Claus Kremoser
Max Planck Society
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Featured researches published by Claus Kremoser.
Cell | 1995
Uwe Drescher; Claus Kremoser; Claudia Handwerker; Jürgen Löschinger; Masaharu Noda; Friedrich Bonhoeffer
The results of previous in vitro experiments indicate that a glycosylphosphatidylinositol (GPI)-anchored protein may play an important role in the guidance of temporal retinal axons during the formation of the topographically ordered retinotectal projection. We have purified and cloned a GPI-anchored, 25 kDa glycoprotein that is a good candidate for a molecule involved in this process. During the time of innervation by retinal ganglion cells, this protein is gradedly expressed in the posterior part of the developing tectum. In two different in vitro assay systems, the recombinant protein induces growth cone collapse and repulsion of retinal ganglion cell axons. These phenomena are observed for axons of temporal as well as nasal origin, indicating that an additional activity may be necessary to confer the nasotemporal specificity observed in previous assays. We named the protein RAGS (for repulsive axon guidance signal). The sequence of RAGS shows significant homology to recently identified ligands for receptor tyrosine kinases of the Eph subfamily.
The EMBO Journal | 1997
Bruno Monschau; Claus Kremoser; Kunimasa Ohta; Hideaki Tanaka; Tomomi Kaneko; Tomoko Yamada; Claudia Handwerker; Martin Hornberger; Jürgen Löschinger; Elena B. Pasquale; Doyle A. Siever; Michael F. Verderame; Bernhard Müller; Friedrich Bonhoeffer; Uwe Drescher
Two ligands for Eph‐related receptor tyrosine kinases, RAGS and ELF‐1, have been implicated in the control of development of the retinotectal projection. Both molecules are expressed in overlapping gradients in the tectum, the target area of retinal ganglion cell axons. In two in vitro assays ELF‐1 is shown to have a repellent axon guidance function for temporal, but apparently not for nasal axons. RAGS on the other hand is repellent for both types of axons, though to different degrees. Thus, RAGS and ELF‐1 share some and differ in other properties. The biological activities of these molecules correlate with the strength of interaction with their receptors expressed on RGC axons. The meaning of these findings for guidance of retinal axons in the tectum is discussed.
European Journal of Neuroscience | 1998
Thomas Ciossek; Bruno Monschau; Claus Kremoser; Jürgen Löschinger; Susanne Lang; Bernhard Müller; Friedrich Bonhoeffer; Uwe Drescher
Previous results of an in vitro guidance test, the stripe assay, have demonstrated the presence of a repulsive axon guidance activity for temporal retinal axons in the posterior part of the vertebrate optic tectum. Ephrin‐A5 and Ephrin‐A2 are ligands for the EphA subfamily of Eph receptor tyrosine kinases, which are expressed in overlapping gradients in the posterior part of the tectum. When recombinantly expressed, both proteins have been shown to guide retinal ganglion cell axons in the stripe assay. While these results suggest that Ephrin‐A5 and Ephrin‐A2 form part of the posterior repulsive guidance activity, they do not elucidate whether they are necessary components. Here we report that soluble forms of the ligands at nanomolar concentrations completely abolish this repulsive activity. Similar results were obtained with the soluble extracellular domain of EphA3, which is a receptor for Ephrin‐A2 and Ephrin‐A5, but not with the corresponding domain of EphB3, a receptor for the transmembrane class of Eph ligands. These experiments show that the repulsive axon guidance activity seen in the stripe assay is mediated by Ephrin‐A ligands.
Journal of Pharmacology and Experimental Therapeutics | 2012
E. Hambruch; Shinobu Miyazaki-Anzai; Ulrike Hahn; Silke Matysik; Alfred Boettcher; Sanja Perović-Ottstadt; Thomas Schlüter; Olaf Kinzel; Helen Desiree Krol; Ulrich Deuschle; Michael Burnet; Moshe Levi; Gerd Schmitz; Makoto Miyazaki; Claus Kremoser
Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high-density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (−/−) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (FXR-450) and 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid (PX20606) demonstrated potent plasma cholesterol-lowering activity that affected all lipoprotein species, whereas 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(−/−) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg-LDLR(−/−) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL2c but not HDL3c or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL2 subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists.
PLOS ONE | 2012
Ulrich Deuschle; Julia Schüler; Andreas Schulz; Thomas Schlüter; Olaf Kinzel; Ulrich Abel; Claus Kremoser
The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR−/− mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies. We show reduced NDRG2 mRNA in livers of FXR−/− mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.
Bioorganic & Medicinal Chemistry Letters | 2010
Ulrich Abel; Thomas Schlüter; Andreas Schulz; E. Hambruch; Christoph Steeneck; Martin Hornberger; Thomas Hoffmann; Sanja Perović-Ottstadt; Olaf Kinzel; Michael Burnet; Ulrich Deuschle; Claus Kremoser
To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.
International Journal of Cancer | 2015
Ulrich Deuschle; Manfred Birkel; E. Hambruch; Martin Hornberger; Olaf Kinzel; Sanja Perović-Ottstadt; Andreas Schulz; Ulrike Hahn; Michael Burnet; Claus Kremoser
The nuclear bile acid receptor Farnesoid X receptor (FXR) is strongly expressed in liver and intestine, controls bile acid and lipid homeostasis and exerts tumor‐protective functions in liver and intestine. Histidine‐rich glycoprotein (HRG) is an abundant plasma protein produced by the liver with the proposed function as a pattern recognition molecule involved in the clearance of immune complexes, necrotic cells and pathogens, the modulation of angiogenesis, the normalization of deranged endothelial vessel structure in tumors and tumor suppression. FXR recognition sequences were identified within a human HRG promoter fragment that mediated FXR/FXR‐agonist dependent reporter gene activity in vitro. We show that HRG is a novel transcriptional target gene of FXR in human hepatoma cells, human upcyte® primary hepatocytes and 3D human liver microtissues in vitro and in mouse liver in vivo. Prolonged administration of the potent nonsteroidal FXR agonist PX20606 increases HRG levels in mouse plasma. Finally, daily oral administration of this FXR agonist for seven days resulted in a significant increase of HRG levels in the plasma of healthy human male volunteers during a clinical Phase I safety study. HRG might serve as a surrogate marker indicative of liver‐specific FXR activation in future human clinical studies. Furthermore, potent FXR agonists might be beneficial in serious health conditions where HRG is reduced, for example, in hepatocellular carcinoma but also other solid cancers, liver failure, sepsis and pre‐eclampsia.
Nuclear Receptor Research | 2016
E. Hambruch; Olaf Kinzel; Claus Kremoser
The Farnesoid X Receptor (FXR) has recently moved into the spotlight through the release of clinical data using Obeticholic Acid, an FXR agonist, that demonstrated effectiveness of this bile acid-like drug in patients with Primary Biliary Cirrhosis and Non-alcoholic Steatohepatitis (NASH). FXR holds the promise to become an attractive drug target for various conditions, from Non-alcoholic Fatty Liver Disease (NAFLD), NASH, liver cirrhosis, portal hypertension and a variety of cholestatic disorders to intestinal diseases including inflammatory bowel disease and bile acid diarrhea. Despite the wide therapeutic potential, surprisingly little is known about the pharmacology, pharmacokinetics and tissue distribution properties of drugs targeting FXR. Are tissue specific FXR agonists preferable for different indications, or might one type of ligand fit all purposes? This review aims to summarize the sparse data which are available on this clinically and pharmacologically relevant topic and provides a mechanistic model for understanding tissue-specific effects in vivo.
Current Topics in Medicinal Chemistry | 2014
Christian Gege; Olaf Kinzel; Christoph Steeneck; Andreas Schulz; Claus Kremoser
Archive | 2007
Claus Kremoser; Ulrich Deuschle; Ulrich Abel; Andreas Schulz