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Lymphangiogenesis consists in the formation of new lymphatic vessels from already
established ones. This complex biological process is triggered during inflammation, wound repair or cancer. A decrease or defect in lymphangiogenesis leads to a pathology called lymphedema. This condition is characterised by tissue swelling caused by the accumulation of interstitial fluids. Nowadays there is no curative therapy. Vascular Endothelial Growth Factor Receptors 2 and 3 (VEGFR 2/3) represent interesting therapeutic targets as they are known to be major lymphangiogenesis inducers. Previous work from the host laboratory has identified the endocytic receptor “urokinase plasminogen activator receptor-associated protein” (“uPARAP” encoded by MRC2 gene) as negatively regulating lymphangiogenesis. uPARAP interacts with VEGFR 2/3 and blocks their heterodimerisation and signalisation. More recently, the laboratory has identified the interaction of uPARAP with Vascular Endothelial cadherin (VE-cadherin), a transmembrane protein also known to play key roles in lymphangiogenesis.
The aim of this work is to identify the binding site between uPARAP and VE-cadherin or VEGFR 2/3 in order to provide better knowledge on uPARAP’s functions in lymphatics.
A collaboration with Pr. Miikka Vikkula (UCL) had previously identified 7 uPARAP variants from a primary lymphedema patient cohort. We generated and validated upon this work multiple engineered A431 cell lines to express some known uPARAP partners (VE- cadherin, VEGF-R2 and VEGF-R3). Through proximity ligation assays, we successfully identified two variants (Thr653Met, Arg680Trp) who decreased uPARAP interactions with VE- cadherin. Finally, we tried but failed to produce new lentiviral vectors containing the previously identified variants. Those vectors were though to permit the investigation of variant impacts in primary human lymphatic endothelial cells Le processus de génération de nouveaux vaisseaux sanguins à partir de vaisseaux
préexistants est appelé ‘’lymphangiogenèse’’. Ce processus biologique complexe est déclenché pendant l’inflammation, lors des processus de réparation des tissus ou boen encore lors de cancers. Une diminution ou un défaut de lymphangiogenèse mène au développement d’une pathologie appelée ‘’lymphoedème’’. Cette pathologie est chartérisée par le gonflement des tissus causé par une accumulation de fluides au sein des tissus. Aucune thérapie n’existe actuellement pour soigner définitivement cette pathologie. Les récepteurs aux facteurs de croissance vasculaire endothélial (vascular endothelial growth factor receptors -VEGFRs-) de type 2 et 3 (VEGF-R2 et VEGF-R3) forment des cibles thérapeutiques intéressantes de par leurs rôles majeurs dans l’induction et la régulation de la lymphangiogenèse. De précédent travaux au sein du laboratoire d’accueil ont identifié le récepteur endocytique ‘’urokinase plasminogen activator receptor-associated protein’’ (uPARAP, produit de l’expression du gene MRC2) comme régulant négativement la lymphangiogenèse. uPARAP inhibe la formation d’hétérodimeres VEGF-R2/VEGF-R3 et bloque ainsi leur signalisation. Plus récemment, le laboratoire d’accueil a identifié l’interaction d’uPARAP avec la vascular endothelial cadherin (VE-cadherin), une protein transmembranaire également connue dans la lymphangiogenèse.
Le but de ce travail est d’identifier le ou les site(s) de liaison d’uPARAP avec ses différents partenaires (VE-cadherin ou VEGF-R2/R3) afin d’obtenir une plus profonde connaissance des fonctions d’uPARAP dans le système lymphatique.
En collaboration avec le Professeur Miikka Vikkula (UCL), 7 variants ont précédemment été identifiés. Au cours de ce travail, nous avons induit et validé l’expression de la VE-cadherin at des VEGF-R2 et R3 dans une lignée de cellules cancéreuses (A431). Nous avons ensuite identifié avec succès deux variants (Thr653Met, Arg680Trp) diminuant l’interaction d’uPARAP avec la VE-cadherin. Enfin, nous avons essayé mais échoué à produire de nouveau vecteurs lentiviraux contenant les différents variants. Ces vecteurs étaient destinés à l’évaluation de l’impact des variants au sein de cellules endothéliales lymphatiques humaines.

Lymphangiogenesis --- uPARAP --- VE-cadherin --- VEGF-R2 --- VEGF-R3 --- Binding site --- Sciences du vivant > Biochimie, biophysique & biologie moléculaire

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- angiogenesis --- autoimmunity --- semaphorins --- MMPs --- EMMPRIN --- TRPs --- YKL-39 --- VEGF

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In the two last decades, proteases have constituted one of the primary and important targets in drug discovery. The U.S. FDA has approved more than 12 protease therapies in the last 10 years, and a number of next-generation or completely new proteases are under clinical development. Protease inhibition strategies are one of the fastest expanding areas in the field of of drugs that show considerable promise. This Special Issue will focus on the recent advances in the discovery and development of protease inhibitors, covering the synthesis of protease inhibitors, the design of new chemical entities acting as inhibitors of special/particular types of proteases, and their mode of actions (Frolova et al. 2020; Slapak et al. 2020; Künnapuu et al. 2021). In addition, the new applications of these interesting compounds/biomolecules and their limitations have been discussed and described (Wang et al. 2020; Bartošová-Sojková et al. 2021).

MMP --- MMP2 --- MMP9 --- MMP7 --- MMP14 --- matrix metalloproteases --- PDAC --- pancreatic cancer --- Bowman–Birk inhibitor --- ranacyclin --- trypsin inhibitor --- structure–activity relationship --- synergistic effect --- Gentamicin --- matrix metalloproteinase --- extracellular matrix --- nuclei --- cancer --- apoptosis --- immune response --- cysteine protease inhibitor --- stefin --- signal peptide --- parasite --- phylogenetic analysis --- diversification --- protein structure --- vascular endothelial growth factors (VEGFs) --- VEGF-A --- PlGF --- VEGF-B --- VEGF-C --- VEGF-D --- angiogenesis --- lymphangiogenesis --- CCBE1 --- proteases --- ADAMTS3 --- plasmin --- cathepsin D --- KLK3 --- prostate-specific antigen (PSA) --- thrombin --- wound healing --- metastasis --- proteolytic activation --- vascular biology --- lymphedema

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This reprint includes contributions from leaders in the field of personalized medicine in ophthalmology. The contributions are diverse and cover pre-clinical and clinical topics. We hope you enjoy reading the articles.

Research & information: general --- Biology, life sciences --- subthreshold micropulse laser --- 577-nm laser --- laser fixed parameters --- diabetic retinopathy --- diabetic macular edema --- optical coherence tomography --- autofluorescence --- real-life --- diabetic macular oedema --- visual prognosis --- indicators --- personalized medicine --- age-related macular degeneration --- choroidal neovascularization --- classification --- machine learning --- type 2 diabetes --- retinopathy --- ethnicity --- general practice --- risk factors --- progression --- glycemic gap --- glucose variability --- ETDRS classification --- biomarkers --- phenotypes --- anti-vascular endothelial growth factor --- diabetic retinopathy severity scale --- panretinal leakage index --- neovascular age-related macular degeneration --- anti-VEGF therapy --- retinal thickness --- visual acuity --- variability --- leakage index --- microaneurysms --- intravitreal aflibercept --- neovascularization --- ultra-widefield fluorescein angiography --- retinal imaging --- quantitative biomarkers --- precision medicine --- autoantibodies --- AT1-receptor --- PAR1 --- VEGF-A --- VEGF-B --- VEGF-receptor 2 --- AMD --- complement system --- semi-quantitative multiplex profilin --- mass spectrometry --- C4 --- vitronectin --- factor I --- genetic variants --- metabolites --- HDL --- central area thickness --- biomarker --- microRNA --- anti-VEGF --- retina --- edema --- OCT --- tomography --- microphysiological systems --- blood-neural barriers --- neurovascular unit --- disease modeling --- 3D models --- organ-on-a-chip --- inner blood-retinal barrier --- n/a

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This reprint includes contributions from leaders in the field of personalized medicine in ophthalmology. The contributions are diverse and cover pre-clinical and clinical topics. We hope you enjoy reading the articles.

Research & information: general --- Biology, life sciences --- subthreshold micropulse laser --- 577-nm laser --- laser fixed parameters --- diabetic retinopathy --- diabetic macular edema --- optical coherence tomography --- autofluorescence --- real-life --- diabetic macular oedema --- visual prognosis --- indicators --- personalized medicine --- age-related macular degeneration --- choroidal neovascularization --- classification --- machine learning --- type 2 diabetes --- retinopathy --- ethnicity --- general practice --- risk factors --- progression --- glycemic gap --- glucose variability --- ETDRS classification --- biomarkers --- phenotypes --- anti-vascular endothelial growth factor --- diabetic retinopathy severity scale --- panretinal leakage index --- neovascular age-related macular degeneration --- anti-VEGF therapy --- retinal thickness --- visual acuity --- variability --- leakage index --- microaneurysms --- intravitreal aflibercept --- neovascularization --- ultra-widefield fluorescein angiography --- retinal imaging --- quantitative biomarkers --- precision medicine --- autoantibodies --- AT1-receptor --- PAR1 --- VEGF-A --- VEGF-B --- VEGF-receptor 2 --- AMD --- complement system --- semi-quantitative multiplex profilin --- mass spectrometry --- C4 --- vitronectin --- factor I --- genetic variants --- metabolites --- HDL --- central area thickness --- biomarker --- microRNA --- anti-VEGF --- retina --- edema --- OCT --- tomography --- microphysiological systems --- blood-neural barriers --- neurovascular unit --- disease modeling --- 3D models --- organ-on-a-chip --- inner blood-retinal barrier