H2020Индивидуална стипендия2018–2020

Sialoglycan Array · Generation of a Cell-Based Sialoglycan Array to Decipher Biological Interactions and Functions of the Human Sialome

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-09-01 → 2020-08-31
Финансиране от ЕС: 200 195 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Слоите от захари (сиалогликани) на повърхността на човешките клетки регулират процеси като взаимодействието между имунната система и патогените. Разбирането на тези структури помага при изучаването на възпаления, автоимунни заболявания и развитието на ракови тумори.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Generation of a Cell-Based Sialoglycan Array to Decipher Biological Interactions and Functions of the Human Sialome

Every human cell is covered by a dense layer of glycans, chains of sugar molecules linked to each other in a combinatorial manner thereby forming short, long, linear, and branched structures. The biosynthesis of glycans takes place in the endoplasmic reticulum and Golgi system by more than 200 glycosyltransferase enzymes that build the diverse glycans that are attached to membrane or secreted glycoproteins and glycolipids. Glycans are frequently terminated by sialic acids that are a family of chemically diverse sugars that can be linked to underlying sugars via different chemical bonds. This process in carried out by 20 sialyltransferase isoenzymes with partially overlapping functions that are not fully elucidated. Due to this combinatorial diversity, human cells produce a vast repertoire of structurally diverse sialic acid-carrying glycans (sialoglycans) at the surface - the Sialome. The Sialome is involved in numerous molecular interactions at the cell surface and biological processes such as cell-cell interactions and cell-extracellular matrix interactions. The Sialome constitute the ligands for sialoglycan-binding proteins such as the Selectins and the Siglec immune receptor family that have regulatory functions in the immune system. Pathogens exploit the Sialome to infect host cells and aberrations in the Sialome have been associated with inflammation, autoimmunity, and cancer. For example, cancer cells are frequently found to present aberrant sialoglycans that are associated with tumor growth and progression. Dissection of the biological interactions with the Sialome could provide insights into these physiological and pathological processes providing novel opportunities for the development of therapeutic approaches targeting the Sialome in major diseases such as infection, autoimmunity, and cancer. So far, the field has mainly focused on developing analysis techniques for sialoglycans in biological samples and their chemical synthesis. However, research into the biological interactions and functions of the Sialome in health and disease is rather limited, because suitable methods to address the Sialome as well as specific sialoglycans in the natural context of the cell surface are lacking. The aim of this project was to develop a cell-based sialoglycan array for display of the Sialome in the natural glycan context of glycoconjugates and the cell membrane suitable for cell-based assays and dissection of the biological interactions with sialoglycan-binding proteins such as the Siglecs.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Human cells display a staggering repertoire of different sialic acid-carrying glycans (sialoglycans) at the surface - the Sialome. The Sialome regulates numerous biological processes including cell communication and migration and is involved in diseases such as infections , autoimmunity and cancer. However, most biological interactions and functions of the Sialome remain elusive, because suitable methods to address the Sialome as an ‘Ome’ and to dissect specific sialoglycan functions in the cell context are lacking. Therefore, I propose to generate a cell-based sialoglycan array for the display of all human sialoglycans in the natural context of individual glycoconjugates at the cell surface in an arrayable format. Using precision genome editing (CRISPR/Cas9) genes involved in sialoglycan synthesis will be targeted to create a library of isogenic human cells each displaying a unique part of the Sialome. These isogenic cells together form the cell-based sialoglycan array and will be used for high-throughput screening and discovery of binding specificities of sialoglycan-binding proteins such as Siglecs, selectins and factor H. Finally, the cell-based sialoglycan array will be used for the production of a representative panel of recombinant glycoproteins carrying homogenous N-linked or O-linked sialoglycans. The proposed research will take place at the at the Copenhagen Center for Glycomics a world leader in Glycomics and pioneer in precision genome editing in Glycobiology where I will be trained in precision genome editing, glycoengineering and state-of-the-art glycan mass spectrometry. Altogether, the cell-based sialoglycan array will be indefinitely sustainable, addressable by any multiplex assay, and serve as production platform for recombinant sialoglycoproteins. Ultimately, I expect that the proposed cell-based sialoglycan array will open the door for wide discovery of biological interactions and functions and of the human Sialome.

Оригинален текст от CORDIS (на английски).

Участници

KOBENHAVNS UNIVERSITET · KOBENHAVNКоординаторДания