CRC 1607 and The Department of Ophthalmology and the University of Cologne

The University of Cologne (UoC), established in 1388, is one of the largest and oldest universities of Europe and encompasses six faculties that cover a broad range of disciplines. In addition UoC is one the most research active Universities in Germany with currently the highest number of “Sonderforschungsbereichen” (SFBs/CRCs) in Germany (with speaker in Cologne; 6/2024). Over the last decade the University has actively restructured its strategic agenda, to better reflect and define its key successful research endeavors. This resulted in the establishment of eight key profile areas, of which the first, Aging Associated Diseases, is centered around the Cologne Excellence Cluster on Stress Responses in Aging and Agingassociated Diseases (CECAD), a collaborative enterprise of the UoC Faculty of Medicine and the Faculty of Mathematics and Natural Sciences together with the Max Planck Institutes for Metabolism Research (MPI-MR) and for Biology of Aging (MPI-AGE). The two faculties have a long history of successful collaborations aimed at exploring basic molecular principles underlying diseases, thereby allowing novel translational opportunities. This collaborative spirit was based on the establishment of the Center for Molecular Medicine Cologne (CMMC) promoting interdisciplinary research between basic scientists and clinician scientists. Our CRC 1607 follows this successful path and is well embedded in this key profile area of the University of Cologne and will significantly strengthen the KPA ‘Aging Associated-Diseases’.

The Medical Faculty (MF) has its research focused on age-related diseases, inflammation and regeneration as well as on oncology. Our CRC 1607 cooperates with all of them, the CECAD excellence cluster and both local Max Planck Institutes—for Metabolism Research and Biology of Ageing. The core mission of the Medical Faculty (MF) Cologne and University Hospital Cologne (UHC) is to foster clinical, translational, and basic medical research with the aim of developing and applying novel, state-of-the-art diagnostic procedures and modern therapies. A particular emphasis is placed on ageing-associated diseases, a focus that has been developed by the MF and MNF into a key profile area of the University of Cologne (UoC).

The Department of Ophthalmology has a strong focus on clinical and experimental imaging and on translational research and comprises more than 45 full time physicians and scientists. There are two reading centers for phase II-IV studies and one clinical trial center in the department with over 15 ongoing phase II-IV clinical trials. The research is funded by the German Research Foundation (DFG) via the recently established priority research unit CRC 1607 (“Towards immunomodulatory and anti(lymph)angiogenic therapies for age-related blinding eye diseases”) and several individual DFG grants; by two EU research grants (COST Action Aniridia-Net, co-chaired in Cologne by Prof. Cursiefen and the EU Horizon project Restore Vision with one PL in Cologne (CC; www.restorevision-project.eu); the reading center for EU FP7 STRONG Study, also chaired in Cologne); by a large BMBF grant (CrossCornealVision, CC), by several private foundations and other sources. In the past three years, third-party funding has increased manifold compared to previous years, amounting to over 26 million euros. There is access to animal care facilities in house and on campus and the research area is more than 300 square meters.

Table of contents

Focus Areas of the CRC 1607

Focus Area “A” – Inflammatory and (lymph)angiogenic reduction of corneal transparency and vision:
addresses insufficient understanding of and insufficient therapies for inflammatory and (lymph)angiogenic reduction of corneal transparency and vision loss at the cornea. This means that all projects work on the same ocular tissue and are closely connected by several joint mechanisms (corneal) lymphangiogenesis, UV irradiation, dendritic cell [DC] activation etc.). The cornea is the transparent “windscreen” of the eye, which can lose its transparency by several causes:

  • reduced pump function of the corneal endothelium,
  • pathologic and aberrant inflammatory responses that are usually combined with pathologic corneal hem- and lymphangiogenesis (which subsequently also endanger the success of cornea transplantation, as the current main therapeutic approach) or
  • stem cell deficiency, thus endangering the continuous repair of the ocular surface by limbal stem cells.

The first project A01, therefore targets the modulation of inflammatory and secondary fibrotic extracellular matrix (ECM) pathology in Fuchs corneal endothelial dystrophy, the most common disease leading to corneal transplantation; A02 addresses strain-dependent genetic variations of (lymph)angiogenesis that can be identified using the cornea as a model system in Collaborative Cross Line Mice, thereby identifies novel endogenous regulators of lymphangiogenesis in metabolically altered mice and examines their functional influence on corneal wound healing. A02 in addition will identify and functionally characterize additional new endogenous modulators of lymphangiogenesis in collaboration with all other A-projects and several B- and Cprojects. A03 addresses the disease-specific and individual differences in a variety of high- and low-risk corneal transplantation settings (characterized by pathologic [lymph]angiogenesis and DC activation) and aims to develop personalised anti-lymphangiogenic and immunomodulatory therapeutic approaches to promote graft survival after corneal transplantation (with a special focus on UV light-mediated alterations of lymphatic vessels and altered DC activation). In addition, A04 examines the novel concept of metabolic control of corneal hem- and (lymph)angiogenesis also with respect to corneal transplant immunology. A05 studies the role of ABCB5+ limbal stem cell populations in corneal (lymph)angiogenesis, inflammation and UV-induced pterygium pathogenesis (again, a disease characterized by aberrant [lymph]angiogenesis).

Focus Area “B” – Severe ocular surface inflammation and (lymph)angiogenisis in dry eye disease, ocular GVHD, and allergy:
studies mechanisms and new therapeutic approaches in severe ocular surface inflammation with a focus on dry eye disease, ocular GVHD and allergy. All projects are connected by the investigation of inflammatory changes at the ocular surface, i.e. corneal surface, conjunctival surface and tear film, and focus on dampening inflammatory and lymphangiogenic activation in that ocular location. Here, in B01 the novel pathogenic role of lymphatic vessels in ocular graft versus host disease is studied. A specific focus is on the role TSP1 and NFKb signaling in lymphangiogenesis and inflammation in oGVHD. In B02 the role of osmosensation in macrophage activation and (lymph)angiogenesis in inflammatory diseases of the ocular surface is analyzed. Project B03 tests the hypothesis that CD83-based immunomodulation can alter immunological diseases of the ocular surface (using various disease models with a special focus on dry eye disease and herpetic keratitis). Finally, the variability and organ-specificity of lymphatic vessel‒DC interactions in the eye – also using the eye as a model – are analyzed (using ocular conjunctival allergy and a new innovative model as an example) in B04.

Focus Area “C” – Immune-mediated and (neo)vascular vision loss in glaucoma, ocular tumours, and AMD:
studies immune-mediated and neovascular vision loss in glaucoma, ocular tumours and age-related maculopathy. These groups are working mainly on tissue in the posterior part of the eye and are—besides the two main pathogenic mechanisms—linked by investigating the effects of altered inflammation and (lymph)angiogenesis primarily on retinal and uveal tissues. Again, it also aims to develop new therapeutic concepts. Here, the role of mitochondrial dysfunction in mediating retinal neuroinflammation in glaucoma is studied in C01, as are the novel roles of lymphangiogenic mediators in Schlemm’s canal and their relevance for glaucoma pathogenesis and therapy in C02, a very timely topic in glaucoma research. SVEP-1 will be characterized as a novel lymphangiogenesis modulator and therapeutic target in glaucoma. C01 and 2 will interact closely. The second two projects deal with (lymph)angiogenesis in ocular tumours with a special focus on midkine in regulating tumour growth and (lymph)angiogenesis (C03), as well as the role of DCs and inflammatory cytokines in the therapeutic targeting of conjunctival melanoma (C04). Furthermore, project area C deals with aberrant cellular immunity in immune-mediated and neovascular vision loss in AMD. Here, one topic is the role of galectins in the retina and its influence on AMD (C05), as well as the role of reactive oxygen species production in retinal inflammatory diseases (C06) and, finally, the role of inflammasome in degenerative retinal diseases such as AMD (C07). C05-07 are closely linked through their work on microglia as inflammatory target cell.

Focus Area “Z” – Core Units: To supplement all project areas and individual projects as well as to strengthen our core goals of TRANSLATION and optimized IMAGING five core units are in project area Z. This includes
Z01: Translational core unit: “Therapeutic antibody production facility” The aim of Z01 is to foster
translation of basic research into the clinic throughout the whole funding period of CRC1607 (PI: Prof. M. Koch).
Z02: “Imaging Core Unit (ICU)” comprises a state-of-the-art and worldwide unique animal eye imaging facility funded by the Medical Faculty of UoC and DFG during the FOR2240 period at our department (2015-2023; PI: Prof. F. Bock).
Z03 is the administrative core unit, also responsible for Clinician-Scientist support (PI Prof. C. Cursiefen).
Z04: The Research Training Group Eye and Inflammation is of essential importance to educate and train young scientists for the field of the eye research and inflammation leading CRC, but also nationwide. PIs: Prof. V. Prokosch and Prof. F. Bock.
Z05 – INF project: This project is about data storage and data mining (mainly driven by the director of the Institute of Medical Informatics, Prof. Oya Beyan) and AI-based image analysis (PI: Prof. K. Bozek).

Background – Why this CRC 1607 now?

  1. Age-related blinding eye diseases are increasing in prevalence. The pressure to better understand and, based on that understanding, target these diseases with novel concepts is significantly increasing.
  2. It is increasingly evident that most of these vision-threatening age-related diseases are associated with aberrant inflammation, (lymph)angiogenesis and cellular immunity.
  3. A dramatic knowledge shift recently occurred in the perception of the role of lymphatic vessels in numerous diseases, including the eye, thus making them a novel, interesting therapeutic target also in ophthalmology (with the help of external experts). Same applies to the field of cellular immunity/inflammation.
  4. Now it is necessary to broaden our pathomechanistic understanding of the interface between cellular immunity and (lymph)angiogenesis by including more (outside) expertise and focus on the eye and its diseases to move forward to the next level, that is better disease understanding and development of new therapeutic concepts for age-related blinding eye diseases.
  5. Our previous DFG Forschungsgruppe (RU 2240; www.for2240.de) has created a very synergistic group of experts in ocular (lymph)angiogenesis and cellular immunity research in Cologne. Young talents have developed within that framework and e.g. the CCSP and this group with now manifold interactions within the MF (Medical Faculty), CMMC, CECAD etc. in Cologne needs longterm structural stability to even further grow and contribute as lighthouse to translational research in Cologne.
  6. Pharmaceutical industry recently is increasingly interested in ophthalmology thus increasing the chances for translational progress. Here, we currently see a considerable need for additional clinically oriented basic research and preclinical testing.
  7. The diseases mentioned here can partly be classified as “widespread diseases” (“Volkskrankheiten”). Half of all 80-year-olds in Germany suffer from one or other form of AMD, 20% of over 50-year-olds suffer from various forms of glaucoma. More than 5% of over 50-year-olds suffer from corneal dystrophies (such as Fuchs endothelial dystrophy), which subsequently lead to corneal transplantation and possible rejection responses. Dry eye disease also affects about 10% of the total population – just to give some examples. Moreover, these unmet needs also apply to several rare but paradigmatic diseases.
  8. We want to promote the eye not only as target for eye disease-oriented research, but also as model system. For example, the unravelling of the molecular mechanisms of melanoma cell and lymphatic vessel interaction in ocular melanoma should provide universal insights that are also valid outside the eye.

Primary goals of the CRC

  • the concerted investigation of the as yet still poorly understood pathogenesis of aberrant ocular immune and neovascular processes, with a strong focus on age-related diseases (although this CRC does not focus on ageing mechanisms per se) and
  • the development and (partial) translation of innovative new diagnostic and therapeutic concepts for these diseases.

The close interaction between clinicians and basic scientists will allow for easier and faster bench-tobedside and back transfer in specific projects. By using the eye not only as a direct target of (ophthalmological) research, but also as a “model” system our interdisciplinary team not only addresses unmet research needs in ophthalmology with external help, but also wants to decipher general disease principles and therapeutic strategies which will have an impact beyond ophthalmology. The normally transparent and avascular cornea e.g. is an excellent model to study the mechanisms of (lymph)angiogenesis as is the murine model of corneal transplantation a perfect model to study immune cell-lymphatic vessel interactions. Findings in these models have impact way beyond ophthalmology. The same is e.g. true for its use in Collaborative Cross Line Mice in identifying novel endogenous regulators of lymphangiogenesis also having relevance beyond ophthalmology (e.g. Tyrosinase, TSP1, TRAIL, Cysthationine B synthase etc.).