<p>The rotator cuff is a group of four muscles and tendons in the shoulder that function to lift and rotate the arm. Rotator cuff tendon tears are increasingly common: more than 545,000 rotator cuff surgeries occur annually in the US. However, treatment is often complicated by disorganized collagen matrix formed via fibrosis and results in high re-tear rates. Tendon tissue engineering seeks to solve the problem using biomaterials to promote neo-tendon formation to augment repair or regenerate tendon. However, while current biomaterials provide the opportunity to improve tendon healing, they frequently still exhibit fibrosis in preclinical studies. Therefore, a critical need exists to understand the mechanisms of aligned collagen formation when designing biomaterials for tendon tissue engineering. Matrix architecture and transient receptor potential cation channel subfamily V member 4 (TRPV4) regulate aligned collagen formation during tenogenesis in vitro, but the mechanism remains to be determined. Recently, TRPV4 stimulation was found to induce nuclear localization and activation of transcriptional co-activators Yes-associated protein (YAP). YAP expression is upregulated during tendon development, a process characterized by aligned collagen formation, and in response to physiological mechanical stimulation, suggesting it could play an important role in tendon. The objective of this work is to improve tissue engineering strategies and progress toward making a device that regenerate tendon after injury. Aim 1 incorporates tendon-derived matrix into synthetic polymer scaffolds to add biological signaling cues to induce tenogenesis. Aim 2 uses a 2D photolithography system (microphotopatterning) to optimize architectural and structural cues to promote stem cell differentiation toward tenogenic, chondrogenic, and osteogenic lineages. Aim 3 investigates dynamic tensile loading protocols to promote collagen matrix synthesis and improve engineered tendon mechanical function. Aim 4 investigates the role of TRPV4 and YAP in collagen alignment during engineered tendon development.</p>

Ce projet de recherche porte sur l’étude de la régulation des systèmes cannabinoïdes et vanilloïdes chez Caenorhabditis elegans (C. elegans), dans le but d’évaluer les effets antinociceptifs du tétrahydrocannabinol (THC) et du cannabidiol (CBD). C. elegans est un modèle largement utilisé pour étudier la nociception, visant principalement à caractériser les réponses nociceptives induites par le THC et le CBD, ainsi qu’à identifier les mécanismes et les cibles moléculaires impliqués. Les résultats des études sur l’utilisation du cannabis dans le traitement de la douleur chronique chez les mammifères sont controversés. Cette recherche vise à étudier l’effet du CBD et du THC sur la réponse nociceptive chez C. elegans et à approfondir la compréhension des mécanismes pharmacologiques sous-jacents. La méthodologie consiste à quantifier l’effet antinociceptif du CBD et du THC chez C. elegans par la méthode de la thermotaxie. Les nématodes sauvages (N2) étaient exposés à des concentrations croissantes de phytocannabinoïdes pour évaluer la relation concentration-effet. D’autres tests étaient effectués sur des souches mutantes exprimant des récepteurs cannabinoïdes et vanilloïdes afin d’identifier préalablement leurs cibles. Enfin, les analyses protéomiques et bioinformatiques seront effectuées pour identifier les voies de signalisation et les processus biologiques induits par l’interaction entre les phytocannabinoïdes et leurs cibles. Cette étude démontre l’activité antinociceptive du CBD et du THC chez C. elegans avec des effets rémanents pour THC, en ciblant respectivement le vanilloïde pour le CBD et le cannabinoïde pour les systèmes THC. Les analyses protéomiques et bio-informatiques mettent en évidence des différences significatives dans leurs voies de signalisation et leurs processus biologiques. / The objective of this research project was to focus on studying the regulation of cannabinoid and vanilloid systems in Caenorhabditis elegans (C. elegans) to evaluate the anti-nociceptive effects of tetrahydrocannabinol (THC) and cannabidiol (CBD). C. elegans is a widely used model for studying nociception, with the main objective being to characterize nociceptive responses induced by THC and CBD, as well as identify the underlying molecular mechanisms and targets involved. Recent studies on the use of cannabis for the treatment of chronic pain in mammals have shown controversial results. This research aims to investigate the effect of CBD and THC on the nociceptive response in C. elegans and understand the underlying pharmacological mechanisms. The methodology consisted in quantifying the antinociceptive effect of CBD and THC in C. elegans using the thermotaxis method. WT(N2) were exposed to decreasing concentrations of phytocannabinoids to evaluate the dose and effect relationship. Further tests performed on mutant expressing cannabinoid and vanilloid receptors allowed preliminarily identification of their targets. Finally, proteomic and bioinformatics analyses were used to identify the signaling pathways and biological processes induced by these phytocannabinoids. The result of this study confirmed the antinociceptive effect of CBD and THC in C. elegans, with a remanent effect of THC. This effect is mediated by the vanilloid system for CBD and the cannabinoid system for THC, respectively. Also, proteomics and bioinformatics analyses revealed significant differences in signaling pathways and biological processes.