metabolic tissues and therefore these experiments need to be done in the context of the whole body. - Donated human islets, modified to contain more or less miR-125b. The use of human samples is essential to ensure the translatability of our findings to the clinic.- Mouse and human beta cell lines, modified to contain more or less miR-125b or M6PR, which allow to study biological processes in detail and reduces an unnecessary use of animals.MiRNAs are novel candidates for drug targeting and our study will provide preclinical data on the potential of beta cell miR-125b inhibition for the treatment of T2D. It will also provide new fundamental insights into how beta cells work in health and disease, which, in the long term, could reveal new ways to treat diabetes.

世界上超过8.5％的成年人口患有糖尿病。如果治疗不佳，糖尿病会导致非常高的血糖水平，从而使疾病恶化并导致并发症，例如肾衰竭和失明，在2型糖尿病（T2D）的情况下，预期寿命缩短了10年。胰腺β细胞负责分泌胰岛素，以响应血糖升高。 β细胞无法分泌足够的胰岛素有助于糖尿病的发展。重要的是，高血糖的患病率会加速β细胞衰竭，并通过尚不清楚的机制导致β细胞损失。更好地理解导致β细胞衰竭的过程对于能够停止T2D发展的药物的发展至关重要。 miRNA是小的RNA分子，不产生蛋白质本身，但能够降低产生其他蛋白质（其“靶标”）的速率。 MicroRNA存在于β细胞中，这些细胞调节重要功能，例如产生和分泌胰岛素的能力。同样，β细胞中某些miRNA水平的变化与T2D的发展有关。我们最近提出了三个重要的发现。首先，当小鼠和人β细胞暴露于高水平的葡萄糖时，它们的miRNA miRNA miR-125b（miR-125b-5p）水平上升。其次，在小鼠的β细胞中引入其他miR-125b会导致它们产生和分泌少于胰岛素并患上糖尿病。我们还观察到，在培养物中减少人β细胞中的miR-125b量可以提高其对葡萄糖的分泌能力。因此，我们假设miR-125b的β细胞选择性抑制具有保护β细胞功能免受高血糖症的潜力。第三，我们已经看到，高水平的miR-125b导致溶酶体的出现，而低水平的miR-125b导致线粒体形态的变化以及与线粒体功能相关的基因含量。溶酶体和线粒体是亚细胞细胞器，对于分别对细胞成分和废物的回收以及能量产生非常重要。因此，我们假设miR-125b通过调节溶酶体和/或线粒体功能来调节β细胞功能。这两个过程对于足够的β细胞功能至关重要，并且在糖尿病中改变了。在此方面，我们已经证明，miR-125b靶向阳离子依赖性的溶酶体糖体6-磷酸受体（M6PR），将溶酶体酶传递到充足的溶酶体向溶酶体运输到足够的功能。然而，尚未研究M6PR在β细胞中溶酶体和分泌功能的作用。因此，该建议的具体目的是确定：1。 beta细胞中miR-125b的选择性消除/减少如何防止T2D进展2。 miR-125b在溶酶体和线粒体功能中的作用3。 M6PR在Beta Cellsto中的功能达到了这些目标，我们将使用β细胞中选择性地删除/过表达miR-125b的小鼠组合。需要使用小鼠，因为维持葡萄糖稳态需要在所有代谢组织之间进行相互作用，因此这些实验需要在整个身体的背景下进行。 - 捐赠的人类胰岛，被修改为包含或多或少的miR-125b。 The use of human samples is essential to ensure the translatability of our findings to the clinic.- Mouse and human beta cell lines, modified to contain more or less miR-125b or M6PR, which allow to study biological processes in detail and reduces an unnecessary use of animals.MiRNAs are novel candidates for drug targeting and our study will provide preclinical data on the potential of beta cell miR-125b inhibition for the treatment of T2D.它还将提供有关β细胞在健康和疾病中如何工作的新基本见解，从长远来看，这可以揭示治疗糖尿病的新方法。