Project No. 2119
Diego Gomez-Nicola – University of Southampton
Gary Gilmour – Director of Preclinical Research, COMPASS Pathways
Serotonin [5-hydroxytryptamine (5-HT)] plays an important role in many organs as a peripheral hormone, as well as being key neurotransmitter in brain function.
Most of the body’s 5-HT is circulating in the bloodstream, transported by blood platelets and released upon activation. The functions of 5-HT are mediated by members of the 7 known mammalian serotonin receptor subtype classes (15 known subtypes), differentially expressed by cells and tissues, allowing for specific functions to take place. All immune cells express at least one serotonin receptor subtype, with a number of immunoregulatory functions. However, a deep and detailed characterisation of the function of specific receptor subtypes in key immune cells has not been performed to date.
Here, we hypothesise that specific 5-HT receptor subtypes are in charge of tissue-specific immunomodulatory effects, becoming key switches of the immune response than can be modulated pharmacologically. To address this hypothesis, the student will tackle the following objectives:
- Study the expression of 5-HT receptor subtypes in immune cells, including tissue-resident cells such as microglia in the brain
- Investigate the immunomodulatory effects of specific 5-HT receptor subtypes
- Study the pharmacological properties of 5-HT receptor agonists and antagonists as potential immunomodulatory agents
The student will address objective 1 by isolating specific immune cell types, from mouse and human, using both in vivo and in vitro approaches. Objectives 2 and 3 will be achieved by modelling immune activation in vivo, via stimulation with classical bacterial and/or viral mimetics, followed by specific modulation of 5-HT receptor subtypes with available pharmacological agents. Additionally, we will use immune cell specific depletion paradigms, as well as adoptive transfer experiments, in order to pinpoint the cellular selectivity of the observed physiological effects of different 5-HT receptor modulators. The experimental plan will be developed in close interaction with COMPASS Pathways, a company interested in the translational potential of 5-HT receptor modulators for neurological and immune disorders.
This project will provide a solid training platform for a PhD student, by tackling outstanding biological questions within an enriching academic-industrial collaboration. This will lead to valuable insights about the immune system, with direct translation into our understanding of the role of immune function and dysfunction.