H2020Индивидуална стипендия2018–2020

EATing more · Enhancing Engulfment of Apoptotic cells: basic biology to Therapy

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

Период: 2018-06-01 → 2020-05-31
Финансиране от ЕС: 160 800 €
Участници: 1
Схема: MSCA-IF

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Накратко на български

Механизмите за поглъщане на умиращи клетки от макрофаги се анализират чрез търсене на вещества, които да ускорят този процес. По-ефективното почистване на клетъчните остатъци може да намали хроничното възпаление при заболявания като артрит и атеросклероза.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Enhancing Engulfment of Apoptotic cells: basic biology to Therapy

The controlled death and turnover of cells in our bodies is critical for healthy physiology, development and resolving inflammatory responses. Many cells can ‘eat’ other cells, and normally dying cells are rapidly removed by phagocytosis. Professional eaters (phagocytes), such as macrophages, have a large capacity for dead cell engulfment. This process, specifically referred to as efferocytosis, is generally anti-inflammatory and contributes to resolution and tissue healing. Problems with dead cell clearance contribute to chronic inflammation and disease: numerous inflammatory diseases are associated with a high burden of uncleared cell corpses, and a reduced capacity for macrophages to perform efferocytosis. For example, atherosclerosis, arthritis, inflammatory bowel disease, chronic respiratory conditions and autoimmunity. This project aimed to address the hypothesis that enhancing dying cell clearance is an effective strategy to treat disease. The rationale for this is twofold: first, by enhancing removal of dying cells, since these uncleared corpses are a form of 'debris' that can perpetuate inflammation. Second, the ‘anti-inflammatory’ effects of efferocytosis could promote healing in specific disease settings. There is a need for appropriate tools to boost dead cell removal in the body. We (1) aimed to identify compounds, from libraries of biologically active drugs, that were able to increase macrophage capacity for dead cell elimination in vitro. Then, (2) we addressed how these small molecules act at the cellular level to boost efferocytosis by macrophages – and whether they have the same effect on other phagocytes in the body. (3) We aimed to investigate how such molecules could modulate the inflammatory environment, e.g. by the subsequent release of soluble factors by macrophages. The eventual goal (4) is to test the identified small molecule boosters of efferocytosis for beneficial effects in models of inflammatory disease, to potentially offer a new strategy in therapies. Furthermore, our findings will provide insights into the process of dead cell clearance itself.

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

Цел на проекта

Our bodies turn over billions of cells every day to keep us healthy. Old, damaged or excess cells need to be cleared, and professional and non-professional phagocytes engulf cells dying by apoptosis. The efficiency of this process is critical for homeostasis, minimising inflammation, and promoting organ function. Deficiencies in engulfment predispose to autoimmune and inflammatory diseases, and the host lab has shown that mice deficient in molecular components of engulfment exhibit exaggerated inflammatory responses.We hypothesise that apoptotic cell phagocytosis can be boosted via small molecules that target the engulfment machinery, and that this could open new avenues for therapy in specific disease contexts. Here, I propose to perform an unbiased drug screen to identify small molecule candidates that can enhance apoptotic cell uptake – that is, a ‘gain of function’ screen for engulfment. The host lab has recently developed a fluorescence-based engulfment assay to quantitatively measure apoptotic cell uptake. I will develop this assay into a high-throughput screen to test a large library of compounds. I will address the consequences of pharmacologically enhanced engulfment on professional and non-professional phagocytes, and employ state-of-the-art nucleomics and proteomics approaches to explore the cellular targets of these candidate molecules. Finally, I will test whether the administration of small molecule ‘engulfment enhancers’ can be of benefit in inflammatory disease models relevant to human pathology. This proposal uniquely exploits the complementary expertise of the host lab (pathways of apoptotic cell clearance) and myself (inflammation and disease models), while benefitting from the significant resources of the host institute. While the mechanistic complexities of apoptotic cell clearance are just beginning to be deciphered, we anticipate that this study will also provide insight into molecular pathways of apoptotic cell uptake and processing.

Оригинален текст от CORDIS (на английски).

Участници

VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия