Coimbra Center of Vision and Ophthalmology * CVO*

1. Coimbra Center of Vision and Ophthalmology * CVO* Coimbra – University Town – pop. 200.000 Center of Portugal Portugal – the most Western Country of Europe (the closest to USA!) Belongs to the European Union

2. Coimbra Centre of Vision Sciences and Ophthalmology • University Hospital – Department • Institute of Biomedical Research on Light and Image • Association for Innovation and Research - AIBILI

3. Coimbra Centre of Vision Sciences and Ophthalmology Network of 3 units: 1. Institute of Biomedical Research on Light and Image, Fac. Medicine (IBILI) 2. Department of Opthalmology, University Hospital of Coimbra 3. Association for Innovation and Research on Light and Image (AIBILI)

4. IBILI – Institute of Biomedical Research on Light and Image • - Multidisciplinary Research Institute of the Faculty of Medicine - Research Programmes I. Phenotyping Retinal and Brain Degenerations Age-related Degenerative Diseases of Retina and Brain. New methods of diagnosis and innovative therapies Technology Transfer on Clinical Imaging and Drug Delivery Research Units of Ophthalmology and Vision Sciences, Biophysics, Pharmacology and Biomedical Engineering

5. Research Units: Centre of Ophthalmology Biophysics Biomathemathics and Neurosciences Physiology Pharmacology Instrumentation and Imaging IBILI – Institute of Biomedical Research on Light and Image

6. 2. Department of Ophthalmology, University Hospital of Coimbra Outpatients 71.128 Inpatients 1.576 Beds 28 Surgical procedures 8.463 Medical staff 27 Residents 8

7. 3. AIBILI – Non-profit contract organization - Centre for Clinical Trials • - Centre for Bioequivalence Studies • - Centre for New Technologies for Medicine • Technology transfer unit • Quality management • European Network of Clinical Trial Centres (Coordin.)

8. Main Research Areas Retinal Degenerations Functional Imaging of the Retina and Brain Focus Interactions between Retina and Brain

9. RP1 Visual Neuroscience Laboratories Head: Miguel Castelo-BrancoKey questions Understanding Structure/Function relations at the level of the retina and the cortex Unraveling Genotype/Phenotype relations at the level of the retina and the cortex • - Sensory Systems • - Basic and Clinical Cognitive Neuroscience

10. We are taking advantage of new tools for in vivo histology of the retina, and functional methods to isolate cone and ganglion cell function, namely spectral electrophysiology, psychophysics, and scanning laser imaging coupled with photoreceptor stimulation in humans. We could isolate specific magnocelullar and visual motion dysfunctions in a genetic neurodevelopmental model, Williams Syndrome 105 nV/deg2

11. Brain mapping of visual areas Neural correlates of visual motion perception

12. RP2 – Phenotyping Retinal Degenerations • Human Hereditary Diseases • AMD • Diabetic Retinopathy • Glaucoma • Brain Degeneration Diseases

13. RP2 – Diabetic Retinopathy Phenotypes Clinical Follow-up of mild NPDR in diabetes type 2 2 year – visits at 6 months intervals – 57 patients 7 years – yearly intervals combining: Retinography (microaneurysm counting) Retinal thickness (RTA, OCT) Fluorescein Angiography (FAZ) Retinal Leakage Analysis (VF, RLA)

14. N.P.D.R. Phenotypes – Diabetes type 2

15. 57 eyes from patients with mild NPDR 35 – Pattern A (61%) – no CSME 12 – Pattern B (21%) – five eyes CSME (41%) 10 – Pattern C (18%) – five eyes CSME (50%) Different phentypes – Different risk profiles 7 year Follow-up

16. CONTROL MG132 RP2 – Molecular Mechanisms of Retinal Degenerations Example: Ubiquitin – Proteasome Pathway UPP down-regulates intercellular communication through gap-junctions in response to hyperglycemia and oxidative stress Fernandes et al 2004 J BIOL CHEM 279:27219

17. A new model for quality control: ubiquitin-dependent degradation versus refolding The ubiquitin- proteasome pathway competes with molecular chaperons for degradation of damaged proteins. Failure to eliminate damaged proteins may lead to accumulation of insoluble aggregates, contributing for the pathophysiology of AMD (Marques et al FASEB J 2006)

18. Oxidative inactivation of the proteasome may contribute to the inflammatory component of AMD Oxidative stress UPP MKK3/6 HIF-1 NF-B p38 MAPK VEGF MCP-1 IL-8 Increased inflammation Decreased macrophage recruitment Choroidal neovascularization Fernandes AF .J. Biol. Chem. (submitted) Fernandes, AF (2006). Exp Eye Res.83

19. RP3 – Tools for Clinical Imaging and Drug Delivery Example: Multimodal Macula Mapping Strategy to expand the scope of individual exams by combining exams at once in systematic fashion

20. Multimodal Macula Mapping HRA – Retinal Leakage Analyzer Step 1 Fluorescein Angiography Retinography Step 2 OCT Map OCT cross section Integration Step 3 mfERG Map Integration mfERG

21. Retinography Leakage Map SLO FA OCT OCT Thickness Map mfERG ID: 30 Visit: 1 AMD

22. SLO FA Step 1 Retinography Leakage Map ID: 30 Visit: 1 AMD

23. Step 2 ID: 30 Visit: 1 AMD

24. Step 3 ID: 30 Visit: 1 AMD

25. ID: 30 Visit: 1 AMD

26. Doctorate Programmes Neuropsychology of vision Ageing and Degenerations of Complex Systems Interuniversity Doctorate Programme in Vision Sciences with University of Valladolid and University of Murcia (Spain)

27. International collaborations and networking - EU Integrated Research Project – EVI-Genoret - Functional Genomics of the Retina in Health and Disease - 25 participating institutions • European Network of Clinical Trial Centres of Ophthalmology. EVI.CT.SE • - 36 members • - Multicenter clinical trials using standardized SOPs • Other European Union Programmes • - Eurovision Net – FP 2.4-5.9-2007 • - Mirror – Novel Optical Technologies of imaging the eye fundus • – FF1.2-2.6 -2007

28. Fellowships and Grants: Gulbenkian Foundation – www.gulbenkian.pt Champalimaud Foundation - www.fchampalimaud.org Foundation for Luso–American Development (FLAD) www.flad.pt Foundation for Science and Technology (FCT) – www.fct.mctes.pt

29. Contacts Coimbra Centre for Vision and Ophthalmology AIBILI www. aibili.pt Email: aibili@aibili.pt