Vascular anomalies are localized defects of vascular morphogenesis. They cause important morbidity due to pain, bleeding and distruction of adjacent tissues. Current treatments are limited to surgical resection and sclerotherapy, both of which have limitations. Better understanding of the etiopathogenic causes is needed. Although the majority of vascular anomalies are sporadic, inherited forms are observed. Thus, our long term goals are: 1) to identify the molecular causes of the inherited forms of vascular anomalies;2) to test the Knudson double-hit model as an explanation for the multifocal nataare of these lesions;3) to extrapolate the results from the often rare inherited forms to the common sporadic forms;4) to characterize in vitro the altered function of the mutated proteins and the associated pathophysiological cascades;and 5) to create genetically manipulated mouse lines to obtain in vivo models that recapitulate the malformations and allow testing of novel therapeutic approaches. Such data would not only serve the numerous vascular anomaly patients, but also the management of other angiogenic disorders, such as rheumatoid arthritis, diabetic retinopathy and cancer. Our earher studies on hereditary vascular anomalies unraveled SOX18 and VEGFR3 mutations in lymphedema, KRITl mutations in cutaneous capillary-venous malformations, TIE2 mutations in hereditary mucocutaneous venous malformations, glomulin mutations in glomuvenous malformations, and RASAl mutations in a disorder we named capillary malformation-arteriovenous malformation. Recently, we showed that 49% of sporadic venous malformations are due to somatic TIE2 mutations. Finally, with Project 1 and 2 we described genetic changes involved in hemangioma pathogenesis. In this grant, we aim 1) to characterize in vitro and in vivo the effects of the TIE2 mutations on endothelial cell function;2) to characterize in vitro and in vivo the effects of glomulin loss-of-function on VSMC differentiation, and 3) to further screen patients with venous anomalies for (somatic) mutations in novel loci. This data would unravel the pathogenic mechanisms that lead to venous anomalies, generate in vivo models of them, and identify novel factors important for their etiopathogenesis. This project depends on samples provided by Cores B and C, and the tight collaborations with Projects 1 and 2, with which we aim to characterize the pathogenic pathways involved in hemangiomas.
This project aims to characterize the genetic causes and mechanisms that lead to the development of venous anomalies (""""""""cavernous angiomas""""""""), and to make mouse models for them. This would help diagnosis and management of these patients, and allow development of novel therapeutic approaches.
|Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron et al. (2016) Inhibition of Hif1Î± prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A 113:E338-47|
|Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R et al. (2016) VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 52-54:127-40|
|Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin et al. (2015) Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis. Matrix Biol 42:56-73|
|Smadja, David M; Levy, Marilyne; Huang, Lan et al. (2015) Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost 114:735-47|
|Huang, Lan; Nakayama, Hironao; Klagsbrun, Michael et al. (2015) Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33:133-45|
|Limaye, Nisha; Kangas, Jaakko; Mendola, Antonella et al. (2015) Somatic Activating PIK3CA Mutations Cause Venous Malformation. Am J Hum Genet 97:914-21|
|Nakayama, Hironao; Huang, Lan; Kelly, Ryan P et al. (2015) Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins. Biochem Biophys Res Commun 464:126-32|
|Boscolo, Elisa; Limaye, Nisha; Huang, Lan et al. (2015) Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest 125:3491-504|
|Dellinger, Michael T; Garg, Nupur; Olsen, Bjorn R (2014) Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone 63:47-52|
|Lee, D; Boscolo, E; Durham, J T et al. (2014) Propranolol targets the contractility of infantile haemangioma-derived pericytes. Br J Dermatol 171:1129-37|
Showing the most recent 10 out of 50 publications