U NIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME PROJECT SYNOPSIS TEMPLATE 1 Project title Tracking down the antimigraine effect of triptans; The relationship between 5-HT1B receptors in the vasculature and parenchyma Mentor 1 Gitte Moos Knudsen. Professor, Neurobiology Research Unit (NRU), Rigshospitalet ([email protected]) Mentor 2 Birger Brodin. Professor, Department of Pharmacy, UCPH ([email protected]) Framework The selected candidate will work in a translational environment, where competences ranging from molecular biology to in vivo imaging are used to address a major health problem; the origin of migraine and the effect and site of action of antimigraine compounds. The project will carried out in a collaboration between the labs of Gitte Moos Knudsen and Birger Brodin. The lab of Gitte Moos Knudsen represents “state of the art” within in vivo radioligand imaging and receptors characterization. Birger Brodin’s lab specializes in in vitro characterization of brain microvasculature, including expression of receptors and transporters and basic capillary biology. Both groups have strong national and international networks, strong traditions for collaborative research projects and are well recognized in their fields, securing a good collaborative working environment and a solid network for the selected candidate. Project The serotonin 1B receptors (5-HT1BR) are involved in several psychophysiological synopsis functions and disorders: locomotor activity, depression, anxiety states, and aggressive-like behaviour. Therapeutically, the 5-HT1BR constitutes an important target in migraine intervention, where headache is alleviated by administration of triptans that mediate an agonist action on the 5-HT1B/1D/1F receptors resulting in vasoconstriction of the vessels. It is still debatable exactly where the triptans exert 1 The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme. their antimigraine effects: in the brain parenchyma, at the intravascularlyPAGE located 2 OF 2 receptors, or through the nociceptive input from the trigeminal nerves. The 5-HT 1B receptors are distributed in cerebral regions such as the occipital cortex and the ventral pallidum, but they are also distribution in smooth muscles and endothelial cells in cortical microvessels. In the Knudsen lab, the 5-HT 1B receptors are studied with in vivo PET imaging in both healthy volunteers and migraine patients. With PET imaging it is not possible to distinguish the signal from the vasculature from the parenchyma because of the low spatial resolution. However, it is of great interest to know the distribution of this receptor in the two compartments (vasculature and parenchyma). In the project we will take advantage of established techniques in two labs. In the Brodin lab, the porcine brains will be fractionated/separated into the several components: large vessels, microvasculature and parenchyma from varying brain regions. Homogenate binding assays will be performed at NRU using the specific 5- 3 HT 1B receptor radioligand [ H]AZ10419369. This will be compared with in vivo PET imaging data quantified with different kinetic models. By combining the information from in vitro and in vivo experiments, it will be possible to deduct where the anti-migraine drugs exert the primary mode of action. Profile of • PhD in the field of molecular biology, biochemistry, human biology or similar potential • Knowledge in the field of neuroscience/brain vasculature fellow • Practical experience within vitro brain studies/receptor characterization • Self-driven and innovative, ability to thrive in a collaborative environment • Knowledge and practical experience with radioligands are considered an advantage UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME MENTOR CV TEMPLATE 1 Name Gitte Moos Knudsen Title Professor, overlæge, dr.med. Current Neurobiology Research Unit (NRU) & NeuroPharm (The Center for department(s) Experimental Medicine Neuropharmacology), Dept of Neurology, The Neuroscience Center, Rigshospitalet Current position(s) Professor, overlæge, dr.med., Head of NRU and NeuroPharm Education /training MD from University of Copenhagen (UCPH), 24.1.1984. Board certified user of radioisotopes 1986. FMGEMS exam (US) 1989. Board certified in neurology January 1995. DMSc (dr.med.) from UCPH, 16.12.1994. Scientific career I am a translational neurobiologist and clinical neurologist with interest in profile advanced methodological developments that I subsequently apply in my research to address pertinent neurobiological and clinical issues. My scientific interests include blood-brain barrier transport, neurobiology of cerebral blood flow and metabolism and the neurobiology of cerebral neurotransmission with particular emphasis on molecular brain imaging. I have a particular focus on multimodality neuroimaging of neuro-transmission in healthy individuals and in patients with neurological or psychiatric disorders. NRU encompasses around 50 staff members and has an annual budget of roughly €3.5 million. NRU has extensive experience in organization and governance of large scale research collaborative projects, e.g., the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) and Center for Experimental Medicine Neuropharmacology (NeuroPharm) and has participated in many European collaborations most recently INMiND supported by EU FP7. NRU collaborate nationally and internationally and has expertise in molecular, functional and structural brain imaging in brain disorders. The NRU preclinical laboratory includes standard wet laboratory facilities and NRU also has two psychological/physiological test rooms equipped with all the required facilities. As of 2019, NRU will apart from a SPECT- scanner have its own brain research dedicated 3T MR-scanner and mock-up MR scanner installed in the North Wing at Rigshospitalet. Bibliometric Published 351 Medline indexed scientific papers and reviews as well as 28 summary books/book chapters. No. citations >13,500. H-index: 56 (Web of Science). ResearcherID: C-1368-2013 , ORCID-ID: orcid.org/0000-0003-1508-6866 1 Do not exceed two pages. The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme PAGE 2 OF 3 Hansen HD, Mandeville JB et al. Functional characterization of 5-HT1B receptor drugs in non-human primates using simultaneous PET-MR. J Neurosci. 2017 Nov1;37(44):10671-10678 da Cunha-Bang S, Hjordt LV et al. Serotonin 1B receptor binding is associated with trait anger and level of psychopathy in violent offenders. Biol Psychiatry. 2017 Aug 5;82(4):267-274 Beliveau V, Ganz M et al. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System. J Neurosci. 2017 Jan 4;37(1):120-128 Mc Mahon B, Andersen SB et al. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder. Brain. 2016 May;139(Pt 5):1605-14 Knudsen GM, Jensen PS et al. The Center for Integrated Molecular Brain Imaging (Cimbi) Database. NeuroImage. 2016 Jan 1;124(Pt B):1213-1219 Frokjaer VG, Pinborg A et al. Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study. Biol Psychiatry. 2015 Oct 15;78(8):534-43 Haahr ME, Hansen DL et al. Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals.J Neurosci.2015 Apr 8;35(14):5884-9 Fisher PM, Haahr ME et al. Fluctuations in [11C]SB207145 PET binding associated with change in threat-related amygdala reactivity in humans. Neuropsychopharmacology. 2015 May;40(6):1510-8 Haahr ME, Fisher PM et al. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study. Mol Psychiatry. 2014 Apr;19(4):427-32 Fisher PM, Madsen MK et al. Three-week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling. Biol Psych. 2014 Aug 15;76(4):332-9 Contributions to My mentoring philosophy is that each student is unique and is entitled to be mentored mentoring, according to his/her skills, wishes, and personal ambitions. As the main supervisor of a substantial number of PhD-students and postdocs it becomes natural and necessary to training, have a collaborative learning environment, where PhD-students have a daily supervision supervisor in terms of either a more experienced PhD-student and/or a postdoc. PhD- students often get assistance from pregraduate students which means that at virtually every level of training, you get to teach and train people. In my view, this supports a vibrant collaborative team-work spirit. Since 1999, I have supervised a total of 24 PhD-students (hereof 14 females) who have defended their PhD degrees. After earning their PhD degree, they were recruited as post docs by different foreign institutions: Childrens Hospital Harvard Medical School (Cecilie Licht), Stanford University (Birgitte Kornum; Mikael Palner), Imperial College London (David Erritzøe), and Charité Berlin (Jan Kalbitzer). Of the remaining, eight became either senior researchers or post docs in Danish academic institutions, four went on to clinical training for specialization, and two became employed in drug companies in Denmark and Sweden. Currently, I am supervising