CCBE1 AND LYMPHATICS · Functional and genetical characterization of Ccbe1, a novel regulator of lymphangiogenesis
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-03-01 → 2012-02-29
- Финансиране от ЕС
- 161 249 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Протеинът CCBE1 и неговата роля при формирането на лимфните съдове се изследват чрез опити с мишки. Това помага да се разбере механизмът на развитие на лимфната система и причините за заболявания като синдрома на Хенекам.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Functional and genetical characterization of Ccbe1, a novel regulator of lymphangiogenesis
Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, and other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist. Hence, CCBE1 deficient mice were generated to understand the function of CCBE1 in cardiovascular development, and CCBE1 recombinant protein was used in both in vivo and in vitro settings to gain insight into the molecular function of CCBE1. Phenotypic analysis of murine Ccbe1 mutant embryos showed a complete lack of definitive lymphatic structures, even though Prox1 lymphatic endothelial cells get specified within the cardinal vein. Mutant mice die prenatally. Proximity ligation assays indicate that vascular endothelial growth factor receptor 3 activation appears unaltered in mutants. Human CCBE1 protein binds to components of the extracellular matrix in vitro, and CCBE1 protein strongly enhances vascular endothelial growth factor-C- mediated lymphangiogenesis in a corneal micropocket assay. Conclusions: Our data identify CCBE1 as a factor critically required for budding and migration of Prox-1 lymphatic endothelial cells from the cardinal vein. CCBE1 probably exerts these effects through binding to components of the extracellular matrix. CCBE1 has little lymphangiogenic effect on its own but dramatically enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Thus, our data suggest CCBE1 to be essential but not sufficient for lymphangiogenesis.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Ccbe1 has recently been identified as an essential regulator of lymphangiogenesis in zebrafish. Loss of function of this secreted factor leads to a failure of lymphangioblast budding and a complete lack of lymphatics. Intriguingly, mutations in human CCBE1 are causative for a congenital lymphatic malformation disease, termed Hennekam syndrome (HS). The main goal of this project is to understand the function of Ccbe1 in development and disease. Firstly, since the mode of action of Ccbe1 is completely unknown, we will focus on identifying interaction partners for this secreted protein by three different approaches: (1) I will test the interactions between Ccbe1 and one potential binding partner identified in a yeast-two-hybrid assay (2) I will perform IP experiments with myc-tagged Ccbe1 protein, followed by Mass Spectrometry for protein identification. (3) I will analyze an additional gene causing HS, identified in the human clinic. For all three approaches, candidate genes will be validated further through expression pattern analysis in zebrafish and mouse, in conjunction with functional tests through morpholino injections and co-IP studies with Ccbe1 in zebrafish. Secondly, I will focus on analyzing Ccbe1 conditional mouse knock out models. Using inducible and constitutive tissue specific Cre-recombinase lines, I will identify those tissues and cell types which require Ccbe1 activity for their normal physiological functioning. Particular attention will be on the role of Ccbe1 in those organ systems that are affected in HS patients, i.e. the lymphatic system and the brain. Furthermore, the inducible knockout of Ccbe1 in adult mice will answer the key question whether Ccbe1 is also required during adult stages for lymphangiogenesis. CCBE1 is one of very few genes known to be essential for lymphatic function. The proposed project will help to better understand the mode of action of this recently identified, critical factor in human lymphangiogenesis.
Оригинален текст от CORDIS (на английски).
Участници
- KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW · AMSTERDAMКоординаторНидерландия
Връзки
Данни: CORDIS, © Европейски съюз