A5024289997- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Photoreceptor and optogenetics research
- Neonatal Respiratory Health Research
- Immune cells in cancer
- Hearing, Cochlea, Tinnitus, Genetics
- Connexins and lens biology
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Inflammasome and immune disorders
- interferon and immune responses
- Immune Response and Inflammation
- Pediatric health and respiratory diseases
- Neuroscience and Neural Engineering
- Cellular transport and secretion
- RNA regulation and disease
- Cancer Research and Treatments
- Neuroscience and Neuropharmacology Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cholesterol and Lipid Metabolism
- Immunotherapy and Immune Responses
- Pneumonia and Respiratory Infections
- CRISPR and Genetic Engineering
- bioluminescence and chemiluminescence research
- Asthma and respiratory diseases
- Erythropoietin and Anemia Treatment
University of Freiburg
2013-2023
Eisai (Germany)
2023
Johannes Gutenberg University Mainz
2007-2022
Institute of Neuroimmunology of the Slovak Academy of Sciences
2019
Synovo (Germany)
2018
Icahn School of Medicine at Mount Sinai
2016
Research Center Borstel - Leibniz Lung Center
2011-2016
University Medical Center Freiburg
2012-2016
University of Lübeck
2011
Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, systemic features at birth resembling the sequelae of congenital infection but in absence an infectious agent. Genetic defects resulting activation type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which a PTS. Ubiquitin-specific peptidase 18 (USP18) key negative regulator I IFN signaling. In this study, we identified...
The human Usher syndrome (USH) is the most frequent cause of combined deaf-blindness. USH genetically heterogeneous with at least 12 chromosomal loci assigned to three clinical types, USH1-3. Although these types exhibit similar phenotypes in human, corresponding gene products belong very different protein classes and families. scaffold harmonin (USH1C) was shown integrate all identified USH1 USH2 molecules into networks. Here, we analyzed a network organized absence by proteins SANS (USH1G)...
Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous the absence neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies brain, as well reduction dopaminergic neurons defective dopamine...
For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in rhodopsin gene. Validation a mutation-independent suppression and replacement therapy for this disorder undertaken. The provides means correcting defect manner thereby circumventing diversity. Separate adeno-associated virus (AAV) vectors were used...
Protein modification by the ubiquitin-like protein ISG15 is an interferon (IFN) effector system, which plays a major role in antiviral defense. counteracted isopeptidase USP18, negative regulator of IFN signaling, was also shown to exert its regulatory function isopeptidase-independent manner. To dissect enzymatic and nonenzymatic functions USP18 vivo, we generated knock-in mice (USP18(C61A/C61A)) expressing enzymatically inactive USP18. USP18(C61A/C61A) displayed increased levels...
Similar to the brain, eye is considered an immune-privileged organ where tissue-resident macrophages provide major immune cell constituents.However, little known about spatially restricted macrophage subsets within different compartments with regard their origin, function, and fate during health disease.Here, we combined single-cell analysis, mapping, parabiosis, computational modeling comprehensively examine myeloid in distinct parts of homeostasis.This approach allowed us identify...
The rd1 natural mutant is one of the first and probably most commonly studied mouse model for retinitis pigmentosa (RP), a severe frequently blinding human retinal degeneration. In several decades research, link between increase in photoreceptor cGMP levels extremely rapid cell death gave rise to number hypotheses. Here, we provide clear evidence that presence cyclic nucleotide gated (CNG) channels outer segment membrane key rod loss. Cngb1−/−× double mutants devoid regular CNG channels, are...
Abstract Translational read‐through‐inducing drugs (TRIDs) promote read‐through of nonsense mutations, placing them in the spotlight current gene‐based therapeutic research. Here, we compare for first time relative efficacies new‐generation aminoglycosides NB30, NB54 and chemical compound PTC124 on retinal toxicity efficacy a mutation USH1C gene, which encodes scaffold protein harmonin. This causes human Usher syndrome, most common form inherited deaf‐blindness. We quantify TRIDs cell...
We investigated the therapeutic potential of premature termination codon (PTC) readthrough-inducing drug PTC124 in treating retinal phenotype Usher syndrome, caused by a nonsense mutation USH1C gene. Applications cell culture, organotypic retina cultures, and mice vivo revealed significant readthrough recovery protein function. In comparison with other drugs, namely clinically approved aminoglycoside gentamicin, exhibits better biocompatibility. Its high efficiency combination excellent...
Monocytes are circulating mononuclear phagocytes, poised to extravasate sites of inflammation and differentiate into monocyte-derived macrophages dendritic cells. Tumor necrosis factor (TNF) its receptors up-regulated during monopoiesis expressed by monocytes, as well effector monocytes infiltrating certain inflammation, such the spinal cord, experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro vivo assays, we show that deficient for TNF or outcompeted...
Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with activation, we found that profound morphological changes and MHC-II CD80 upregulation occurred upon GVHD induction. RNA sequencing–based analysis purified obtained from mice revealed TNF upregulation. Selective gene deletion Cx3cr1creER Tnffl/– reduced expression decreased CNS T cell infiltrates VCAM-1+ endothelial cells. increased...
Retinitis pigmentosa (RP) denotes a family of inherited blinding eye diseases characterized by progressive degeneration rod and cone photoreceptors in the retina. In most cases rod-specific genetic defect results early functional loss rods, which is followed cones daylight vision at later stages. Microglial cells, immune cells central nervous system (CNS), are activated retinas RP patients several mouse models. However, it still matter debate whether microglial may be responsible for...
Inflammasomes are known to contribute brain damage after acute ischemic stroke (AIS). TAK1 is predominantly expressed in microglial cells and can regulate the NLRP3 inflammasome, but its impact on other inflammasomes including NLRC4 AIM2 AIS remains elusive. EPO has been shown reduce protein levels different disease models. Whether EPO-mediated neuroprotection conveyed via an EPO/TAK1/inflammasome axis microglia be clarified. Subjecting mice deficient for microglia/macrophages (Mi/MΦ)...
The ability of AAV2/5 to target murine photoreceptors was used optimize vector expression cassettes for rhodopsin replacement gene therapy in the retina. Defects this pivotal protein visual cycle are associated with various forms inherited eye defects including retinitis pigmentosa. A final optimized design led functional correction and regeneration rod outer segment a mouse model deficiency. (RHO) encodes highly expressed G protein-coupled receptor that is central transduction...
Purpose.: The human Usher syndrome (USH) is the most frequent cause of inherited combined deaf-blindness. USH clinically and genetically heterogeneous, assigned to three clinical types. severe type USH1, characterized by profound inner ear defects retinitis pigmentosa. Thus far, no effective treatment for ophthalmic component exists. p.R31X nonsense mutation in USH1C leads a disease causing premature termination gene translation. Here, we investigated capability novel synthetic...
Human Usher syndrome (USH) is the most frequent cause of inherited deaf-blindness. It clinically and genetically heterogeneous, assigned to three clinical types which severe type USH1. No effective treatment for ophthalmic component USH exists. Gene augmentation an attractive strategy hereditary retinal diseases. However, several genes, like USH1C, are expressed in various isoforms, hampering gene augmentation. As alternative strategy, we applied zinc-finger nuclease (ZFN) technology...
Abstract In vertebrate rod photoreceptor cells, arrestin and the visual G‐protein transducin move between inner segment outer in response to changes light. This stimulus dependent translocation of signalling molecules is assumed participate long term light adaptation photoreceptors. So far cellular basis for transport mechanisms underlying these intracellular movements remains largely elusive. Here we investigated dependency on actin filaments microtubule cytoskeleton cells. Co‐cultures...