Targeting endothelial-erythrocyte glycocalyx exchange for the novel diagnosis and treatment of renal disease

靶向内皮-红细胞糖萼交换用于肾脏疾病的新诊断和治疗

• 批准号: MR/W024187/1
• 负责人: Matthew Butler
• 金额: $ 138.44万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW024187%2F1
• 关键词: Targeting; endothelial; erythrocyte; glycocalyx; exchange

Endothelial cells form a continual lining within our blood vessels. They are covered by a protective layer called the glycocalyx. This layer is made from a mix of proteins and sugars. It forms a jelly like covering on the cells surface. This glycocalyx performs several important jobs. It regulates the passage of cells and proteins from the blood into the tissues. It detects how fast the blood is moving (helping to regulate tissues blood flow), and it prevents blood from clotting unnecessarily. When the glycocalyx fails to perform these roles blood vessels cease to function optimally, which subsequently results in organs becoming damaged. Damage to the delicate glycocalyx layer occurs in several human diseases. In diabetes damage to the endothelial glycocalyx happens very early on, before predisposed patients develop detectable kidney disease. In animal models of diabetes, I have shown that intervening at this early stage when the glycocalyx is damaged (but before protein starts to be detectable in the urine) can prevent the development of kidney disease. In humans not everyone with diabetes develops glycocalyx damage or kidney disease. We believe that patients that develop a damaged glycocalyx early in the disease course will be the most likely to subsequently develop diabetic kidney damage. Identifying these high-risk patients would allow clinicians to prioritise which patients to see more regularly and which patients to treat more aggressively with existing medications.Currently, human glycocalyx damage is not easily detectable with a clinical test. However, I have developed a novel blood test to study glycocalyx changes that could be developed for clinical practice. In this project I will confirm that my test is giving us a true picture of how the glycocalyx changes throughout the body by simultaneously studying the endothelial glycocalyx at multiple sites. This study needs to be performed in animal models of disease to allow us access to all the tissue we need. To perform this study in the UK would need large numbers of diabetic animals. However, by collaborating with a research group in Los Angeles I can re-use a technique that I developed to measure glycocalyx depth changes during my PhD. Using their cutting edge microscope, I can image blood vessels deep inside anesthetised mice and measure how the glycocalyx is changing inside the organs and skin as diabetes develops. I can measure the glycocalyx depth at these sites every week and compare the changes I detect with my blood test to prove that my test is reflecting the changes we see.To check that my test can predict which diabetic patients will go on to develop damage to their blood vessels I will include my test in the established European study 'BEAt-DKD'. This study is currently enrolling participants and will allow me to compare my test to the current gold standard tests of endothelial damage and collect follow-up data to test my hypothesis that we can predict who will develop detectable diabetic nephropathy. I will simultaneously work on the development of my test by working with computer scientists at the University of Bristol to refine and automate the analysis whilst integrating machine learning into the programming. Machine learning should let the computer get better and better at performing the analysis for us as it learns from its mistakes to become a faster and more reliable with time.Finally, I will be use the information I learn by studying changes in the endothelial glycocalyx to develop a novel method of reapplying key parts of the glycocalyx to the blood vessel wall. My method will target the areas of the circulation where the glycocalyx is most damaged by focusing repairs on areas where the blood does not flow smoothly. This novel repair system could be used when patients are at the highest risk of acute glycocalyx damage e.g. after trauma and sepsis, or in patients with chronic glycocalyx damage e.g. patients on haemodialysis.

内皮细胞在我们的血管内形成连续的内壁。它们被称为糖萼的保护层覆盖。该层由蛋白质和糖的混合物制成。它在细胞表面形成果冻状覆盖物。这种糖萼执行多项重要的工作。它调节细胞和蛋白质从血液进入组织的通道。它检测血液流动的速度（有助于调节组织血流），并防止血液不必要的凝结。当糖萼无法发挥这些作用时，血管就会停止最佳功能，从而导致器官受损。多种人类疾病都会导致脆弱的糖萼层受损。在糖尿病中，内皮糖萼的损伤很早就发生，在易感患者出现可检测到的肾脏疾病之前。在糖尿病动物模型中，我已经证明，在糖萼受损的早期阶段（但在尿液中开始检测到蛋白质之前）进行干预可以预防肾脏疾病的发展。在人类中，并非所有糖尿病患者都会出现糖萼损伤或肾脏疾病。我们认为，在病程早期出现糖萼受损的患者最有可能随后出现糖尿病肾损伤。识别这些高风险患者将使临床医生能够优先考虑哪些患者需要更频繁地就诊，以及哪些患者需要使用现有药物进行更积极的治疗。目前，通过临床测试不容易检测到人类糖萼损伤。然而，我开发了一种新的血液测试来研究糖萼的变化，可以用于临床实践。在这个项目中，我将确认我的测试通过同时研究多个部位的内皮糖萼，为我们提供了糖萼在整个身体中如何变化的真实图像。这项研究需要在疾病动物模型中进行，以便我们能够获得所需的所有组织。在英国进行这项研究需要大量患有糖尿病的动物。然而，通过与洛杉矶的一个研究小组合作，我可以重复使用我在博士期间开发的测量糖萼深度变化的技术。使用他们的尖端显微镜，我可以对麻醉小鼠体内深处的血管进行成像，并测量随着糖尿病的发展，器官和皮肤内部的糖萼如何变化。我可以每周测量这些部位的糖萼深度，并将我检测到的变化与血液测试进行比较，以证明我的测试反映了我们看到的变化。为了检查我的测试是否可以预测哪些糖尿病患者将继续对其血管造成损害，我将把我的测试纳入已建立的欧洲研究“BEAt-DKD”中。这项研究目前正在招募参与者，将使我能够将我的测试与当前内皮损伤的金标准测试进行比较，并收集后续数据来测试我的假设，即我们可以预测谁会患上可检测的糖尿病肾病。我将同时与布里斯托大学的计算机科学家合作开发我的测试，以完善和自动化分析，同时将机器学习集成到编程中。机器学习应该让计算机越来越好地为我们执行分析，因为它会从错误中学习，随着时间的推移变得更快、更可靠。最后，我将利用通过研究内皮糖萼的变化学到的信息来开发一种将糖萼的关键部分重新应用到血管壁的新方法。我的方法将针对糖萼受损最严重的循环区域，重点修复血液流动不顺畅的区域。当患者处于急性糖萼损伤的最高风险时，例如，可以使用这种新颖的修复系统。创伤和脓毒症后，或患有慢性糖萼损伤的患者，例如接受血液透析的患者。

项目成果

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

• DOI: 10.1186/s12933-024-02133-1
• 发表时间: 2024-02-01
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3

The microvascular endothelial glycocalyx: An additional piece of the puzzle in veterinary medicine.

微血管内皮糖脂：兽药中的另一个难题。

• DOI: 10.1016/j.tvjl.2022.105843
• 发表时间: 2022-07
• 期刊: VETERINARY JOURNAL
• 影响因子: 2.2
• 作者: Lawrence-Mills, Sara J.;Hughes, David;Hezzell, Melanie J.;Butler, Matthew;Neal, Chris;Foster, Rebecca R.;Welsh, Gavin I.;Finch, Natalie
• 通讯作者: Finch, Natalie

Aldosterone: Essential for Life but Damaging to the Vascular Endothelium.

• DOI: 10.3390/biom13061004
• 发表时间: 2023-06-17
• 期刊: Biomolecules
• 影响因子: 5.5

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.

志贺毒素靶向足细胞，通过激活内皮补体引起溶血性尿毒症综合征。

• DOI: 10.1016/j.medj.2023.09.002
• 发表时间: 2023
• 期刊: Med (New York, N.Y.)
• 作者: Bowen EE

Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx.

• DOI: 10.1172/jci.insight.154164
• 发表时间: 2023-03-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Crompton, Michael;Ferguson, Joanne K.;Ramnath, Raina D.;Onions, Karen L.;Ogier, Anna S.;Gamez, Monica;Down, Colin J.;Skinner, Laura;Wong, Kitty H.;Dixon, Lauren K.;Sutak, Judit;Harper, Steven J.;Pontrelli, Paola;Gesualdo, Loreto;Heerspink, Hiddo L.;Toto, Robert D.;Welsh, Gavin I.;Foster, Rebecca R.;Satchell, Simon C.;Butler, Matthew J.
• 通讯作者: Butler, Matthew J.