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.

糖尿病是一种糖（葡萄糖）水平不能得到适当控制的疾病，因为胰腺，使细胞产生葡萄糖，不工作。糖尿病患者有严重的并发症，影响心脏和血管（心血管系统），导致生活质量差，与健康或没有糖尿病的人相比，预期寿命较短。全世界有5.37亿人患有糖尿病，因此了解心血管并发症发生的原因以及如何预防这些并发症不仅对患者和护理人员很重要，对社会和医疗保健也很重要。为了预防心血管并发症，2014年，NICE建议糖尿病患者服用他汀类药物，这是一类降低不良胆固醇/脂质水平的药物。这一建议是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（T2 D）而不是1型糖尿病（T1 D）患者。这一点很重要，因为T2 D是一种与T1 D非常不同的疾病。T2 D约占病例的90%，受年龄，饮食和生活方式因素的影响，并已被证明可以随着体重减轻而改善/逆转。T1 D约占病例的8%，可在年幼时（儿童期）发生，需要终身注射治疗，无法预防或逆转到不再需要药物治疗的程度。重要的是，T1 D和T2 D之间的脂质分布是不同的; T1 D患者的脂质水平较高，对心血管系统有保护作用，而T2 D患者的“坏”胆固醇水平较高。对于患有T1 D的人来说，缺乏临床证据导致了对他汀类药物使用的担忧，以至于他们拒绝开始他汀类药物治疗。同样，对于临床医生来说，缺乏证据使得他们很难决定是否以及何时开始使用他汀类药物。该项目旨在使用可以从血液中非侵入性生长的细胞，并提供“血管窗口”，以进一步了解T1 D和他汀类药物的使用如何影响血管系统。我已经证明，在对照（健康）供体中，他汀类药物减少了从血液中生长的内皮细胞（构成血管的细胞）（称为血液生长内皮细胞; BOEC）对感染的炎症反应。我现在将扩展这项工作，研究从T1 D患者身上生长的BOEC和冠状动脉内皮细胞和平滑肌细胞（也构成血管的细胞）。首先，我将测试当添加他汀类药物时，从对照组生长的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有多快，（ii）它们从一个区域移动到另一个区域的速度有多快，（iii）当药物被添加到它们时，它们释放的东西以及（iv）它们有多“粘性”。其次，我将在静态条件下和定向流动下接种的细胞中重复这些实验，以模拟体内血液的流动。第三，我将进行一项小型临床研究，在该研究中，我将对接受他汀类药物治疗或未接受他汀类药物治疗的T1 D患者的上述反应进行头对头比较。最后，为了更好地了解T1 D中某些基因/蛋白质是否以及如何变化，他汀类药物如何影响这种表达并最终确定潜在的生物标志物，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如何影响T1 D中的BOEC。总体而言，该项目的研究结果不仅影响T1 D患者，还影响T2 D患者和其他他汀类药物已被证明有益的疾病，如癌症和感染。使用BOEC进行T1 D研究为个性化药物和快速有效的药物筛选提供了机会，并减少了研究中对动物的需求。