A5005827006- Pancreatic function and diabetes
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Pancreatic and Hepatic Oncology Research
- Amino Acid Enzymes and Metabolism
- Drug Transport and Resistance Mechanisms
- Calcium signaling and nucleotide metabolism
- Neuroblastoma Research and Treatments
- Epigenetics and DNA Methylation
- Receptor Mechanisms and Signaling
- Adenosine and Purinergic Signaling
- Erythrocyte Function and Pathophysiology
- Polyamine Metabolism and Applications
- Mesenchymal stem cell research
- Molecular Sensors and Ion Detection
- Metabolomics and Mass Spectrometry Studies
- Mitochondrial Function and Pathology
- Trace Elements in Health
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Sphingolipid Metabolism and Signaling
- Health, Environment, Cognitive Aging
- Neuroscience and Neuropharmacology Research
- Pharmacogenetics and Drug Metabolism
- Microbial Metabolic Engineering and Bioproduction
CeMM Research Center for Molecular Medicine
2020-2025
Austrian Academy of Sciences
2020-2025
Medical University of Vienna
2022
University of Bern
2017-2020
Abstract About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain information allowing their deorphanization. Here we describe network strong indicating contribution mitochondrial respiration redox metabolism SLC25A51/MCART1,...
Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamics simulations probe...
Abstract Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib for PanNET treatment. In addition, a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well autophagy. We investigated sunitinib-induced autophagy possible mechanism therapy resistance. Sunitinib accumulated lysosomes induced cell lines. Adding chloroquine...
Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy currently approved PanNET therapies is limited. While novel treatment options being developed, patient stratification permitting more personalized selection in yet not feasible since no predictive markers established. The lack representative vitro vivo models as well rarity heterogeneity prevailing reasons for this. In this study, we...
Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure concentrations in real time live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor intracellular aspartate, engineered through displaying screening libraries on mammalian In cells, AspSnFR able to precisely quantitatively cytosolic...
Abstract Research on the understudied solute carrier (SLC) superfamily of membrane transporters would greatly profit from a comprehensive knowledgebase, synthesizing data and knowledge different aspects SLC function. We consolidated multi-omics sets with selected curated information public domain, such as structure prediction, substrate annotation, disease association subcellular localization. This SLC-centric is made accessible to scientific community via web portal, featuring interactive...
The human SLC39A8 ( hSLC39A8 ) gene encodes a plasma membrane protein (ZIP8) that mediates the specific uptake of metals Cd 2+ , Mn Zn Fe Co and Se 4+ . Pathogenic variants within are associated with congenital disorder glycosylation type 2 (CDG II) or Leigh-like syndrome. However, numerous mutations uncertain significance also linked to different conditions benign traits. Our study characterized 21 measured their impact on localization intracellular levels We identified four disrupt...
Solute carrier (SLC) transporters control fluxes of nutrients and metabolites across membranes thereby represent a critical interface between the microenvironment cellular subcellular metabolism. Because substantial functional overlap, interplay relative contributions SLCs in response to environmental stresses remain poorly elucidated. To infer relationships metabolites, we developed strategy identify able sustain cell viability proliferation under growth-limiting concentrations essential...
With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for uptake and efflux of nutrients, metabolites, xenobiotics in human cells. SLCs are associated with a wide variety diseases, including cancer, diabetes, metabolic neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics scarce. Additionally, many small molecules reported literature to poorly characterized. Both...
Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked function identity. Despite their key role, individual functions members SLC superfamily were not evaluated systematically. We determined transcriptional profiles upon overexpression knock-out or wild-type isogenic cell backgrounds. Targeted metabolomics provided a fingerprint 189 intracellular metabolites, while transcriptomics...
DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for show an increased risk relapse. The tumor-associated pathways activated upon how this event may induce chromosomal instability (CIN) alternative lengthening telomeres (ALT) are still unknown. Both involved DNA methylation regulation. heterochromatin non-coding sequences is extremely important the maintenance genomic stability. We analyzed association and/or CIN with global human PanNET...
A modern, rational approach to a large class of proteins broadly relevant for pharmacology is enabling both from postgenomic perspective and reasons economy scale. The international public–private consortia RESOLUTE (https://re-solute.eu/) REsolution (https://re-solute.eu/resolution) are generating systematic functional assignment each the 451 different human solute carrier (SLC) and, at same time, trying catalog interpret associated main genetic variants. SLCs superfamily facilitative...
Solute carrier (SLC) transporters form a protein superfamily that enables transmembrane transport of diverse substrates including nutrients, ions and drugs. There are about 450 different SLCs, residing in variety subcellular membranes. Loss-of-function an unusually high proportion SLC is genetically associated with plethora human diseases, making SLCs rapidly emerging but challenging drug target class. Knowledge their environment may elucidate the molecular basis for functional integration...
Abstract Solute carriers (SLCs), the largest superfamily of transporter proteins in humans with about 450 members, control movement molecules across membranes. A typical human cell expresses over 200 different SLCs, yet their collective influence on phenotypes is not well understood due to overlapping substrate specificities and expression patterns. To address this, we performed systematic pairwise gene double knockouts using CRISPR-Cas12a -Cas9 colon carcinoma cells. total 1,088,605 guide...
Autophagy is a highly conserved degradation mechanism that essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there immense interest in targeting therapeutic approaches. Accordingly, need to determine autophagic activity tissues, an endeavor hampered by the fact characterized flux of substrates whereas histology informs only about amounts localization regulators at single timepoint. Despite this challenging task, considerable...
Creatine is an essential metabolite for the storage and rapid supply of energy in muscle nerve cells. In humans, impaired metabolism, transport, distribution creatine throughout tissues can cause varying forms mental disability, also known as deficiency syndrome (CDS). So far, 80 mutations transporter (SLC6A8) have been associated to CDS. To better understand effect human genetic variants on physiology SLC6A8 their possible impact CDS, we studied 30 missense including 15 unknown...
Abstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamic simulations...
Excitatory amino acid transporters (EAAT/SLC1) mediate Na+-dependent uptake of extracellular glutamate and are potential drug targets for neurological disorders. Conventional methods to assess transport in vitro based on radiolabels, fluorescent dyes or electrophysiology, which potentially compromise the cell's physiology generally less suited primary screens. Here, we describe a novel label-free method human EAAT function living cells, i.e., without use chemical modifications substrate...
Abstract Solute carrier (SLC) transporters control fluxes of nutrients and metabolites across membranes thereby represent a critical interface between the microenvironment cellular subcellular metabolism. Because substantial functional overlap, interplay relative contributions members this family in response to environmental stresses remain poorly elucidated. In order infer relationships SLCs metabolites, we developed strategy identify human able sustain cell viability proliferation under...
Iron is a trace element that critical for most living organisms and plays key role in wide variety of metabolic processes. In the mitochondrion, iron involved producing iron-sulfur clusters synthesis heme kept within physiological ranges by concerted activity multiple molecules. Mitochondrial uptake mediated solute carrier transporters Mitoferrin-1 (SLC25A37) Mitoferrin-2 (SLC25A28). While mainly erythropoiesis, cellular function ubiquitously expressed remains less well defined. Furthermore,...