AMPK-mediated regulation and roles of miR-125b and miR-184 in pancreatic beta-cell function.

AMPK 介导的 miR-125b 和 miR-184 在胰腺 β 细胞功能中的调节和作用。

• 批准号: MR/P023223/1
• 负责人: Aida Martinez-Sanchez
• 金额: $ 66.87万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP023223%2F1
• 关键词: AMPK; mediated; regulation; roles; miR

Diabetes affects 8% of the world population. When poorly treated, blood sugar levels run dangerously high, which can lead to blindness, kidney failure, limb loss and death. In the UK the NHS spends over £10 billion every year on diabetes care, but we are no closer to a cure. In fact, the incidence of type 2 diabetes (which accounts for >90% cases) continues to rise unabated. Central to the development of diabetes is the failure of beta-cells, which are dispersed throughout the pancreas in the islets of Langerhans. The failing beta-cells are unable to secrete enough insulin to lower blood sugar levels. Crucially, a high prevailing blood sugar will itself further accelerate beta-cell failure in a vicious cycle. A deeper understanding of the molecules that control beta-cell function and survival is essential for the development of better targeted drugs that can prevent, slow down or even reverse beta cell demise and hence effectively treat diabetes. I have spent most of my career studying microRNAs (miRNAs), which are tiny molecules inside cells that have recently been discovered to regulate the genes that are required for a cell to function normally. There are more than 2000 different miRNAs in the human body and all cells, including the beta-cells, need miRNAs to work adequately. It has also been demonstrated that alteration of miRNAs can lead to diabetes. Nevertheless, very little is known about which miRNAs are important for beta-cell function, how they exert their influence and how their actions are controlled. I have now demonstrated that two miRNAs, miR-184 and miR-125b, are closely related to the activity of AMPK. AMPK is an enzyme that helps the beta-cell recognize what the prevailing blood sugar level is and it is vital to their survival and normal functioning. Furthermore, I have demonstrated that these miRNAs themselves go up and down in response to changes in the amount of the sugar. All of this points to AMPK and its related miRNAs as being important potential drug targets for diabetes. In fact, existing diabetes medications are already thought to work in part by modulating AMPK, but our understanding of the exact mechanisms and molecular interactions is patchy, which limits the development of even more effective treatments. In this project I will use state-of-the-art techniques to:1. Fully elucidate the contribution of miR-184 and miR-125b (and their interactions with AMPK) towards beta-cell function and survival.2. Show the real-life importance of this in animal models and donated human beta-cells - this is hugely important to ensure that this new knowledge can be potentially translated into highly effective new treatments for diabetes.

糖尿病影响着世界 8% 的人口。如果治疗不当，血糖水平会达到危险的高水平，可能导致失明、肾衰竭、肢体丧失和死亡。在英国，NHS 每年在糖尿病护理上花费超过 100 亿英镑，但我们距离治愈糖尿病还差得很远。事实上，2 型糖尿病（占病例的 90% 以上）的发病率持续上升，有增无减。糖尿病发展的核心是β细胞的衰竭，这些细胞分散在胰岛的朗格汉斯岛中。衰竭的β细胞无法分泌足够的胰岛素来降低血糖水平。至关重要的是，高血糖本身会进一步加速β细胞衰竭，形成恶性循环。更深入地了解控制 β 细胞功能和存活的分子对于开发更好的靶向药物至关重要，这些药物可以预防、减缓甚至逆转 β 细胞死亡，从而有效治疗糖尿病。我职业生涯的大部分时间都在研究 microRNA (miRNA)，它们是细胞内的微小分子，最近被发现可以调节细胞正常运作所需的基因。人体内有超过 2000 种不同的 miRNA，所有细胞（包括 β 细胞）都需要 miRNA 才能充分发挥作用。研究还表明，miRNA 的改变可能导致糖尿病。然而，对于哪些 miRNA 对 β 细胞功能很重要、它们如何发挥影响以及如何控制它们的作用，人们知之甚少。我现在已经证明，两个 miRNA，miR-184 和 miR-125b，与 AMPK 的活性密切相关。 AMPK 是一种酶，可以帮助 β 细胞识别当前的血糖水平，这对于它们的生存和正常功能至关重要。此外，我还证明这些 miRNA 本身会随着糖含量的变化而上下变化。所有这些都表明 AMPK 及其相关 miRNA 是糖尿病的重要潜在药物靶点。事实上，现有的糖尿病药物已经被认为部分通过调节 AMPK 发挥作用，但我们对确切机制和分子相互作用的理解并不完整，这限制了更有效治疗方法的开发。在这个项目中，我将使用最先进的技术来：1。充分阐明miR-184和miR-125b（及其与AMPK的相互作用）对β细胞功能和存活的贡献。2．在动物模型和捐赠的人类β细胞中展示这一点在现实生活中的重要性——这对于确保这一新知识能够转化为高效的糖尿病新疗法非常重要。

项目成果

Glucose-Dependent miR-125b is a Negative Regulator of ß-Cell Function

葡萄糖依赖性 miR-125b 是细胞功能的负调节因子

• DOI: 10.2337/figshare.19609827.v1
• 发表时间: 2022
• 作者: Martinez-Sanchez A

MiR-184 expression is regulated by AMPK in pancreatic islets.

• DOI: 10.1096/fj.201701100r
• 发表时间: 2018-05
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Martinez-Sanchez A;Nguyen-Tu MS;Cebola I;Yavari A;Marchetti P;Piemonti L;de Koning E;Shapiro AMJ;Johnson P;Sakamoto K;Smith DM;Leclerc I;Ashrafian H;Ferrer J;Rutter GA
• 通讯作者: Rutter GA

Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq"

• DOI: 10.1016/j.lfs.2023.121436
• 发表时间: 2023-01-28
• 期刊: LIFE SCIENCES
• 影响因子: 6.1
• 作者: Chabosseau, Pauline;Yong, Fiona;Rutter, Guy A.
• 通讯作者: Rutter, Guy A.

Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of ß-cell-dependent contrast enhancement in the pancreas.

基于 exendin-4 的 MRI 探针的合成和体内行为，能够在胰腺中实现细胞依赖性对比度增强。

• DOI: 10.1039/d0dt00332h
• 发表时间: 2020
• 期刊: 2003)
• 作者: Clough TJ

Manipulation and Measurement of AMPK Activity in Pancreatic Islets.

胰岛 AMPK 活性的操作和测量。

• DOI: 10.1007/978-1-4939-7598-3_26
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Martinez-Sanchez A