H2020Индивидуална стипендия2018–2020

PerMet · Role of peroxisomal fatty acid β-oxidation in vessel sprouting

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

Период: 2018-04-01 → 2020-03-31
Финансиране от ЕС: 160 800 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Метаболизмът на мастните киселини в пероксизомите на ендотелните клетки влияе върху образуването на нови кръвоносни съдове. Разбирането на този процес помага за разработването на терапии за нормализиране на съдовете при рак и дегенерация на макулата.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Role of peroxisomal fatty acid β-oxidation in vessel sprouting

Endothelial cells (ECs) form the inner lining of blood vessels and are involved in the development of devastating diseases like cancer or the eye disease age-related macular degeneration (AMD). ECs are traditionally divided into three subtypes: While being quiescent 'phalanx' cells in established blood vessels, they differentiate into actively proliferating 'stalk' cells and migrating 'tip' cells during the formation of new vessel branches (vessel sprouting or ‘angiogenesis’). However, ECs might be far more heterogeneous than this simple taxonomy suggest, considering the distinctly different functions they serve across tissues. Blood vessel formation from existing quiescent blood vessels in cancer and AMD is promoted by inducing excessive EC proliferation and migration. In cancer, this leads to the formation of highly disordered vessels which enable the survival of the tumor. Thus, anti-angiogenic therapies aimed to reduce tumor vessel development constitute an important approach for cancer therapeutics. The host lab recently showed that angiogenesis is controlled by metabolic processes in ECs, like for instance mitochondrial fatty acid oxidation (FAO). The manipulation of EC metabolism could thus be therapeutically used to normalize blood vessel formation in cancer and other diseases. Peroxisomes are small metabolic organelles and are present in virtually every human cell. Genetic defects causing the loss of peroxisomes can have severe consequences for patients. Although our knowledge about peroxisomes is very limited, this indicates that these organelles are vital for human health. Among others, they are crucial for oxidizing specific fatty acids (e.g. very long chain fatty acids, VLCAs) by peroxisomal FAO (pFAO). Though peroxisomes are numerously present in ECs, their role in the formation of blood vessels is entirely unknown. Investigating their role could offer valuable insights into the metabolic workings of ECs and thus provide us with potential therapeutic approaches for diseases characterized by abnormal angiogenesis. The objective of this project was to study the function of peroxisomes in ECs by investigating the effects of peroxisomal gene silencing on EC function and vessel sprouting in cultured ECs and in an EC-specific knock-out mouse model (Aim 1). Additionally, we planned to characterize the (metabolic) gene signature of different EC subtypes (beyond quiescent, tip and stalk cells), and investigate the impact of peroxisomal gene loss on the distribution of different subtypes using single-cell RNA-sequencing (scRNAseq, Aim 2). Furthermore, we aimed to characterize the metabolic fate of peroxisomally oxidized VLCFAs (Aim 3).

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

Цел на проекта

MAIN GOAL: To characterize the role of peroxisomal fatty acid oxidation (pFAO) and its relative importance in the differently active endothelial cell (EC) subtypes during blood vessel sprouting (angiogenesis).BACKGROUND & RATIONALE: Activation of ECs by growth factors such as VEGF induces vessel sprouting, requiring a switch from quiescent phalanx ECs to a leading tip EC and proliferating stalk ECs. The host lab recently showed that this angiogenic switch requires a metabolic switch, with specific roles for glycolysis and mitochondrial fatty acid oxidation (FAO). ECs also have peroxisomes, which metabolize very long chain fatty acids (VLCFAs), but nothing is known about the possible role of peroxisomes/pFAO in ECs. Multifunctional protein 2 (MFP2) is the key enzyme of pFAO. Initial data from the host lab indicates that MFP2 silencing in ECs impairs vessel sprouting in vitro. I hypothesize that pFAO regulates the tip/stalk/phalanx EC subtypes differently during sprouting and will examine the underlying (peroxisomal) metabolic mechanisms. METHODOLOGY: I will use a multidisciplinary approach, combining molecular and cellular biology, in vitro and in vivo angiogenesis models, and conditional mouse genetics, to characterize the role of MFP2 in vascular sprouting. I will use scRNA-seq to define the (peroxisomal) metabolic gene signature of the 3 EC subtypes and explore whether MFP2 loss results in population shifts of tip, stalk and phalanx ECs. Furthermore, I will use state-of-the-art metabolomics and 13C tracing to define the metabolic fate of peroxisomally metabolized VLCFAs, with the ultimate goal of evaluating their physiological relevance in ECs.NOVELTY AND TRANSLATIONAL IMPACT: The data promise first insights in pFAO’s role in vessel sprouting and the first (peroxisomal) metabolic gene signature of tip, stalk & phalanx EC subtypes at single cell level, and may identify pFAO genes as potential novel targets in strategies to inhibit pathological angiogenesis.

Оригинален текст от CORDIS (на английски).

Участници

VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия