Professor Therese Kinsella

Senior Lecturer

Email: Therese.Kinsella@ucd.ie

Phone: +353 1 716 6727

Location: Conway Institute, Belfield, Dublin

Research interests

Signal transduction, (cardio)vascular biology, cell and molecular biology, gene correction.
The primary research activities of my group focus on the elucidation of prostanoid receptor-mediated intracellular signalling. The prostanoids, which include the prostaglandins (PGs) and thromboxanes, are a family of potent, biologically active lipid mediators that act through their signature G-protein coupled receptors (GPCRs) to mediate diverse cellular effects in various cell and tissue types under a range of physiologic and pathophysiologic settings. For example, within the vasculature PGI₂, also referred to as prostacyclin, largely produced by endothelial cells lining the blood vessel wall, inhibits platelet aggregation and induces vaso-dilation whereas thromboxane (TX) A₂, produced mainly by platelets, is a potent mediator of platelet aggregation and constrictor of vascular smooth muscle cells. The actions of prostacyclin and TXA₂ play a central role in the maintenance of circulatory hemostasis and imbalances in these compounds, or their receptors, have been implicated in a number of cardiovascular disorders. The main themes of our research focuses on delineation of the cell signalling mechanisms mediated by prostacyclin and TXA₂ and other prostanoids; investigation of the structure/function relationships and regulation of the prostanoid subfamily of GPCRs and their coupling "G" proteins. Basic cell and molecular biology techniques are employed to understand the signal transduction events mediated by prostacyclin and TXA₂ that result in the relatively complex pathophysiologic responses in which these autocoids are implicated. Moreover, owing to the strong clinical link between prostacyclin and TXA₂ in various vascular diseases, we are actively involved in determining the modes of regulation and in identifying the factors that regulate expression of the genes encoding the prostacyclin and TXA₂ receptors in humans.
We also have an active research prorgamme investigating the role of protein isoprenylation and protein function particularly pertaining to the role of isoprenylation of the prostayclin receptor and of members of the p21-ras subfamily of (proto)oncoproteins in their control of cell growth and differentiation, as relevant to various cancers. We are also investigating intracellular mechanisms of TXA₂ and prostacylcin receptor- and other GPCR-mediated mitogenic responses, and are interested in the application of oligonucleotide-mediated "Gene Correction/RNA_interferance" in various clinical and / or industrial situations.

Publications

1. The role of N-linked glycosylation in determining the surface expression, G protein interaction and effector coupling of the alpha (a) sioform of the human Thromboxane A₂ receptor. Kelley LP, Kinsella BT, Biochem. Biophys. Acta. (2003) 1621, 192-203

2. The a, but not the b, isoform ot the human thromboxane A₂ receptor is a target for nitric oxide-mediated desensitization: INDEPENDENT MODULATION OF TPa SIGNALLLING BY NITRIC OXIDE AND PROSTACYCLIN. Reid, H , Kinsella BT. J. Biol. Chem. (2003) 278, 51190-51202

3. Dual lipidation of the prostacyclin receptor: Identification of the sequence determinants of palmitoylation and analysis of the relevant roles of isoprenylation and palmitoylatin for receptor signalling. Miggin SM, Lawlor, OA, Kinsella BT. J. Biol. Chem. (2003) 278, 6747-6958

4. Investigation of the mechanisms of G protein : effector coupling by the human and mouse prostacyclin receptors; identification of critical species-dependent differences. Miggin, SM & Kinsella, BT. J. Biol. Chem. (2002) 277, 27053-64.

5. Characterisation of the 5^, untranslated region of a and b isoforms of the human thromboxane A₂ receptor (TP): Differential promoter utilisation by the TP isoforms. Coyle AT, Miggin SM & Kinsella BT. Eur. J. Biochem. (2002) 269, 4058 ­ 4073.

6. Regulation of Extracellular Signal-Regulated Kinase Cascades by alpha- and beta-Isoforms of the Human Thromboxane A(2) Receptor. Miggin SM, Kinsella BT. Mol Pharmacol. (2002) 61, 817-31.

7. Investigation of a functional requirement for isoprenylation by the human prostacyclin receptor. Miggin SM, Lawler OA, Kinsella BT. Eur J Biochem. (2002) 269,1714-25.

8. Protein kinase A mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to G_s-, to G_i- and to G_q-coupled effector signalling. (2001) Lawler OA, Miggin SM & Kinsella, BT. J. Biol. Chem. 276, 33596-33607.

9. Thromboxane A₂ signalling in humans: a "tail" of two receptors. (2001) Kinsella, BT. Biochemical Society Transactions. 29, 641-654.

10. The effects of the statins lovastatin and cerivastatin on signaling by the prostacyclin receptor. Lawler, OA., Miggin, SM & Kinsella, BT.British Journal of Pharmacology,2001, 132(8),1639-1649.

11. Prostaglandin D₂receptor (DP)-mediated desensitisation of the aisoform of the human thromboxane A₂ receptor. Foley, JF., Kelley, LP & Kinsella, BT. Biochemical Pharmacology, 2001, 62, 229-239

12. Thromboxane A₂receptor mediated activation of the mitogen activated protein kinase cascades in human uterine smooth muscle cells. Miggin, SM & Kinsella, BT. Biochem. Biophys. Acta. 2001, 1539 (1-2), 147-162.

13. Regulation of the human prostanoid TPaand TPb receptor isoforms mediated through activation of the EP₁and IP receptors. Walsh, M-T., & Kinsella, BT. (2000) Br. J. Pharmacology, 131, 601-609.

14. The a, but not the b, isoform of the human thromboxane A₂ receptor (TP) is a target for prostacyclin mediated desensitization." Walsh, M-T., Foley, JF., Kinsella, B.T. (2000) J. Biol. Chemistry,275, 20412-20423.

15. "Investigation of the role of the carboxyl terminal tails of the aand b isoforms of the human thromboxane A₂ receptor (TP) in mediating receptor : effector coupling." Walsh, M-T., Foley, JF., Kinsella, B.T. (2000) Biochem. Biophys. Acta.1496, 164-182.

16. "The Prostacyclin Receptor is isoprenylated; isoprenylation is required for efficient receptor :: effector coupling." Hayes, JS., Lawler, O., Walsh, M-T., Kinsella, BT. (1999) J. Biol. Chemistry, 274, 23707 - 23718.

17. "Expression and tissue distribution of the mRNA's encoding the human thromboxane A₂ receptor (TP) aandb isoforms. Miggin, SM. and Kinsella, BT. (1998) Biochemica et Biophysica Acta. 1425, 543 -557

18. "Characterization of the role of N-linked Glycosylation on the cell signalling and expression of the human thromboxane A₂ receptor Alpha and Beta isoforms". Walsh, MT., Foley JF. and Kinsella, BT (1998) J. Pharmacology and Experimental Therapeutics 286, 1028-1036

19. "The human thromboxane A₂ receptor isoform (TPa ) functionally couples to the G-proteins G_q and G₁₁ in vivo and is activated by the isoprostane 8-epi prostaglandin F_2a " Kinsella, B.T., O'Mahony, D.J. and FitzGerald, G.A. (1997) J. Pharmacology and Experimental Therapeutics 281, 957-964.

20. "Cellular Responses to Eicosanoids: Molecular Biology of Eicosanoid Receptors." O'Mahony, D.J., Kinsella, B.T. and FitzGerald, G.A. (1997) Editor E.E Bittar, JAI Press Ltd. In: Principles of Modern Medicine,Volume 8B " Molecular and Cellular Pharmacology (Part 1)" p 393 - 410.

21. "Regulated expression of the gene coding for the human thromboxane A₂ receptor". Kinsella, B.T., O'Mahony, D.J. Griffin, F. and FitzGerald, G.A. (1995) Advances in Prostaglandins, Thromboxane and Leukotriene Research. 23, 247-250.

22. Phosphorylation and Regulated Expression of the human Thromboxane A₂ receptor." Kinsella, B.T., O'Mahony, D.J. and FitzGerald, G. A. (1994) J. Biol. Chemistry. 269, 29914-29919.

23. Lipid modification of G proteins". Kinsella, B.T. and O'Mahony, D.J. (1994) Trends in Cardiovascular Medicine, 4, 27-34.

24. rab GTP-binding proteins with three different carboxyl-terminal cysteine motifs are modified in vivo by 20-carbon isoprenoids." Kinsella BT, Maltese WA. (1992) J Biol Chemistry. 267, 3940-3945.