Wound healing of irradiated skin

Description

The laboratory of Julie Fradette is seeking a motivated student to pursue graduate studies (preferably PhD) at Université Laval in Quebec city.

The topic is highly original and the project will use a unique model of living human biological dressing reconstructed using tissue engineering methods, from adipose derived stem/stromal cells.

Candidates with prior experience in cell culture, animal work and protein analyses are especially invited to postulate.

Description: Background. Radiotherapy for cancer treatment can lead to incapacitating hard-to-heal skin wounds. Our team developed a murine model recapitulating skin lesions following local irradiation in order to assess the therapeutic outcome of various treatments. We can recreate a range of lesions representative of moderate to severe radiodermatitis, and assess both acute and late stages of its development. We also engineered biological dressings from human adipose-derived stem/stromal cells (ASCs) that secrete high levels of prohealing factors. We hypothesize that the properties of new ASC-based dressings will enhance wound repair mechanisms in irradiated skin, prompting healing of these complex wounds.
Our goals are to: engineer optimized biological dressings based on ASCs using a xenogen-free culture system (Aim 1); evaluate their efficacy in vivo as a function of the severity of the initial radiation insult and treatment plan (Aim 2); determine pivotal dressing-activated repair mechanisms contributing to healing in irradiated skin (Aim 3).

Approaches. Aim 1: Biological dressings will be produced using our self-assembly tissue engineering method using undifferentiated ASCs. The benefits of these living dressings rely on their natural human matrix content as well as the growth factors they secrete. We will optimize their production using a xenogen-free culture system to favor both their mechanical properties and secretory profiles. Aim 2: The efficacy of the optimized dressings will be evaluated in preclinical studies. Local irradiation will be performed on the mouse back skin with doses (45 and 80 Grays) resulting in radiodermatitis of increasing severity and associated impaired healing of surgical wounds. Treatments will consist of weekly dressing application onto the wound surface to stimulate endogenous repair in comparison to untreated and control groups. Two treatment plans will be compared, pre- and post-surgical challenge. The healing kinetics and quality of the healed tissues will be determined by assessing the attenuation of radiation-induced features such as fibrosis, reduced angiogenesis, and inflammation. Aim 3: The main mechanisms of repair induced by the dressings such as neoangiogenesis will be examined, first using cell signaling arrays. We hypothesize that the dressings will act, in part, by promoting proangiogenic effects mediated by the stimulation of the LRP1 axis.
Impact. The functional optimization and testing of this new bioactive dressing has the potential to provide a novel treatment modality to improve healing of incapacitating skin wounds. Our work will provide an evidence-based evaluation of the efficacy of the dressings to stimulate healing of skin at various stages of radiation-induced toxicity. The high translational potential of this project could result in faster recovery and return to a higher quality of life for these patients recovering from cancer.

Requirements and Conditions

- Knowledge of French and English is required.
- Prior experience of cell culture methods and work in an animal facility would be strongly advantageous.
- To apply, please send a short letter of presentation, a complete CV and copies of your grades to Pr Julie Fradette.