The role of endocannabinoids receptors in regulating trophoblast cell function

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BACKGROUND Endogenous cannabinoids are lipid-based signaling molecules which regulate pain, appetite, neuroendocrine function. Recently it has been reported that cannabinoid receptors 1 and 2 (CB1and CB2), along with a third subtype, GPR55, may be linked to endocannabinoid signaling in reproductive tissues. They may contribute to the development of the placenta and the function of trophoblast cells (the stem cells which comprise the placenta). However, the specific roles and the mechanisms by which these receptors regulate the primary interface that governs maternal/fetal interactions are poorly understood. In vitro evidence from my laboratory suggests that stimulation of the endocannabinoid receptor(s) in cultured trophoblast cells substantially reduce their ability to invade and form a fused syncytium; essential steps in forming the maternal-fetal interface. HYPOTHESIS Our hypothesis is that disruption of cannabinoid receptor signaling in trophoblast cells will result in altered progression of the processes associated with placental development; invasion, vascular remodeling and endocrine function. RESEARCH PROGRAM Aim 1. Elucidation of the functional pathways impacted by cannabinoid receptor signaling in cultured human trophoblasts. Mechanistic studies will be conducted using human trophoblast cells since there are no universally accepted rodent trophoblast cell lines. We will evaluate the impact of activating and inhibiting CB1, CB2 and GPR55 with receptor specific agonists and antagonists in trophoblast cell lines. Trophoblast functional outcomes such as invasion, syncytium formation and endocrine signaling (hormone production) will be monitored. We will confirm our observations using isolated human primary trophoblasts. Aim 2. The role of mitochondria in endocannabinoid signaling. We will determine the contribution of mitochondrial free radical production and changes in organelle morphology towards cannabinoid receptor signaling by disrupting these process with various pharmacological and molecular approaches and evaluate the consequences on trophoblast function (Aim 1). Aim 3. Consequences of systemic disruption of endocannabinoid receptor signaling on trophoblast function and placentation. We will evaluate the consequence of activating or inhibition of subtype-specific cannabinoid receptor signaling pathways on the progression of placentation at two time points during gestation. We will evaluate changes in trophoblast invasion and vascular remodeling; two processes which are critical to placentation. We will associate these outcomes with fetal growth. TRAINING OF HQP My program facilitates the training of graduate, undergraduate students using an integrated approach to technical training and knowledge translation. My commitment to training HQP extends beyond my laboratory as I have developed a pan-university outreach program which facilitates undergraduate and graduate student training in science communication.