U NIVERSITY OF 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 . 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 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 /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 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 , The Neuroscience Center, Rigshospitalet

Current position(s) Professor, overlæge, dr.med., Head of NRU and NeuroPharm

Education /training MD from (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 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 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 and Sweden. Currently, I am supervising 9 PhD students and mentoring 10 post docs. My laboratory supervises about 20 national and international pregraduate and PhD students every year. Regular teaching of pregraduate medical, pharmaceutical and human biology students and organizer of 1-2 PhD courses per year. Regularly teaching at international courses: annually at the PET Pharmacokinetic course (80 students) and at summer courses.

UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES

BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME

MENTOR CV TEMPLATE 1

Name Birger Brodin

Title Professor, PhD

Current Department of Pharmacy, The Faculty of Health and Medical Sciences department(s)

Current position(s) Professor, group leader, CNS Drug Delivery and Barrier Modelling

Education /training Sep 2018 : Leading Research – a leadership course. HR Department, University of Copenhagen Nov 2015.: Seminar on Responsible Conduct of Research, The Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Aug-Nov 2011. Leadership Development for Research Group Leaders. HR- Department, University of Copenhagen. 24/01-1995 Lic. Scient (PhD) in Cellular Physiology, Faculty of Science, University of Copenhagen. 29/01-1991 Candidate of Science (MSc) in Biology at the University of Copenhagen Scientific career My research focus is transport of drug compounds across tissue barriers, with profile focus on CNS barriers, their basic biology and expression of drug transporters . In my group, we have developed novel techniques to isolate capillaries, culture cells from the neurovascular unit, and generate in vitro models of the brain endothelium and use these for mechanistic investigations of basic barrier biology and drug compounds. We have a palette of tools, ranging from CLSM imaging, molecular biology methods, radioisotope-techniques, HPLC and MS-analysis, to advanced triple- culture barrier modelling. The research group presently includes 2 assistant professors, 1 research scientist, a lab technician and 6 masters student. We have a large network of Danish and international collaborators (WP leader in

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

the national Lundbeck Foundation initiatibe on Brain Barriers and anPAGE H2020 2 OF 3 IMI Consortium) Bibliometric Author of 92 scientific peer reviewed publications in international scientific summary journals and periodicals (78 peer-reviewed research papers and reviews, 11 textbook chapters, 2 conference proceedings and 1 dataset), 8 as first author and 42 as last author. Furthermore I have been editor of 1 textbook, 1 GenBank submission, >200 abstracts. Hirsch Index 23

Hersom M, Helms HC, Schmalz C, Pedersen T, Buckley S, Brodin B. (2018) The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells, but does not mediate insulin entry from blood-to-brain. American Journal of Physiology – Endocrinology and Metabolism. DOI: 10.1152/ajpendo.00350.2016 Ozgür B, Saaby L, Langthaler K, Brodin, B. (2018) Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for identification of P-gp substrates. European Journal of Pharmaceutical Sciences, 112:112-121 Cai C, Fordsmann JC , Jensen SH, Gesslein B, Lønstrup M, Hald BO, Zambach SA, Brodin B , Lauritzen MJ. (2018)Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proceedings of the National Academy of Sciences USA. https://doi.org/10.1073/pnas.1707702115 Siupka P, Hersom M, Lykke-Hartmann K, Johnsen KB, Thomsen LB, Andresen TL, Moos T, Abbott NJ, Brodin B, Nielsen MN. (2017) Bidirectional apical-basal traffic of the cation-independent mannose-6-phosphate receptor in brain endothelial cells. Journal of Cerebral Blood Flow and Metabolism. 37(7):2598-2613 Helms HC, Abbot NJ, Burek M, Cecchelli R, Couraud PO, Deli M, Förster C, Galla HJ, Romero IA, Shusta EV, Stebbins MJ, Vandenhaute E, Weksler B, Brodin B. (2016) In vitro models of the blood–brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use. Journal of Cerebral Blood Flow & Metabolism 36(5):862-90 Saaby, L, Helms, HC, Brodin, B. (2016) IPEC-J2 MDR1, a novel high-resistance cell line with functional expression of human P-glycoprotein (ABCB1) for drug screening studies. Molecular Pharmaceutics 13 (2):640–652 Helms, HC, Hersom, M, Kuhlmann, LB, Badolo L, Nielsen, CU & Brodin, B. (2014) An electrically tight blood- brain barrier model displays net brain-to-blood efflux of substrates for the ABC-transporters, P-gp, BCRP and MRP-1. AAPS Journal. 16(5):1046-1055 Helms, HC, Brodin, B . (2014) Generation of Primary cultures of Bovine Brain Endothelial cells and setup of Co-Cultures with Rat Astrocytes. Methods in Molecular Biology. 1135:365-382 Helms, H.C., Nielsen, R., Waagepetersen, H.S. , Nielsen, C.U., Brodin, B. (2012) In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to- blood transport of glutamate. Glia 60(6):882-893 Helms, H.C., Waagepetersen, H.S. , Nielsen, C.U. , Brodin, B. (2010) Paracellular tightness and Claudin-5 expression is increased in the BCEC/astrocyte blood-brain barrier model by increasing media buffer capacity during growth. AAPS Journal. 12(4):759-770 Contributions to My mentoring philosophy is that “learning” is more important than mentoring, “teaching”. I aim to bring students in a situation where their learning training, is optimized, by solving concrete problems and gaining knowledge and supervision self-confidence in collaborative projects where they receive supervisor and peer-feedback. I have been involved in almost all aspects of teaching, from participating in new teaching initiatives to evaluation of students. I have taught at all levels of the education, from Bachelor to PhD. Have served as supervisor of bachelor (>70), master (>40) and PhD (9/14) students. The majority of my former students are now employed in the Pharma industry, universities and regulatory agencies in Denmark and abroad. Two of my former PhD students are now University Professors (full).