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

• 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

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% 的成年人患有糖尿病。如果治疗不当，糖尿病会导致血糖水平非常高，从而使病情恶化并导致肾衰竭和失明等并发症，从而使 2 型糖尿病 (T2D) 的预期寿命缩短 10 年。胰腺β细胞负责分泌胰岛素以应对血糖升高。 β细胞无法分泌足够的胰岛素会导致糖尿病的发生。重要的是，高血糖的流行会加速 β 细胞衰竭，并通过尚不清楚的机制导致 β 细胞损失。更好地了解导致 β 细胞衰竭的过程对于开发能够阻止 T2D 发展的药物至关重要。 miRNA 是小 RNA 分子，它们本身不产生蛋白质，但能够降低其他蛋白质（它们的“目标”）的产生速度。 MicroRNA 存在于 β 细胞中，调节重要功能，例如产生和分泌胰岛素的能力。此外，β 细胞中某些 miRNA 水平的变化与 T2D 的发展有关。我们最近取得了三个重要发现。首先，当小鼠和人类 β 细胞暴露于高水平的葡萄糖时，它们的 miRNA miR-125b (miR-125b-5p) 水平会上升。其次，在小鼠的β细胞中引入额外的miR-125b会导致它们产生和分泌较少的胰岛素并患上糖尿病。我们还观察到，减少培养的人β细胞中miR-125b的量可以提高它们响应葡萄糖而分泌胰岛素的能力。因此，我们假设β细胞选择性抑制miR-125b有可能保护β细胞功能免受高血糖的影响。第三，我们发现高水平的miR-125b导致溶酶体增大，而低水平的miR-125b导致线粒体形态和与线粒体功能相关的基因含量的变化。溶酶体和线粒体是亚细胞细胞器，分别对于细胞成分和废物的回收以及能量生产非常重要。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 β 细胞功能的充分发挥至关重要，并且在糖尿病中会发生改变。此外，我们还证明 miR-125b 靶向阳离子依赖性溶酶体甘露糖 6-磷酸受体 (M6PR)，该受体将溶酶体酶转运至溶酶体以实现其充分发挥功能。然而，M6PR对β细胞溶酶体和分泌功能的作用尚未被研究。因此，本提案的具体目的是确定： 1．选择性消除/减少 β 细胞中的 miR-125b 是否以及如何预防 T2D 进展2。 miR-125b 在溶酶体和线粒体功能中的作用3。 M6PR 在β 细胞中的功能为了实现这些目标，我们将使用- 在β 细胞中选择性删除/过表达miR-125b 的小鼠的组合。使用小鼠是必要的，因为维持葡萄糖稳态需要所有代谢组织之间的相互作用，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，经过修饰以含有或多或少的 miR-125b。人类样本的使用对于确保我们的研究结果向临床的可转化性至关重要。-小鼠和人类β细胞系，经过修饰以含有或多或少的miR-125b或M6PR，从而可以详细研究生物过程并减少不必要的动物使用。miRNA是药物靶向的新型候选者，我们的研究将提供关于β细胞miR-125b抑制治疗T2D的潜力的临床前数据。它还将为β细胞如何在健康和疾病中发挥作用提供新的基本见解，从长远来看，这可能会揭示治疗糖尿病的新方法。