Understanding the impact of type 1 diabetes and statin use on vascular cells

了解 1 型糖尿病和他汀类药物的使用对血管细胞的影响

• 批准号: MR/Y001028/1
• 负责人: Blerina Ahmetaj-Shala
• 金额: $ 90.31万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001028%2F1
• 关键词: Understanding; impact; type; diabetes; statin

Diabetes is a disease where sugar (glucose) levels cannot be controlled properly because the pancreas, which makes the cells that produce glucose, does not work. People with diabetes have serious complications effecting the heart and blood vessels (cardiovascular system) resulting in a poor quality of life and shorter life expectancy compared to people that are healthy or do not have diabetes. There are 537 million people worldwide that have diabetes so understanding why cardiovascular complications occur and how we can prevent these complications is not only important to patients and caregivers, but also to society and healthcare. To prevent cardiovascular complications, in 2014, NICE recommended that adults with diabetes take statins, a class of drugs that reduce the level of bad cholesterol/ lipids. This recommendation was based on extensive clinical study data looking at statin use mainly in people with type 2 diabetes (T2D) not type 1 diabetes (T1D). This is important because T2D is a very different disease to T1D. T2D, which makes up approximately 90% of cases, is influenced by age, diet and lifestyle factors and has been shown to improve/ reverse with weight loss. T1D, which makes up approximately 8% of cases, can develop at a young age (childhood), requires life-long treatment with injections and cannot be prevented or reversed to a point where medication is no longer needed. Importantly, the lipid profile is different between T1D and T2D; people with T1D have higher levels of lipids that are protective to the cardiovascular system whereas people with T2D have higher levels of 'bad' cholesterol. For people with T1D, the lack of clinical evidence has resulted in worry about statin-use to the point where they are refusing to start statin therapy. Similarly, for clinicians, this lack of evidence has made it difficult to decide if and when to start their patients on a statin.This project aims to use cells that can be grown non-invasively from blood, and provide a 'window into the vasculature', to further understand how T1D and statin use effects the vasculature. I have shown that in control (healthy) donors statins reduce inflammatory responses of endothelial cells (cells that make up blood vessels) grown from blood (called blood outgrowth endothelial cells; BOECs) in response to infection. I will now expand on this work to look at BOECs and coronary artery endothelial and smooth muscle cells (cells that also make up blood vessels) grown from people with T1D. Firstly, I will test how BOECs and coronary artery cells grown from controls respond to inflammation when a statin is added. I will look specifically at how statins effect the ability of the cells to do their job, such as; (i) how fast these cells grow within a certain time, (ii) how quickly they move from one area to another, (iii) the things they release when drugs are added to them and (iv) how 'sticky' they are. Secondly, I will repeat these experiments in cells plated in static conditions and under directional flow to mimic the flow of blood in the body. Thirdly, I will run a small clinical study where I will compare head-to-head the responses above from people with T1D that are either on statin therapy or not on statin therapy. Finally in order to better understand if and how certain genes/ proteins change in T1D, how statin use effects this expression and ultimately identify potential biomarkers, I will use techniques called RNA Sequencing and O-link. This will allow me to confirm how statins effect BOECs in T1D.Overall, the findings from this project impacts people with not only T1D but also T2D and other diseases where statins have been shown to be beneficial such as cancer and infection. The use of BOECs for research in T1D provides opportunities for personalised medicine and fast and effective drug screening and reduces the need for animals in research.

糖尿病是一种疾病，无法正确控制糖（葡萄糖）水平，因为胰腺导致产生葡萄糖的细胞不起作用。与健康或没有糖尿病的人相比，糖尿病患者患有严重的并发症，影响心脏和血管（心血管系统），导致生活质量差，预期寿命较短。全球有5.37亿人患有糖尿病，因此了解为什么会发生心血管并发症以及我们如何预防这些并发症不仅对患者和护理人员很重要，而且对社会和医疗保健也很重要。为了防止心血管并发症，2014年，NOCE建议患有糖尿病的成年人服用他汀类药物，这是一类降低不良胆固醇/脂质水平的药物。该建议基于广泛的临床研究数据，研究他汀类药物主要用于2型糖尿病患者（T2D）而不是1型糖尿病（T1D）。这很重要，因为T2D与T1D是非常不同的疾病。占病例约90％的T2D受年龄，饮食和生活方式因素的影响，并已被证明会随体重减轻而改善/逆转。占病例约8％的T1D可以在年轻时（童年）发育，需要对注射寿命进行终身治疗，并且不能阻止或反转至不再需要药物。重要的是，T1D和T2D之间的脂质分布不同。具有T1D的人具有较高水平的脂质，这些脂质对心血管系统具有保护作用，而T2D患者的脂质含量更高。对于患有T1D的人来说，缺乏临床证据导致他担心他汀类药物的使用，以至于他们拒绝开始他汀类药物治疗。同样，对于临床医生而言，这种缺乏证据使很难决定是否以及何时在他汀类药物上开始患者。本项目的目的是使用可以从血液中生长的细胞，并提供“进入脉管系统的窗口”，以进一步了解T1D和汀类药物使用如何影响血管造成血管造成的脉管系统。我已经表明，在对照（健康的）供体中，他汀类药物减少了从血液（称为血液生长的内皮细胞； BOEC）生长的内皮细胞的炎症反应（构成血管的细胞），以响应感染。现在，我将扩大这项工作，以查看BOEC和冠状动脉内皮和平滑肌细胞（也构成血管的细胞），该细胞从患有T1D的人中生长出来。首先，我将测试在添加他汀类药物时从对照组中生长的BOEC和冠状动脉细胞对炎症的反应。我将专门研究他汀类药物如何影响细胞完成其工作的能力，例如； （i）这些细胞在一定时间内生长的速度，（ii）它们从一个区域转移到另一个区域，（iii）将药物添加到它们时释放的东西以及（iv）它们是多么“粘性”。其次，我将在静态条件下和方向流下镀以模仿体内血液流动的细胞中重复这些实验。第三，我将进行一项小型临床研究，在该研究中，我将比较汀类药物治疗或不接受他汀类药物治疗的T1D患者的上述反应。最后，为了更好地了解T1D中某些基因/蛋白的变化以及他汀类药物的使用如何影响这种表达并最终识别潜在的生物标志物，我将使用称为RNA测序和O-Link的技术。这将使我能够确认他汀类药物在T1D中如何影响BOEC。该项目的发现不仅会影响T1D的人，而且会影响T2D和其他疾病，这些疾病已被证明是汀类药物有益的，例如癌症和感染。在T1D中使用BOEC为个性化医学和快速有效的药物筛查提供了机会，并减少了研究中对动物的需求。