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Characterisation of glycan ligands recognised by collectin-11 in ischaemic kidney and development of a specific antagonistic probe

缺血肾中collectin-11识别的聚糖配体的表征以及特异性拮抗探针的开发

基本信息

批准号：
MR/R010757/1
负责人：
Steven Sacks
金额：
$ 93.99万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR010757%2F1
关键词：
Characterisation glycan ligands recognised collectin

项目摘要

The cells making up our tissues and organs are covered with sugar molecules. This coating normally is important in organ development and maintenance but can be a target for our immune system, causing tissue damage. We have found that blood flow disturbance to the kidney can lead to an abnormal pattern of sugars on the cell surface and this triggers inflammation through a molecule called collectin-11. Collectin-11 is a normal tissue product that acts in self defence. However, in abnormal circumstances such as when the organ is donated for transplantation, the sugar pattern can change and this can provoke inflammation and loss of function of the organ. Our aim is to identify the biochemical composition of the abnormal sugar pattern, because this will provide the key to improved treatment and diagnosis. Very simply, if we can work out how collectin-11 recognises the abnormal pattern, we can potentially mask it from collectin-11. The first steps of our research involve extracting a representative sample of the hundreds and possibly thousands of sugars (glycans) found in human kidneys after the organs have been removed from the donor. We can then screen the array of glycans to determine which ones bind strongly to collectin-11. To help us manage the complexity and scale of this procedure, we will make use of robotics to display the glycans and mix them with collectin-11. We can then examine the composition of the most interesting sugars which have strong affinity for collectin-11 and find out where and when they are expressed in kidney biopsies from patients. These studies of human tissue will not only reassure us we are on the right track, but they will help identify which patients could potentially benefit from the treatment to block the abnormal sugar pattern and prevent inflammation. A blocking agent that we are developing for this purpose will need further modification to ensure it fits like a glove over the abnormal sugar. That way the treatment will be more selective and have fewer side effects.

构成我们组织和器官的细胞被糖分子所覆盖。这种涂层通常在器官发育和维护中很重要，但可能是我们免疫系统的目标，导致组织损伤。我们发现，肾脏的血流紊乱会导致细胞表面糖的异常模式，这会通过一种名为collectin-11的分子引发炎症。Collectin-11是一种正常的组织产物，具有自卫作用。然而，在异常情况下，例如器官捐赠用于移植时，糖模式可能会发生变化，这可能会引起炎症和器官功能丧失。我们的目标是确定异常糖模式的生化组成，因为这将提供改善治疗和诊断的关键。很简单，如果我们能弄清楚collectin-11是如何识别异常模式的，我们就有可能从collectin-11中掩盖它。我们研究的第一步涉及在器官从捐赠者身上取出后，提取人体肾脏中发现的数百甚至数千种糖（聚糖）的代表性样本。然后，我们可以筛选聚糖的阵列，以确定哪些聚糖与聚集蛋白11强烈结合。为了帮助我们管理这个过程的复杂性和规模，我们将利用机器人技术来展示聚糖并将其与collectin-11混合。然后，我们可以检查最感兴趣的糖的组成，这些糖对collectin-11具有很强的亲和力，并找出它们在患者肾脏活检中表达的位置和时间。这些对人体组织的研究不仅可以让我们放心，我们走在正确的道路上，而且还可以帮助确定哪些患者可能从阻断异常糖模式和预防炎症的治疗中受益。我们正在为此目的开发的阻断剂需要进一步修改，以确保它像手套一样适合异常糖。这样的治疗将更具选择性，副作用更少。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Collectin-11 (CL-11) Is a Major Sentinel at Epithelial Surfaces and Key Pattern Recognition Molecule in Complement-Mediated Ischaemic Injury.

DOI：
10.3389/fimmu.2018.02023
发表时间：
2018
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Nauser CL;Howard MC;Fanelli G;Farrar CA;Sacks S
通讯作者：
Sacks S

Structural and functional diversity of collectins and ficolins and their relationship to disease.

DOI：
10.1007/s00281-017-0642-0
发表时间：
2018-01
期刊：
Seminars in immunopathology
影响因子：
9
作者：
Howard M;Farrar CA;Sacks SH
通讯作者：
Sacks SH

Fucose as a new therapeutic target in renal transplantation.

DOI：
10.1007/s00467-020-04588-2
发表时间：
2021-05
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
0
作者：
Howard MC;Nauser CL;Vizitiu DA;Sacks SH
通讯作者：
Sacks SH

Local complement synthesis-A process with near and far consequences for ischemia reperfusion injury and transplantation.

局部补体合成-对缺血再灌注损伤和移植具有近远影响的过程。

DOI：
10.1111/imr.13144
发表时间：
2023
期刊：
Immunological reviews
影响因子：
8.7
作者：
Nauser CL
通讯作者：
Nauser CL

Collectin-11 Promotes the Development of Renal Tubulointerstitial Fibrosis.

DOI：
10.1681/asn.2017050544
发表时间：
2017-11
期刊：
Journal of the American Society of Nephrology : JASN
影响因子：
0
作者：
Weiju Wu;Chengfei Liu;C. Farrar;Liang Ma;Xia Dong;S. Sacks;Ke Li;Wuding Zhou
通讯作者：
Weiju Wu;Chengfei Liu;C. Farrar;Liang Ma;Xia Dong;S. Sacks;Ke Li;Wuding Zhou