Betaadrenergic cutaneous vascular remodelling – BETASKIN2
BETASKIN 2: Betaadrenergic cutaneous vascular remodelling
Background: This project follows a first BiotechS ANR grant 2009 which aimed at developing a topical formulation of propranolol for the treatment of cutaneous hemangiomas, in partnership with Pierre Fabre Laboratories, Toulouse, France, following patenting at our institution and exclusive licencing of our discovery to the company. Indeed, our team has shown that systemic administration of propranolol, a non specific ß adrenergic antagonist, can stop the growth phase of cutaneous hemangiomas, and accelerate tremendously their involution. The initial report has been cited in more than 180 papers since the initial NEJM publication, and the field of application appears to apply to non cutaneous lesions, other vascular lesions, and remodelling of vessels during angiogenesis, a so far neglected role for betaadrenoreceptors (ßAR). This grant is intended to look at cellular and molecular signalling involved in this effect, and to develop more specific molecules.
Team: Our team is a newcomer in this field but has several assets for implementing a successful research programme. It combines the clinical recruitment at a national referral centre (Centre de Référence pour les maladies rares de la peau, with a special focus on vascular skin lesions), expertise in (1) biotherapy for genetic disorders using lentiviral vectors, (2) sophisticated culture models of skin cells including three-dimensional models, and (3) hypoxia regulated pathways translated from hematopoietic stem cells to skin cells (Inserm U 1035). A partnership with a local research group which has developed investigative tools and models for cardiovascular disorders will help implementing new models for skin vasculogenesis (Inserm U 1034). A partnership within the pole de compétitivité Cancer-Bio-Santé based in Toulouse will build on previous and current joint projects with Pierre Fabre Laboratories around the clinical development of propranolol and related drugs in this field. Our preliminary work has targeted cells to study in the cutaneous hemangioma model, technical difficulties to overcome for obtaining animal models, and will guide further development of in vitro and animal models. It shows promising data concerning vascular remodelling using propranolol which have prompted this application to the Blanc programme.
Objectives: The main objective is to understand the observed effect of propranolol in infantile hemangioma and to translate this knowledge to adrenergic control of normal and dysregulated vasculogenesis. Since propranolol is a non selective antagonist, the type of receptor and of target cells mediating the pharmacologic effect have been screened in preliminary studies but need more in depth approaches, using omics and pluricellular in vitro models, as well as ßAR knockout and overexpressing mouse models. This grants aims at the establishment of in vitro models, combined with functional assays for screening new molecules with more selective vascular remodelling effects, as well as animal models for long term studies of novel agents.
The project is divided in three workpackages, using human (normal endothelial cells, cells from infantile hemangiomas, human cell lines for mast cells) and mouse endothelial cell lines, normal and immunodeficient mice for mouse grafts, and ßAR knock-out and overexpessing mouse models.
1. Cellular and molecular targets of propranolol in hemangiomas
2. Mouse models
3. Development of selective ß adrenergic agonists/antagonists for vascular remodelling
The experimental approaches developed in this application should provide clues to signalling downstream ß adrenergic receptors in target cells which regulate vasculogenesis, with the perspective to design more specific drugs applicable to aberrant vasculogenesis in skin and posssibly other organs (i.e. retinal and kidney vascularisation which affect morbidity in diabetes and non diabetic disease)
Monsieur Alain Taieb (Biothérapies des maladies génétiques et cancers INSERM U1035) – email@example.com
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Biothérapies des maladies génétiques et cancers INSERM U1035
Inserm U1034 Adapatation cardiovasculaire à l'ischémie INSERM 1034
Help of the ANR 423,317 euros
Beginning and duration of the scientific project: December 2012 - 36 Months