H2020Индивидуална стипендия2019–2021

STRomA · Novel Matrix Stiffness-regulated Genes in Lymphangiogenesis and Angiogenesis

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

Период: 2019-10-01 → 2021-09-30
Финансиране от ЕС: 162 806 €
Участници: 1
Схема: MSCA-IF-EF-ST

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Накратко на български

Ендотелните клетки, които облицоват кръвоносните и лимфните съдове, реагират на твърдостта на околната тъкан. Разбирането на тези процеси помага за откриването на нови цели за лечение на съдови заболявания като атеросклероза и лимфедем.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Novel Matrix Stiffness-regulated Genes in Lymphangiogenesis and Angiogenesis

From October 2019 until September 2021, the Marie Skłodowska Curie Action ‘Novel Matrix Stiffness-regulated Genes in Lymphangiogenesis and Angiogenesis’ (Acronym: STRomA) has been analyzing the role of endothelial proteins that are regulated via the surrounding tissue environment of endothelial cells (ECs). ECs form the innermost cell layer of all blood and lymphatic vessel types in the body and function as a dynamic barrier between the circulating blood or lymph on their luminal side (the inside of the vessel) and the surrounding tissue on their abluminal side. ECs recognize and respond to mechanical forces from the luminal and abluminal microenvironment through their cell-cell and cell-matrix adhesions and translate mechanical stimuli into biological responses in a process called mechanotransduction. The composition and mechanical properties of the surrounding tissue environment, the so called extracellular matrix (ECM), that enwraps the ECs, differ across the vascular tree and in development and disease. It is important to note that most vascular diseases, such as cardiovascular disease, atherosclerosis and lymphedema, are frequently associated with pathological ECM changes. However, our knowledge on how, in particular, changes of ECM stiffness regulate vascular development and contribute to blood and lymphatic vessels dysfunction is still limited. Findings of the STRomA action have enabled a better understanding of ECM stiffness-regulated endothelial signaling mechanisms and have the far-reaching potential to provide novel therapeutic targets to treat vascular diseases associated with pathological ECM changes. Using human primary EC cultures and genetically modified mouse models in combination with advanced microscopy and live cell imaging, objectives of STRomA have been (i) to elucidate the function of an actin-regulating protein family in angiogenesis, (ii) to identify the role of a cGMP-regulating protein in lymphangiogenesis and (iii) to develop novel fluorescent stiffness sensor tools to live-visualize stiffness changes in ECs. A parallel goal of the STRomA action has been to foster the development of the individual researcher (IR) and support her to become an independent research group leader.

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

Цел на проекта

Endothelial cells (ECs) recognize and respond to mechanical forces through their cell-cell and cell-matrix adhesions and translate physical stimuli into biological responses in a process called mechanotransduction. The composition and mechanical properties of the extracellular matrix (ECM) differ across the vascular tree, in its surrounding tissues and in development and diseases, such as edema formation. I have recently shown for the first time that ECM stiffness fundamentally controls lymphangiogenesis. I hypothesize that changes in ECM stiffness are a key regulatory mechanism of angiogenic processes in development and disease. A comprehensive analysis of novel ECM stiffness-regulated genes is pivotal to understand these processes integrally. In a preliminary study, I have performed differential RNA sequencing of blood (B) and lymphatic (L) ECs cultured on soft and stiff matrices. 3200 genes were regulated similarly in BECs and LECs in response to changes in matrix stiffness. Interestingly, the same number of genes was differently regulated. In the next two years, I will study the role of selected genes in lymphangiogenesis and angiogenesis in vitro and in transgenic mouse models with state-of-the-art microscope and live imaging techniques. First, I will analyze an actin-regulating protein family that is significantly regulated by matrix stiffness in both, BEC and LECs, suggesting a more general role in lymphangiogenesis and angiogenesis by regulating cytoskeletal dynamics. Second, I will study a molecule, which is involved in intracellular cGMP signaling and is predominantly regulated in LECs, suggesting a more specific role in lymphangiogenesis. Last, I will generate an in vitro fluorescent stiffness sensor to live-visualize changes in stiffness inside the EC. Ultimately, the proposed action can provide novel targets to modulate lymph and blood vessel formation with implications for edema treatment and will support me to become an independent group leader.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF · HamburgКоординаторГермания