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

糖尿病影响着8%的世界人口。如果治疗不当，血糖水平会危险地升高，这可能导致失明，肾衰竭，肢体丧失和死亡。在英国，NHS每年花费超过100亿英镑用于糖尿病护理，但我们并没有更接近治愈。事实上，2型糖尿病的发病率（占>90%的病例）继续有增无减。糖尿病发展的核心是β细胞的衰竭，β细胞分散在胰岛中的整个胰腺中。失败的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恶性循环中的β细胞衰竭。深入了解控制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（miRNAs），这是细胞内的微小分子，最近发现它们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miRNAs，所有细胞，包括β细胞，都需要miRNAs才能充分发挥作用。研究还表明，miRNAs的改变可导致糖尿病。然而，人们对哪些miRNAs对β细胞功能很重要，它们如何发挥影响以及它们的作用是如何控制的知之甚少。我现在已经证明了两种miRNAs，miR-184和miR-125 b，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，这对它们的生存和正常功能至关重要。此外，我已经证明了这些miRNAs本身会随着糖含量的变化而上升和下降。所有这些都表明AMPK及其相关的miRNAs是糖尿病重要的潜在药物靶点。事实上，现有的糖尿病药物已经被认为部分通过调节AMPK起作用，但我们对确切机制和分子相互作用的理解是不完整的，这限制了更有效治疗方法的发展。在这个项目中，我将使用最先进的技术：1。充分阐明miR-184和miR-125 b（及其与AMPK的相互作用）对β细胞功能和存活的贡献.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可能转化为高效的糖尿病新疗法非常重要。

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.