Prof. Dr. med. Mario Matthaei, Dept. of Ophthalmology, University of Cologne (Publications)
Prof. Dr. rer. nat. Margarete Odenthal, Dept. of Pathology, University of Cologne (Publications)

Fuchs endothelial corneal dystrophy (FECD) is a bilateral gene- and age-related disorder leading to corneal edema and vision loss and represents the most common indication for corneal transplant surgery worldwide. FECD is characterised by accelerated loss of corneal endothelial cells and altered extracellular matrix (ECM) deposition of the underlying basement membrane. Recent studies demonstrate infiltration of the central endothelial layer by cells derived from the monocyte/macrophage lineage leading to early corneal endothelial activation of profibrotic pathways. The chronic low-grade inflammatory processes result in fibrotic remodeling of the corneal endothelial centre. Although the pathophysiology occurs mainly  in the endothelial centre and spreads centrifugally towards the periphery, a shortcoming of most molecular studies investigating gene-expression in FECD is that one identical pathological state is presumed for all cells within the whole endothelial monolayer. Our hypothesis is that there are significant site-specific differences in gene expression and pathology  in FECD that require different medical and/ or surgical approaches. To  improve therapeutic strategies, the proposed project A01 therefore aims to decipher the site-specific chronic inflammatory and fibrotic processes in FECD.

Key methods: single nuclei RNA sequencing, intra- and intercellular pathway analysis, expression profiling (RT-PCR, bulk-RNA sequencing),  tissue/cell culture,  cellular growth characterization upon ECM remodelling, immunofluorescence,  spatial proteomics by imaging mass spectrometry

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Dr. rer. nat. Thomas Clahsen, Dept. of Ophthalmology, University of Cologne (Publications)
Prof. Dr. med. André Reis, Institute of Human Genetics, University Erlangen-Nueremberg, Erlangen (Publications)

There are around 60 million patients with diabetes in the European Union. Diabetics not only suffer from impaired (corneal) wound healing, they also develop various other eye complications such as diabetic retinopathy, macular and corneal edema as well as glaucoma. The disease also affects the corneal epithelium, corneal nerves and tear film. Diabetics show stronger inflammatory reactions after eye surgery, which leads to a higher rate of rejection after corneal transplantation. In this context, impaired inflammatory cell function, reduced secretion of cytokines/growth factors and a prolonged inflammatory phase can be observed in diabetics.

Lymphangiogenesis plays an important role in homeostasis, metabolism and immunity, and also occurs during wound healing. Wound-healing processes lead to the recruitment of macrophages that produce VEGF-C and VEGF-D, and these two factors, in turn, promote lymphangiogenesis. Diabetics, however, show dysfunctional lymphangiogenesis, which slows down the wound-healing process and the recruitment of macrophages. Nevertheless, the detailed mechanism underlying the impaired lymphangiogenesis in diabetes is still elusive.

The goal of this project is to identify novel endogenous factors of inflammatory lymphangiogenesis that play a role in regulating delayed wound healing in diabetic patients using a mouse model that compares collaborative mouse lines with metabolic disorders and thereby using the eye as a model system.

Key methods: QTL analysis, in vivo experiments, IF, image analysis, scRNASeq, cell culture assays (tube formation, migration, proliferation), transfection, qRT-PCR, flow cytometry

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Prof. Dr. med. Claus Cursiefen, Dept. of Ophthalmology, Center for Molecular Medicine Cologne (CMMC), University of Cologne (Publications)
Prof. Dr. rer. nat. Felix Bock, Dept. of Ophthalmology, University of Cologne (Publications)

The healthy cornea is the avascular and transparent “windscreen” of the eye. Several pathologic insults such as chemical or thermal burns, infections, autoimmune diseases, transplant rejection, contact lens-induced hypoxia and trauma can lead to corneal blindness secondary to pathologic corneal neovascularisation and scarring. In addition, these conditions also lead to a so-called “high-risk situation” with increased rejection rates after subsequent corneal transplantation, which is the main cure for corneal blindness. We have previously identified clinically invisible corneal lymphatic vessels as key players defining a high-risk setting. We then showed that targeting pathologic corneal (lymph)angiogenesis in the murine model of corneal high-risk transplantation significantly promotes corneal graft survival. This was achieved either pharmacologically e.g. via VEGF A/C/D depletion or by mechanical lymphangioregression (using, e.g. fine needle cautery). Initial pilot data suggest that this concept of lymphangioregressive pretreatment improves high-risk graft survival also in patients. In fact, a pilot randomised clinical trial is starting in 2022 testing UVA crosslinking to regress lymphatic vessels and promote graft survival in high-risk recipients (BMBF; KS2020-188).However, pilot data from our group also suggest that all the abovementioned different corneal insults leading to a high-risk setting cause different immunological and (lymph)vascular tissue alterations in the recipient. Nonetheless, irrespective of the underlying cause, corticosteroids have hitherto remained the mainstay of immunomodulatory therapy after high-risk corneal transplantation. Similarly, there is no personalised or disease-specific antilymphangiogenic or -regressive approach available as yet for different underlying diseases. Personalised medicine, already approaching clinical routine in oncology, has not reached corneal transplantation medicine yet. Therefore, the aim of this project is to develop personalised and disease-specific immunomodulatory and lymphangiomodulatory therapies pre and post high-risk corneal transplantation due to different underlying diseases to promote graft survival and vision.

Key methods: in vivo models of corneal diseases, RNASeq, Proteomics, bioinformatics, cytokine bead arrays, cell culture, flow cytometry, next generation image analysis, IF

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Prof. Dr. rer. nat. Hamid Kashkar, CECAD, Institute of Molecular Immunology, University of Cologne (Publications)
Dr. rer. nat. Karina Hadrian, Dept. of Ophthalmology, University of Cologne (Publications)

Pathological corneal hem- and lymphangiogenesis is an important component of various blinding corneal diseases and represents an important target in therapeutic interventions. Accumulating recent evidence indicate that endothelial cell (EC) metabolism is intimately linked to EC function and centrally controls vascular growth. We and others could recently show that neoangiogenesis requires a dynamic and timely mitochondrial metabolic switch to guarantee cellular growth under energetically demanding angiogenic processes. The profound metabolic plasticity of ECs does not only safeguard vascular growth under challenging nutrient conditions but also decisively control different cellular components of tissues, in particular, immune cells such as macrophages by releasing distinct metabolites. Our recent data providesed genetic evidence for the involvement of mitochondria in neovascularization (under disease and regenerative conditions) by coordinating the tissue metabolic and inflammatory crosstalk. Here we aim to explore the mitochondrial control of pathological angiogenesis in corneal neovascular diseases.

Key methods: transgenic mouse models, in vivo mouse models, metabolomics, cytokine bead arrays, q-RTPCR, flow cytometry, cell culture assays, ex vivo assays

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Dr. rer. nat. Maria Notara, Dept. of Ophthalmology, Center for Molecular Medicine Cologne (CMMC), University of Cologne (Publications)
Prof. Dr. rer. nat. Björn Schumacher, Institute for Genome Stability in Ageing and Disease, CECAD Excellence Cluster, University of Cologne (Publications)

The ocular limbus is the junction between the avascular cornea and the heavily (lymph)vascularized conjunctiva. It is also the habitat of limbal epithelial stem cells (LESC) which maintain the integrity of corneal epithelium, the outermost layer of the cornea.The limbal barrier for neovascularization and inflammation may be compromised leading to reduced vision. This occurs e.g. in pterygium, a UV-induced fibro-vascular tumour affecting 12% of people worldwide, which advances onto the cornea surface causing immune cell infiltration, neovascularization and, if left untreated, blindness.

The pterygium stroma contains cells, which contribute to the characteristic hyperplasia and fibrosis via myofibroblast hyperproliferation and cross talk with the epithelium. UV also induces DNA damage that has consequences ranging from cell fate alterations such as senescence and stem cell depletion to inflammatory and metabolic responses. We previously showed that LESC, playing a pivotal role in corneal avascularity, become differentiated under UV exposure, while producing pro-inflammatory cytokines. We also found that UV irradiation of LESCs and limbal fibroblasts leads to differentiation characterized by SC marker loss, an upregulation of proinflammatory factors and fibrosis-related proteins.  

In this project, we will investigate a novel limbal mesenchymal stem cell (LMSC) population which has therapeutic potential but  on the other hand, when UV damaged, is involved in pterygium pathogenesis.

The elucidation of the potential immunoregulatory properties as well as the UV-induced (lymph)angiogenic and inflammatory effects employed by LMSC will contribute to the development of new therapeutic strategies against corneal neovascularization/inflammation and pterygium progression and recurrence.

Key methods: primary cell culture, cell culture assays, flow cytometry, cell sorting, proteomics, image analysis, transgenic mouse models, RNASeq, bioinformatics, shRNA, IHC, IF

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Prof. Dr. med. Philipp Steven, Dept. of Ophthalmology, CECAD Excellent in Aging Research Cluster, University of Cologne (Publications)
Prof. Dr. rer nat. Manolis Pasparakis, Institute for Genetics, Faculty of Math. Nat. Sciences, CECAD, University of Cologne (Publications)

Chronic ocular graft-versus-host disease (oGVHD) develops in up to 60% of patients following allogeneic hematopoietic stem cell transplantation. Diagnosis and therapy are challenging due to limited GVHD-specific diagnostic biomarkers especially in early stages and the lack of targeted therapeutic options.

Recent studies from our groups have demonstrated that transient (lymph)angiogenesis takes place in early phases of experimental oGVHD. We demonstrated for the first time that VEGF-C is upregulated in cornea and conjunctiva, and lymphatics grow into the normally avascular cornea. Proof-of-concept experiments demonstrated that desiccating stress during transplantation leads to exacerbation of GVHD including earlier lymphangiogenesis and activation of the IKK/ NF-κB signaling pathway, which is a known regulator of VEGF expression. We furthermore developed advanced deep learning-based algorithms for the analysis of immune cells, nerves, meibomian glands and conjunctival blood vessels in patients, all parameters that are relevant as optical biomarkers for the diagnosis and detection of disease activity and progression in oGVHD.

The project aims to identify new targets related to (lymph)angiogenesis and inflammation that could open the perspective for better and earlier diagnosis as well as specific and preventive treatment of ocular GVHD.

Key methods: in vivo GVHD model, OCT angiography, in-vivo corneal confocal microscopy, RNA isolation, qRT-PCR, bone marrow transplantation, RNAseq, AI-based image analysis

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PD Dr. med. Dr. nat. med. Deniz Hos, Dept. of Ophthalmology, University of Cologne (Publications)
Prof. Dr. med. Jonathan Jantsch, Institute for Medical Microbiology, Immunology and Hygiene University of Cologne (Publications)

Both O₂ and Na⁺ are recognized as important regulators of immunity. The hypoxia-responsive signaling transduction and osmoprotective signaling pathways play a key role in adaptation to low O₂ tensions and to increased Na⁺ levels. Moreover, both signaling pathways contribute to inflammatory outputs and impact the ability of macrophages to fight (skin) infections. In addition, both O₂ and Na⁺ can impact skin hem- and lymphangiogenesis and might play a role in (neovascular) ocular surface diseases. Macrophages are important modulators of a variety of ocular surface diseases and play an important role in adaption of tissues to low O₂ tensions and in response to increased tissue tonicity. The oxygen (O₂)-responsive hypoxia-inducible factor (HIF)-prolyl hydroxylase domain (PHD) system, osmoprotective p38/MAPK activation and downstream NFAT5 play an important role in this respect. Furthermore, there is evidence that HIF stabilization can be increased by exposure to hypertonic conditions. Both regulatory systems may amplify inflammatory signaling of myeloid cells. Importantly, osmoprotective signaling can regulate lymphangiogenesis in skin.

Although the avascular cornea commonly suffers from hypoxic conditions and is in contact with the hyperosmolar tear film e.g. in dry eye disease, not much is known about the impact of the above-mentioned factors and signaling associated with low O₂ and high tonicity in myeloid cells on inflammatory corneal diseases. Here, we will test the hypothesis that inflammatory neovascular corneal diseases result in modification of corneal Na⁺ and oxygen levels and that local modification of HIF/PHD and osmoprotective signaling via p38/MAPK bears therapeutic potential in treating inflammatory (neovascular) corneal diseases.

Key methods: in-vivo mouse models, ELISA, qRT-PCR, FACS sorting, histology, immunohistochemistry, cell culture, RNA-seq

Prof. Dr. rer. nat. Alexander Steinkasserer, Dept. of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (Publications)
Dr. med. Antonia Howaldt, Dept. of Ophthalmology, CCSP (Cologne Clinician Scientist Program), University of Cologne (Publications)

Ocular surface inflammation is involved in multiple ophthalmological diseases leading to corneal hem- and lymphangiogenesis and hence to corneal blindness. Previous studies on autoimmunity and transplantation have shown that the soluble form of the CD83 molecule (sCD83) ameliorates inflammation via the induction of tolerogenic dendritic cells (tDCs) and alternatively activated macrophages (AAMs), both inducing resolution of inflammation and establishing long-term immune tolerance. We have previously shown that sCD83 prolongs the survival of corneal transplants in a high-risk murine keratoplasty model, which is mechanistically mediated via the upregulation of the immune modulators IDO and TGF-ß, leading to the induction/expansion of regulatory T cells (Tregs). Thrombospondin-1 (TSP-1) as a key activator of latent TGF-ß serves as a regulator of inflammatory immune responses and corneal lymphangiogenesis.

Mice lacking TSP-1 develop an immune-mediated form of dry eye disease which involves the maturation of antigen-presenting cells such as dendritic cells (DCs), T cell activation, and secretion of proinflammatory cytokines. In addition, Herpes viruses such as the Herpes simplex virus type 1 (HSV-1) can induce strong proinflammatory immune responses in the corneal stroma via activation of mature proinflammatory DCs and classically activated macrophages (CAMs), leading to herpetic stromal keratitis (HSK). For both conditions (i.e. dry eye and HSK), there is a great unmet medical need for novel therapeutic treatment options targeting inflammatory immune responses. In this project, the candidate will investigate the hypothesis thatr sCD83 can ameliorate ocular surface inflammation and associated (lymph)angiogenesis and induce long-term resolution of inflammation in the immune-mediated Thrombospondin-1 deficient dry eye disease and herpetic stromal keratitis. The knowledge gained in this project will improve our understanding of the basic concept of inflammatory eye disorders and may open avenues for new therapeutic strategies to treat patients with severe ocular surface inflammation.

Key methods: in vivo model of dry eye disease and herpetic stromal keratitis, flow cytometry, cytokine bead array, cell culture,  functional assays, IHC, IF, live cell imaging, qRT-PCR, scRNA-seq, bioinformatics, western blot

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Prof. Dr. rer. nat. Friedemann Kiefer, European Institute for Molecular Imaging, University of Münster, Münster (Publications)
PD Dr. med. Simona Schlereth, Dept. of Ophthalmology, University of Cologne, Cologne (Publications)

Lymphatic vessels are increasingly recognized for their specific roles in the support of organ function and the prevention of pathologies. Here, we focus on the conjunctival lymphatic vasculature and its role in immune cell migration in particular dendritic cell (DC) migration, which is implicated in allergic eye disease. Despite its important function and capacity to affect the distribution and trafficking of innate and adaptive immune cells directly, the precise micro-anatomy of the conjunctival lymphatic vessel bed remains unknown. Lymph vessels may aggravate or ameliorate immune responses depending on whether they transport pro- or anti-inflammatory acting cells.

Using light sheet fluorescence microscopy, we will image the complete murine conjunctival lymph vessel bed with cellular resolution in mouse strains with a strong and a weak natural lymphangiogenic ocular response.

We will address immune cell migration in a disease model of oak processionary moth (OPM) toxin-elicited conjunctivitis that is poorly investigated and mechanistically not understood. OPM outbreaks cause dermal, ophthalmic, and respiratory health problems that have been attributed to exceptionally stable toxins in the burn hairs of OPM caterpillars. In strongly infested areas OPM may affect up to 0.1% of the population. Despite this impact, only two highly related allergenic proteins, termed thaumetopoeins, have been identified and molecularly cloned in the closely related pine processionary moth so far. Moreover, their biological activity has not yet been investigated.

Dendritic cells (DCs) have already been identified as efficient modulators of conjunctival allergy. Therefore, we focus on this immune cell type and address DC migration during development and resolution of the OPM-toxin response. Our investigation of the lymph vessel - DC axis in allergic conjunctivitis is motivated by the aim to identify new opportunities for treatment interventions.

Key methods: in vivo conjunctivitis model, intravital multiphoton microscopy (MPM), light sheet fluorescence microscopy, immunohistochemistry, ELISA

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Dr. med. Hanhan Liu, Dept. of Ophthalmology, CCSP (Cologne Clinician Scientist Program), University of Cologne (Publications)
Prof. Dr. rer. nat. Aleksandra Trifunovic, CECAD, Institute for Mitochondrial Diseases, University of Cologne (Publications)

Glaucoma is an age-associated disease characterized by progressive retinal ganglion cell (RGC) loss and degeneration of optic nerve axons and the leading cause of irreversible blindness worldwide. An estimated 57.5 million people worldwide are affected by primary open angle glaucoma (POAG) with a prevalence of 2.4%. Increased intraocular pressure (IOP) is a main risk factor for development of glaucoma and lowering IOP is the most common treatment to slow disease progression. However, about one third of patients develop normal tension glaucoma (NTG), while some people with elevated IOP never develop the disease. Also, progression of the neurodegeneration is observed even in patients with pharmacologically controlled IOP.

Despite the lack of understanding of the exact mechanism that initiates the pathogenesis of glaucoma, mitochondrial dysfunction is believed to be responsible for the development and progression of glaucoma. In agreement, increased levels of mtDNA mutations are found to be associated with RGC death in both glaucoma patients and an experimental glaucoma model. While respiratory chain deficiency was considered to be the main causal link to most pathologies arising from mitochondrial dysfunction, the discovery of mitochondrial damage-associated molecular patterns (mtDAMPs) adds another layer to the complexity of putative involvement of mitochondrial dysfunction in glaucoma, in particular in the immune cell activation and subsequent neuroinflammation.

Although it is well known that glaucomatous damage is associated with mitochondrial dysfunction linked to higher levels of mtDNA mutations and neuroinflammation, the causative link between the accumulation of mtDNA mutations and neuroinflammation in glaucoma has not been studied. In this project, the candidate will investigate the hypothesis is that neuroinflammation is central in glaucoma, and that increased mtDNA damage causes inflammation by activating microglia in retina rendering RGCs vulnerable to external stimuli.

Key methods:  in vivo transgenic and induced glaucoma models, IF, mtDNA sequencing, mitochondrial characterization techniques, proteomics, scRNA-seq, protein and RNA analysis 

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Prof. Dr. rer.  nat. Stefan Schulte-Merker, Institute for Cardiovascular Organogenesis and Regeneration, Westphalian Wilhelms University Münster (Publications)
Prof. Dr. med. Verena Prokosch, Department of Ophthalmology, University of Cologne (Publications)

The Schlemm’s canal (SC) controls intraocular pressure (IOP) by drainage of the aqueous humor from the eye. Increased resistance to aqueous humor outflow through this system raises IOP and causes glaucoma. IOP is the main risk factor of glaucoma development and progression. Glaucoma is a leading cause of blindness. Our understanding of the pathophysiological changes of IOP increase is scarce. Hence, there is an unmet need for new treatment options to lower IOP.

 To date, it is unknown which changes in SC function cause the pathological increase in IOP. It was only recently discovered that the SC consists of a highly organized, unique hybrid vascular structure combining distinct lymphatic and blood vascular endothelial features (‘atypical lymphatic vessel’). The SC itself is covered by trabecular meshwork cells facing the anterior chamber of the eye. However, most glaucoma studies focus on the trabecular meshwork rather than the SC itself. Analysis of the newly discovered lymphatic features of the SC offers a new understanding of the pathophysiology of IOP increase and provides novel treatment options in different forms of glaucoma.

The student will analyse the role of known glaucoma risk factors in relation to SC function. Specifically the will aim to: 1) describe in detail new pre-clinical Svep1+/- and Svep1/Tie2 +/- mouse models for increased IOP, (2) assess correlated protein expression changes in normal and glaucoma human tissue, (3) decipher the mode of action of SVEP1-mediated regulation of TIE-1/-2/ANG signalling, and (4) develop a new therapeutic treatment/prevention option for glaucoma via activation of TIE1/-2 signalling in SC through providing recombinant SVEP1 protein.

Key methods: in vivo transgenic models, morphometric analysis, IF, cell culture assays, FISH, RNA and protein analysis, cell signalling methodologies; pre-clinical testing

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Prof. Dr. med. Dr. phil. Ludwig M. Heindl, Dept. of Ophthalmology and Center for Integrated Oncology (CIO), University of Cologne (Publications)
Dr. med. Jacobus J. Bosch, Center for Human Drug Research (CHDR), Leiden; Dept. of Ophthalmology and Center for Integrated Oncology (CIO), University of Cologne (Publications)

Ocular melanoma is the most frequent cancer entity in the eye in adults and mainly originates in the uveal tract and conjunctiva. Thus, there are plenty of treatment options for primary uveal and conjunctival melanoma, there is urgent need for therapy options for metastatic uveal and conjunctival melanoma. To develop effective therapies, it is of utmost importance to understand the underlying cellular and molecular mechanisms behind metastasis in ocular melanoma. In our preliminary studies, we were able to identify that peritumoral outgrowth of new lymphatics from pre-existing vessels is  a decisive risk factor for  metastatic spread and a poor prognostic indicator in ocular melanoma. In this course we were also able to detect midkine, a novel player in tumorigenesis of ocular melanoma. Midkine is a key cytokine in tumor-associated lymphangiogenesis, metastasis and immune cell filtration. Extensive analysis of other potential targets has identified two additional important proteins that have potential roles in tumor progression, metastasis, and lymphangiogenesis in ocular melanoma: NRP2 and sFLT1.

In the present project, the characterization of molecular signaling pathways involving midkine will be studied in more detail, by using in vitro and in vivo approaches. Our long-term goal is to be able to translate our findings into clinically used (neo)adjuvant therapeutic strategies in order to improve the recurrence-free and metastasis-free survival rates of ocular melanoma patients.

To carry out this project, the student will employ methods including in vitro and in vivo cancer models, CRISPR-Cas9 technology and pathway analysis, in vitro functional assays and RNA/Protein analysis.

PD Dr. med. Simona Schlereth, Dept. of Ophthalmology, University of Cologne (Publications)
Prof. Dr. rer. nat. Thomas Wunderlich, MPI for Metabolic Research, University of Cologne (Publications)

Conjunctival melanoma (CM) is a rare and potentially fatal malignant tumor on the mucosa of the ocular surface. The molecular and cellular nature of CM, however, is still largely unknown. Due to some similarities to the better-studied cutaneous melanoma, novel therapies for cutaneous melanoma, such as immune checkpoint inhibitors, may benefit patients with metastatic CM. Checkpoint inhibitors promote inflammation and thus the antitumor immune response. To date, only case reports of metastatic CM patients treated with immunotherapy have been published. Hence, there is an urgent need to better understand the immunological responses against CM and to define new therapeutic targets. Our research hypothesis addresses immunomodulatory therapies in CM and understanding the immunological background of the disease, particularly the cellular and molecular aspects of the tumor microenvironment (TME). The TME has a critical impact on carcinogenesis by promoting protumoral immunosuppression and contributing to metastasis and tumor angiogenesis. Published and preliminary work by our groups shows that inflammatory cytokines, particularly osteopontin (OPN) and interleukin-6 (IL-6) as well as dendritic cells (DCs) are important in carcinogenesis of various tumors We therefore hypothesize that inflammatory cytokines such as IL-6 and OPN are essential for CM and represent a therapeutic target. To confirm the hypothesis, the student will employ techniques including transgenic models, single nucleus sequencing, transgenic mouse models, melanoma mouse models, transcriptional profiling, immunocytochemistry, in vitro functional assays, FACS analysis.

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Prof. Dr. rer. nat. Thomas Langmann, Dept. of Ophthalmology, University of Cologne (Publications)
Prof. Dr. med. Dr. nat. med. Adele Rüger, Dept. of Neurology, University of Cologne (Publications)

Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Retinal microglia, the tissue resident immune cells, play pivotal roles in innate immune responses and regulation of tissue integrity. While a short period of microglia activation supports homeostasis, chronic microglia reactivity represents a driving force for retinal cell death and disease. We have previously shown that polysialic acids form a protective layer on retinal cells and that their binding to microglial receptors is strongly anti-inflammatory, indicating a crucial role for glycoproteins in retinal immunity. In very recent experiments, we demonstrated that galectin-3, a member of the β-galactoside-binding lectin family is strongly upregulated in reactive microglia in retinas of dry AMD patients and in two different corresponding mouse models. In this project, the student will identify the role of dysregulated galectins in AMD with a focus on microglia reactivity, neurodegeneration and neovascularization in the retina. The techniques that will be used to carry out the project will include in vitro and animal models, immunohistochemistry, FISH, ELISAs, RNA analysis, pathway and cell signaling analysis, cell transcriptomics.

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Dr. rer. nat. Anne Wolf, Dept. of Ophthalmology, University of Cologne (Publications)

Age-related macular degeneration (AMD) is a heterogeneous and progressive chronic disease of the central retina and a leading cause of vision loss among the elderly in the western world. While the etiology of AMD is still not well understood, we and others have shown that local microglia are key players. Targeting of translocator protein (TSPO), a biomarker of brain microgliosis, improved disease outcome in various preclinical model systems of inflammatory diseases. The precise molecular mechanisms underlying these processes, however, remain to be elucidated.

The overall goal of this project is to increase our understanding of how the TSPO/Nox/ROS axis drives retinal inflammatory diseases, such as AMD. To address this, the student will utilise methods including transgenic animal models, FACS, RNA sequencing, proteomics/phosphoproteomics, Immunohistochemistry.

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Prof. Dr. med. Tim U. Krohne, Dept. of Ophthalmology, University of Cologne (Publications)

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in developed countries, and effective treatment options for the blinding atrophic late stage of the disease are lacking. Hence, there is a high unmet medical need for new therapies for atrophic AMD. Accumulating oxidative/photooxidative damage to the retinal pigment epithelium (RPE), progressive deposition of lipofuscin within the RPE, and chronic local activation of the innate immune system in the outer retina are all factors that are demonstrated to be crucially involved in AMD development and progression. A central regulator of the innate immune system is the intracellular protein complex called ‘the inflammasome’. Inflammasomes act as intracellular sensors for a variety of cellular danger signals and controls the cellular release of highly inflammatory cytokines such as IL-1β and IL-18. Activation of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been demonstrated in the RPE and retina of patients with atrophic AMD.

We have investigated the mechanisms of interactions between the above-mentioned factors of AMD pathogenesis. We have identified lipofuscin-mediated photooxidative damage to lysosomal membranes as a trigger of NLRP3 inflammasome activation in the RPE that may contribute to AMD. We also demonstrated cross-talk of the NLRP3 signaling pathway in the RPE with retinal microglia  and the complement system, and we characterized the mechanisms of RPE cell death in response to NLRP3 inflammasome activation.

In this project, we aim to further elucidate the role of inflammasome activation in atrophic AMD and to develop immunomodulatory treatment strategies. For this, we will investigate NRLP3 inflammasome activation triggered by lipofuscin-mediated photooxidative damage to the RPE, using novel in vivo mouse and ex vivo retinal tissue culture models of AMD. We seek to identify the molecular mechanisms and retinal cell types affected and to test the efficacy of selective NLRP3 inhibitory compounds in suppressing these processes in the retina, thus providing the groundwork for the development of inflammasome inhibitors as a potential treatment for atrophic AMD.

Prof. Dr. phil. Manuel Koch, Institute for Oral and Musculoskeletal Biology, Center for Biochemistry, University of Cologne, Cologne (Publications)

A key goal of our CRC is translating preclinical discoveries into clinical application. Major recent advances in ophthalmology depended on the development of new protein therapeutics (e.g. Aflibercept, Eylea, Ranibizumab and Faricimab in the treatment of AMD). Protein therapeutics include peptides, proteins, monoclonal antibodies, cytokine traps as well as fusion proteins. Commercially available recombinant proteins and therapeutic antibodies are often difficult to obtain in the desired quantity and purity and are very expensive to purchase for in vivo experiments at the University. Within this consortium, this project will provide rapid access to affordable, customized, and large quantity of new protein therapeutics for (i) mechanistic preclinical studies in vitro and in vivo and (ii) translational research in ophthalmology including in situ human tissue experiments.

Newly discovered target proteins from participating projects can either be applied as soluble proteins or inhibited by antibodies or receptor traps, depending on their function. We will also assist in the identification and cloning of therapeutic antibodies using phage display techniques or humanized mouse/rabbit models. In addition, we established cross-linking experiments to define the protein-protein or protein-receptor interaction sites using mass spectrometry, which will allow us to further improve and validate the therapeutic candidates.

Key methods: cloning, phage display, B-cell sorting, cell culture, bacterial culture, chromatography, protein production, Biacore

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Prof. Dr. Felix Bock, Dept. of Ophthalmology, University of Cologne, Cologne (Publications)

Aim of the proposed CRC is to gain a better understanding of the pathogenesis of age-related ocular diseases characterized by aberrant (lymph)angiogenesis and inflammation. Based on the yielded knowledge and insights, new therapies shall be designed for age-related ocular diseases. The proposed Imaging Core Unit (ICU) will contribute to this goal by supporting the research projects that are part of this CRC (A01-C07) through giving access to (already available) cutting edge technology to image ocular structures in health and disease. The Imaging Core Unit will provide imaging solutions and analysis tools for preclinical in-vitro and in-vivo studies as well as clinical studies of the CRC projects later on. In all projects cellular processes of inflammation will be analyzed. Therefore, especially intravital, real-time and non- to minimally invasive imaging is needed in order to capture and follow the induced alterations in animal experiments. The same holds true for (lymph)vascular alterations.

Therefore, the Imaging Core Unit (ICU) will provide comprehensive and efficient service in biomedical imaging. The ICU already offers state-of-the-art platforms for fast multi-image fluorescence microscopy, automated high-throughput live cell microscopy, intravital retinal and corneal imaging microscopy. As a unique feature the unit provides OCT, OCT angiography, and microscopic OCT for small animals bundled in an experimental OCT workstation. The ICU will provide access, training, and support to the members of the CRC in the use of all the imaging devices and analysis tools already available. According to the different needs of the projects, the choice of the right device will be evaluated. In cooperation with the projects, devices and analysis tools will be adapted to the according scientific question. The Imaging Core Unit will support all projects in conducting fluorescence microscopy, live-cell imaging, OCT-imaging, fluorescence angiography, image analysis and data banking. Image analysis will include quantification of 2D and 3D data sets of blood vessels, calculation of blood flow velocities or correlation of fluorescence angiography with OCT images. Algorithms within existing software for quantitative analysis will be provided to enable rapid analysis of large multidimensional data sets. Furthermore, the ICU will develop further standardized, highly qualitative data analysis methods in close cooperation with the individual projects, especially with the INF project (Z05). As a result, highly reliable and innovative imaging data sets will be generated.

Become part of our team. We are looking for a Physicist or scientist specialized in imaging.

Prof. Dr. med. Claus Cursiefen, Dept. of Ophthalmology, Center for Molecular Medicine Cologne (CMMC), University of Cologne (Publications)

Central project Z03 involves the overall coordination and management of the CRC.

Prof. Dr. med. Verena Prokosch, Dept. of Ophthalmology, University of Cologne, Cologne (Publications)
Prof. Dr. rer. nat. Felix Bock, Dept. of Ophthalmology, University of Cologne, Cologne (Publications)

The Integrated Research Training Group on Eye and Inflammation (EI) is specifically designed for early career researchers including graduate and undergraduate students participating in the CRC 1607. The overall goal of the IRTG is to implement a comprehensive and exceptional educational and mentoring platform with a specific focus on the eye, specifically dedicated to the graduate and undergraduate students from the Faculties of Medicine and Natural Sciences participating in the projects of the CRC 1607. Clear focus will be placed on translational training in the following topics: OPHTHALMOLOGY, EYE RESEARCH, OCULAR INFLAMMATION and LYMPHANGIOGENESIS.

Prof. Dr. Katharzyna Bozek, CMMC,  Datascience of Bioimages, University of Cologne, Cologne (Publications)
Prof. Dr. Oya Beyan, Institute for Medical Informatics, University of Cologne (Publications)

The goal of this central INF project is to provide software and hardware infrastructure and methodology for storage, management, retrieval and analysis of the data generated within the CRC 1607, with particular focus on images. Almost every project in this consortium will generate imaging data and will also be linked to the central project Z02. Among various data modalities exploited in this CRC, images will undeniably play a central role. To address the needs and challenges of data handling as well as to make the best quantitative and qualitative use of the experimental outputs of this CRC, we will build data repositories and image analysis pipelines that are applicable across all of its research projects.