CollBioImag · Development of a cell-based system for high-throughput screening of antifibrotics
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2016-03-01 → 2018-02-28
- Финансиране от ЕС
- 195 455 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Нов метод за визуализиране на колагена в клетките помага за проследяване на процесите при фиброзата. Това е важно за по-бързото откриване и тестване на лекарства срещу хронични заболявания на бъбреците, белите дробове, черния дроб и сърцето.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Development of a cell-based system for high-throughput screening of antifibrotics
Fibrosis is a common outcome of many chronic diseases of the kidney (diabetic nephropathy), lungs (idiopathic pulmonary fibrosis), liver (cirrhosis) and heart (heart failure). In pathologies where fibrosis is a feature, there is an increased deposition of extracellular matrix proteins, including collagen. Due to the increasing morbidity and mortality of fibrotic disorders there is an urgent need to develop, test and monitor antifibrotic treatments. Due to its high abundance in collagen, proline has been widely explored as a marker of collagen synthesis by measuring incorporation of either radioactive or non-radioactive isotopic-labelled proline (18F-Pro, 3H/13C/15N-Pro) directly in tissue. The goal of this project was to develop a bioorthogonal imaging approach for visualization of the dynamic processes of fibrogenesis/fibrolysis in cells using collagen as a target. The methodology first involves the metabolic incorporation of a proline derivative equipped with an alkene tag into collagen using collagen-producing cells (Figure 1). Subsequent reaction with fluorogenic tetrazines would allow rapid, efficient and highly specific labelling of collagen (Figure 1). The ultimate goal is to develop a high-throughput screening method for identification of new antifibrotic drugs as collagen is highly expressed in fibrotic tissues.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Liver fibrosis (hepatitis B and C, cirrhosis, etc) represents an enormous health burden responsible for ~1.03 millions death per year worldwide according to the World Health Organization. Fibrosis is also a common outcome of many chronic diseases of the kidney (diabetic nephropathy), lungs (idiopathic pulmonary fibrosis), heart and vasculature (heart failure). In pathologies where fibrosis is a feature, there is an increased deposition of extracellular matrix proteins, including collagens that dramatically limit tissue function. Herein we propose to develop a cell-based assay for high-throughput screening of new antifibrotic therapeutics, which will accelerate fibrosis drug development. Our approach consists in the metabolic incorporation of an alkene-tagged proline in the biosynthesis of collagen, followed by labelling with a fluorescent tetrazine. We recently published preliminary results that provide proof of principle for the use of proline derivatives equipped with reactive handles to tag and label collagen structures. However, this approach suffered from nonspecific reactions of the fluorescent probe with intracellular proteins. The level of selectivity conferred by the proposed inverse-electron-demand Diels-Alder reaction is key in enabling its use in cells. We will use hepatic stellate cells since these cells are responsible for excess collagen production during liver fibrosis. To demonstrate that the cellular model can be used to screen compounds for fibrosis we will validate our system using a library of compounds with known preclinical antifibrotic activities. We will test if their in vivo efficacy can be predicted using cells. If our findings are significant we will use this cellular model to screen a commercial available library of compounds to find new antifibrotic drugs. The efficacy of the best candidate will be tested in vivo using two animal models of induced fibrosis.
Оригинален текст от CORDIS (на английски).
Участници
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз