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- Characterization of bitter taste receptors expression and function in the human blood-cerebrospinal fluid barrierPublication . Duarte, Ana Catarina Abreu; Santos, Cecília Reis Alves dos; Gonçalves, Isabel Maria Theriaga Mendes VarandaBitter taste receptors (TR2) expression and functionality was recently reported in the rat choroid plexus (CP). CP epithelial cells establish a major brain barrier, the blood-cerebrospinal fluid barrier (BCSFB). Given their capacity to bind a large array of chemical compounds, we hypothesised that TR2 might be involved in monitoring the composition of blood and cerebrospinal fluid. Brain barriers play a critical role in the protection of the central nervous system (CNS) by hindering the access of toxic substances to the brain. Consequently, many drugs targeting neurological disorders are impaired to cross these barriers. This is explained through the expression of several membrane transporters in brain barriers cells that efflux drugs, thus impairing drug cell accumulation in the brain. A wide range of compounds that bind to TR2 show neuroprotective and anti-tumoral properties. However, their low bioavailability in the CNS restrains its therapeutic application. Additionally, bitter compounds might interact with transporters that are also found in brain barriers. Therefore, bitter compounds might be effluxed which explains their low bioavailability but can also regulate the action of these transporters in order to increase their or other drugs’ intracellular accumulation. Considering that bitter compounds are TR2 agonists it is possible that TR2 play an important role on the bioactive effects of bitter compounds in the CNS, as reported in other tissues. The main goal of this doctoral thesis was to analyse the expression and function of the bitter signalling pathway in the human BCSFB. Additionally, the role of human TR2 (TAS2Rs) as modulator of specific neuroactive bitter compounds on ABC transporters function and activity at the BCSFB was also evaluated. The first research work presented showed the expression of 13 TAS2Rs as well as of downstream effector proteins of the taste signalling pathway in the human BCSFB. Moreover, we demonstrated that TAS2R14 and TAS2R39 are functional in a human cell model of the BCSFB and respond to bitter compounds quercetin and chloramphenicol, respectively. The second research work evaluated resveratrol transport across the BCSFB and the involvement of TAS2Rs. Results showed that resveratrol is able to cross the BCSFB from blood to cerebrospinal fluid in a dependent manner of TAS2R14 expression at CP epithelial cells. Further, efflux transporters ABCC1, ABCC4 and ABCG2, which are expressed at CP epithelial cells, transport resveratrol. Additionally, resveratrol upregulated ABCG2 expression and regulated ABCC4 and ABCG2 efflux activity in TAS2R14 dependent way. In conclusion, the results obtained during this project demonstrate that TAS2Rs are expressed and functional at the human BCSFB and support their participation in the monitorization of chemical composition of the surrounding fluids. Furthermore, the major achievements of this thesis strongly support the role of BCSFB in the regulation of the transport of molecules into the brain. In the future, it is necessary to further exploit the role of other TAS2Rs as mediators of the effects of bitter compounds in the brain, as well as in the regulation of transport and detoxifying systems at the BCSFB. The knowledge hereby created has far-reaching potential for improving the challenging task of delivering therapeutic drugs into the CNS.