Prof. Dr. Dennis Özcelik

Biochemie und Gentechnik

+49 8161 71-4522

Adresse: A3.411
Am Hofgarten 10
85354 Freising
Funktionen: Laborleitung Biochemie und Gentechnik
Beirat im BayWISS-Verbundkolleg Gesundheit
Fakultät: Fakultät Bioingenieurwissenschaften

Sprechzeiten: nach Vereinbarung

Lehre
Biochemie
Gentechnik
Bioanalytik
Fachliche Schwerpunkte
Arzneimittelforschung und -entwicklung
Pharmakologie und Translationale Biologie
Präzisionsmedizin und KI
Beruflicher Werdegang
Principal Scientist, Translational Biomarkers, Evotec SE, Hamburg, Deutschland
Senior Research Scientist, Translational Biomarkers, Evotec SE, Hamburg, Deutschland
Information Consultant Life Sciences, Informationszentrum Chemie | Biologie | Pharmazie, ETH Zürich, Schweiz
Assistant Professor of Drug Design and Pharmacology, Center for Biopharmaceuticals, University of Copenhagen, Dänemark
Postdoctoral Fellow of the Canadian Institutes of Health Research, National Research Council of Canada & University of Ottawa, Kanada
Postdoktorand, Department of Molecular Genetics, University of Toronto, Kanada
Doktorand, Institut für Molekularbiologie und Biophysik, ETH Zürich, Schweiz
Research Assistant, Academic Medical Center, Niederlande
Diplomand, Molecular, Cellular & Developmental Biology, University of Michigan, Ann Arbor, USA
Studium der Biologie (Diplom), Universität Tübingen, Deutschland
Mitgliedschaften
Deutsche Gesellschaft für Biochemie und Molekularbiologie (GBM)
Deutsche Gesellschaft für Immunologie (DGfI)

Publikationen

Wissenschaftliche Artikel
- Shawna M. Henry, Sabrina A. Kistler, Gavin D. Lagani, Christian R.O. Bartling, Dennis Özcelik, Vita Sereikaite, Kristian Stro̷mgaard, Uwe Beffert, Angela Ho
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Tight control of the APP-Mint1 interaction in regulating amyloid production (2023) Brain Research 1817 , S. 148496. DOI: 10.1016/j.brainres.2023.148496
  
  Generation of amyloid-β (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is a pathogenic event in Alzheimer’s disease (AD). APP is a transmembrane protein and endocytosis of APP mediated by the YENPTY motif is a key step in Aβ generation. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP trafficking and processing. Here, we generated and examined two Mint1 mutants, Tyr633Ala of Mint1 (Mint1Y633A) that enhanced APP binding, and Tyr549Ala and Phe610Ala mutant (Mint1Y549A/F610A), that reduced APP binding. We investigated how perturbing the APP-Mint1 interaction through these Mint1 mutants alter APP and Mint1 cellular dynamics and Mint1′s interaction with its other binding partners. We found that Mint1Y633A increased binding affinity specifically for APP and presenilin1 (catalytic subunit of γ-secretase), that subsequently enhanced APP endocytosis in primary murine neurons. Conversely, Mint1Y549A/F610A exhibited reduced APP affinity and Aβ secretion. The effect of Mint1Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins supporting the APP-Mint1 interaction is a critical factor in Aβ production. Altogether, this study highlights the potential of targeting the APP-Mint1 interaction as a therapeutic strategy for AD.
  Mehr
- Christian R. O. Bartling, Flora Alexopoulou, Sarah Kuschert, Yanni K.-Y. Chin, Xinying Jia, Vita Sereikaite, Dennis Özcelik, Thomas M. Jensen, Palash Jain, Mads M. Nygaard, Kasper Harpsøe, David E. Gloriam, Mehdi Mobli, Kristian Strømgaard
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Comprehensive peptide cyclization examination yields optimized APP scaffolds with improved affinity toward Mint2 (2023) Journal of Medicinal Chemistry 2023 , S. 3045–3057. DOI: 10.1021/acs.jmedchem.2c02017
  
  Peptides targeting disease-relevant protein–protein interactions are an attractive class of therapeutics covering the otherwise undruggable space between small molecules and therapeutic proteins. However, peptides generally suffer from poor metabolic stability and low membrane permeability. Hence, peptide cyclization has become a valuable approach to develop linear peptide motifs into metabolically stable and potentially cell-permeable cyclic leads. Furthermore, cyclization of side chains, also known as “stapling”, can stabilize particular secondary peptide structures. Here, we demonstrate that a comprehensive examination of cyclization strategies in terms of position, chemistry, and length is a prerequisite for the selection of optimal cyclic peptide scaffolds. Our systematic approach identifies cyclic APP dodecamer peptides targeting the phosphotyrosine binding domain of Mint2 with substantially improved affinity. We show that especially all-hydrocarbon stapling provides improved metabolic stability, a significantly stabilized secondary structure and membrane permeability.
  Mehr
- Jean-Pierre Delord, Frédérique Dol-Gleizes, Françoise Bono, Isabelle Blanc, Antoine Alam, Ian Hunneyball, Mark Whittaker, Pierre Fons, Michael R. Paillasse, Michael Esquerré, Florie A. Bertrand, Céline Poussereau-Pomié, Mélanie Pichery, Virgile Visentin, Geneviève Gueguen-Dorbes, Florence Gaujarengues, Pauline Barron, Gaelle Badet, Anne Briaux, Pierre-Benoit Ancey, David Sibrac, Eric Erdociain, Dennis Özcelik, Jérôme Meneyrol, Valérie Martin, Anne Gomez-Brouchet, Janik Selves, Philippe Rochaix, Maxime Battistella, Céleste Lebbé
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Targeting tumor angiogenesis with the selective VEGFR-3 inhibitor EVT801 in combination with cancer immunotherapy (2022) Cancer Research Communications 2 (11), S. 1504–1519. DOI: 10.1158/2767-9764.CRC-22-0151
  
  The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3–positive tumors, and in tumors with VEGFR-3–positive microenvironments. EVT801 suppressed VEGF-C–induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors.
  Mehr
- Nicolas Banholzer, Adrian Lison, Dennis Özcelik, Tanja Stadler, Stefan Feuerriegel, Werner Vach
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  The methodologies to assess the effects of non-pharmaceutical interventions during COVID-19: a systematic review (2022) European Journal of Epidemiology 37 , S. 1003–1024. DOI: 10.1007/s10654-022-00908-y
  
  Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around theworld to control the spread of SARS-CoV-2. Their effectiveness in improving health-related outcomes has been the subjectof numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflectingthe absence of an established methodological framework. On the one hand, variation in methodologies may be desirable toassess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. Toestablish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessingthe effectiveness of non-pharmaceutical interventions between January 1, 2020 and January 12, 2021 (n = 248). We identifiedsubstantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach,and effectiveness assessment. On this basis, we point to shortcomings of existing studies and make recommendations forthe design of future studies.
  Mehr
- Martin Bellgardt, Dennis Özcelik, Andreas Friedrich Christoph Breuer-Kaiser, Claudia Steinfort, Thomas Georg Karl Breuer, Thomas Peter Weber, Jennifer Herzog-Niescery
  
  Berechtigungen: Peer Reviewed
  
  Extracorporeal membrane oxygenation and inhaled sedation in COVID-19-related acute respiratory distress syndrome (2021) World Journal of Critical Care Medicine 10 (6), S. 323-333. DOI: 10.5492/wjccm.v10.i6.323
  
  Coronavirus disease 2019 (COVID-19) related acute respiratory distress syndrome (ARDS) is a severe complication of infection with severe acute respiratory syndrome coronavirus 2, and the primary cause of death in the current pandemic. Critically ill patients often undergo extracorporeal membrane oxygenation (ECMO) therapy as the last resort over an extended period. ECMO therapy requires sedation of the patient, which is usually achieved by intravenous administration of sedatives. The shortage of intravenous sedative drugs due to the ongoing pandemic, and attempts to improve treatment outcome for COVID-19 patients, drove the application of inhaled sedation as a promising alternative for sedation during ECMO therapy. Administration of volatile anesthetics requires an appropriate delivery. Commercially available ones are the anesthetic gas reflection systems AnaConDa® and MIRUSTM, and each should be combined with a gas scavenging system. In this review, we describe respiratory management in COVID-19 patients and the procedures for inhaled sedation during ECMO therapy of COVID-19 related ARDS. We focus particularly on the technical details of administration of volatile anesthetics. Furthermore, we describe the advantages of inhaled sedation and volatile anesthetics, and we discuss the limitations as well as the requirements for safe application in the clinical setting.
  Mehr
- Eduardo Felipe Alves Alves Fernandes, Dennis Özcelik
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Imaging biomarkers for monitoring the inflammatory redox landscape in the brain (2021) Antioxidants 10 (4), S. 528. DOI: 10.3390/antiox10040528
  
  Inflammation is one key process in driving cellular redox homeostasis toward oxidative stress, which perpetuates inflammation. In the brain, this interplay results in a vicious cycle of cell death, the loss of neurons, and leakage of the blood-brain barrier. Hence, the neuroinflammatory response fuels the development of acute and chronic inflammatory diseases. Interrogation of the interplay between inflammation, oxidative stress, and cell death in neurological tissue in vivo is very challenging. The complexity of the underlying biological process and the fragility of the brain limit our understanding of the cause and the adequate diagnostics of neuroinflammatory diseases. In recent years, advancements in the development of molecular imaging agents addressed this limitation and enabled imaging of biomarkers of neuroinflammation in the brain. Notable redox biomarkers for imaging with positron emission tomography (PET) tracers are the 18 kDa translocator protein (TSPO) and monoamine oxygenase B (MAO-B). These findings and achievements offer the opportunity for novel diagnostic applications and therapeutic strategies. This review summarizes experimental as well as established pharmaceutical and biotechnological tools for imaging the inflammatory redox landscape in the brain, and provides a glimpse into future applications.
  Mehr
- Dennis Özcelik
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Chemical biology – a toolbox to unlock neurochemical epigenetics (2020) Neural Regeneration Research 16 (2), S. 298–299. DOI: 10.4103/1673-5374.290890
  
  Mehr
- Dennis Özcelik
  
  Berechtigungen: Peer Reviewed
  
  Treatment of neuroblastoma cells with inhibitors of protein disulfide isomerase upregulates NQO1 activity (2020) Chemical Research in Toxicology 33 (8), S. 2099-2107. DOI: 10.1021/acs.chemrestox.0c00101
  
  Hallmarks of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease include oxidative stress, accumulation of unfolded proteins, and neuronal cell death. One key player in maintaining redox homeostasis and oxidative protein folding is the protein disulfide isomerase (PDI). PDI has been the focus of drug discovery studies in neurodegenerative diseases, which have reported, paradoxically, that PDI inhibition is neuroprotective in cellular disease models. This study investigated the molecular implications of PDI inhibition by examining the effect of the PDI inhibitors securinine and 16F16 on the gene expression profile of SH-SY5Y neuroblastoma cells. Microarray analysis identified 36 genes that were differentially expressed in both inhibitor treatments. Computational approaches revealed that these differentially expressed genes are involved in apoptosis and cell death and that they are part of a protein–protein interaction network. Among the 36 identified genes, NAD(P)H quinone dehydrogenase 1 (NQO1) displayed the highest average expression change. As a central player in the cellular oxidative stress response, NQO1 was the focus of further investigation. Immunoblotting confirmed the increased expression level of NQO1, and activity assays demonstrated substantial increases in NQO1 activity in SH-SY5Y cells after treatment with PDI inhibitors. In summary, this study suggests a novel link between PDI inhibition and NQO1 activity, providing insights into the dynamic interplay between protein folding, oxidative stress, and cell death in neurodegenerative diseases, which can be exploited for drug development in the future.
  Mehr
- Dilip Narayanan, Sana Ma, Dennis Özcelik
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  Targeting the redox landscape in cancer therapy (2020) Cancers 12 (7), S. 1706. DOI: 10.3390/cancers12071706
  
  Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, in order to restore redox homeostasis. Mutations in the redox landscape can induce carcinogenesis, whereas increased ROS production can perpetuate cancer development. Moreover, cancer cells can increase production of antioxidants, leading to resistance against chemo- or radiotherapy. Research has been developing pharmaceuticals to target the redox landscape in cancer. For instance, inhibition of key players in the redox landscape aims to modulate ROS production in order to prevent tumor development or to sensitize cancer cells in radiotherapy. Besides the redox landscape of a single cell, alternative strategies take aim at the multi-cellular level. Extracellular vesicles, such as exosomes, are crucial for the development of the hypoxic tumor microenvironment, and hence are explored as target and as drug delivery systems in cancer therapy. This review summarizes the current pharmaceutical and experimental interventions of the cancer redox landscape.
  Mehr
- Ali Farzam, Karan Chohan, Miroslava Strmiskova, Sarah J. Hewitt, David S. Park, John Paul Pezacki, Dennis Özcelik
  
  Berechtigungen: Open Access
  
  Berechtigungen: Peer Reviewed
  
  A functionalized hydroxydopamine quinone links thiol modification to neuronal cell death (2019) Redox Biology 28 , S. 101377. DOI: 10.1016/j.redox.2019.101377
  
  Recent findings suggest that dopamine oxidation contributes to the development of Parkinson's disease (PD); however, the mechanistic details remain elusive. Here, we compare 6-hydroxydopamine (6-OHDA), a product of dopamine oxidation that commonly induces dopaminergic neurodegeneration in laboratory animals, with a synthetic alkyne-functionalized 6-OHDA variant. This synthetic molecule provides insights into the reactivity of quinone and neuromelanin formation. Employing Huisgen cycloaddition chemistry (or “click chemistry”) and fluorescence imaging, we found that reactive 6-OHDA p-quinones cause widespread protein modification in isolated proteins, lysates and cells. We identified cysteine thiols as the target site and investigated the impact of proteome modification by quinones on cell viability. Mass spectrometry following cycloaddition chemistry produced a large number of 6-OHDA modified targets including proteins involved in redox regulation. Functional in vitro assays demonstrated that 6-OHDA inactivates protein disulfide isomerase (PDI), which is a central player in protein folding and redox homeostasis. Our study links dopamine oxidation to protein modification and protein folding in dopaminergic neurons and the PD model.
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Alle Wissenschaftliche Artikel
Buchbeiträge
- Dennis Özcelik, Filippo Andreetta, Elizabeth L. van der Kam
  
  Translational Pharmacology and Biomarkers: Unlocking GPCR Drug Discovery (2026) Comprehensive Medicinal Chemistry, 4th edition , S. 517-545. DOI: 10.1016/B978-0-443-29808-0.00036-4
  
  Biomarkers, measurable indicators of biological states and conditions, have become pivotal in advancing research and development for novel therapeutics and diagnostics. This chapter describes the different types of biomarkers for either disease or for response to treatment, and how biomarkers fit into the drug development process. They help identify target populations, reduce clinical trial sizes, and accelerate the approval processes of novel drugs. Further, biomarker enable more precise monitoring of treatment effects and patients’ responses. Moreover, they facilitate tailored treatment based on individual biomarker profiles, which is known as precision medicine. This chapter provides multiple examples of biomarkers use cases for GPCRs. The chapter ends with a discussion on the need for validation and standardization as well as how artificial intelligence and machine learning impact biomarker discovery.
  Mehr

Zurück zur Übersicht

Prof. Dr. Dennis Özcelik

Lehre

Fachliche Schwerpunkte

Beruflicher Werdegang

Mitgliedschaften

Publikationen

Wissenschaftliche Artikel

Tight control of the APP-Mint1 interaction in regulating amyloid production (2023) Brain Research 1817 , S. 148496. DOI: 10.1016/j.brainres.2023.148496

Comprehensive peptide cyclization examination yields optimized APP scaffolds with improved affinity toward Mint2 (2023) Journal of Medicinal Chemistry 2023 , S. 3045–3057. DOI: 10.1021/acs.jmedchem.2c02017

Targeting tumor angiogenesis with the selective VEGFR-3 inhibitor EVT801 in combination with cancer immunotherapy (2022) Cancer Research Communications 2 (11), S. 1504–1519. DOI: 10.1158/2767-9764.CRC-22-0151

The methodologies to assess the effects of non-pharmaceutical interventions during COVID-19: a systematic review (2022) European Journal of Epidemiology 37 , S. 1003–1024. DOI: 10.1007/s10654-022-00908-y

Extracorporeal membrane oxygenation and inhaled sedation in COVID-19-related acute respiratory distress syndrome (2021) World Journal of Critical Care Medicine 10 (6), S. 323-333. DOI: 10.5492/wjccm.v10.i6.323

Imaging biomarkers for monitoring the inflammatory redox landscape in the brain (2021) Antioxidants 10 (4), S. 528. DOI: 10.3390/antiox10040528

Chemical biology – a toolbox to unlock neurochemical epigenetics (2020) Neural Regeneration Research 16 (2), S. 298–299. DOI: 10.4103/1673-5374.290890

Treatment of neuroblastoma cells with inhibitors of protein disulfide isomerase upregulates NQO1 activity (2020) Chemical Research in Toxicology 33 (8), S. 2099-2107. DOI: 10.1021/acs.chemrestox.0c00101

Targeting the redox landscape in cancer therapy (2020) Cancers 12 (7), S. 1706. DOI: 10.3390/cancers12071706

A functionalized hydroxydopamine quinone links thiol modification to neuronal cell death (2019) Redox Biology 28 , S. 101377. DOI: 10.1016/j.redox.2019.101377

Buchbeiträge

Translational Pharmacology and Biomarkers: Unlocking GPCR Drug Discovery (2026) Comprehensive Medicinal Chemistry, 4th edition , S. 517-545. DOI: 10.1016/B978-0-443-29808-0.00036-4