Prof. Dr. med. Michael Sinnreich Department of Biomedicine Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 5 foundShow per page10 10 20 50 RNA protein interaction of CUG repeats/Muscleblind like-1 protein (MOA) Research Project | 1 Project MembersNo Description available The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies. Therapies for dysferlinopathies Research Project | 1 Project MembersMuskeldystrophien sind genetisch bedingte Erkrankungen, welche zur Zerstörung von Muskelgewebe führen. Dysferlin ist ein Protein des Muskels, welches der Reparatur von Verletzungen der Muskelzellmembranen dient. Mutationen im Dysferlin-Gen führen zum raschen Abbau des veränderten Dysferlin-Proteins, zu mangelnder Reparatur der Muskelzellmembranen und dadurch zu Muskeldystrophien. Der Forschungsgruppe um Prof. Michael Sinnreich gelang es, die Funktionstüchtigkeit des mutierten Dysferlin-Proteins in kultivierten menschlichen Muskelzellen von Patienten mit Muskeldystrophie wiederherzustellen. Die Forschungsgruppe identifizierte den zellulären Mechanismus, der für den Abbau des mutierten Dysferlin-Proteins verantwortlich ist, und konnte durch medikamentöse Hemmung dieses Mechanismus Verletzungen von Muskelzellmembranen reparieren. Die gewonnenen Erkenntnisse könnten in Zukunft neue Behandlungsmöglichkeiten für bestimmte Muskeldystrophien eröffnen. Eine auf diesem Mechanismus basierende klinische Studie, mit einem bereits für andere Indikationen zugelassenen Medikament (Proteasom-Inhibitor), wird nun am Neuromuskulären Zentrum, Abteilung für Neurologie, des Universitätsspitals Basel durchgeführt. Diesem Forschungsprojekt wurde kürzlich ein "Rare Diseases - New Approaches" - Grant der Gebert Rüf Stiftung zugesprochen. Das geförderte Projekt hat zudem das Ziel weitere Dysferlin Mutationen, die dieser Therapie zugänglich wären aufzudecken, sowie den zellulären Abbaumechanismus des mutierten Dysferlin noch näher zu untersuchen. The dysferlin interactome application for therapeutic strategies Research Project | 1 Project MembersFinding treatment for muscular dystrophies is imperative, as these diseases have a high personal and socioeconomic impact. As skeletal muscles become weak, patients become dependent on their family members, partners and friends for displacements, personal hygiene and feeding. We are interested in the cell biology of human diseases affecting skeletal muscle. Certain features of skeletal muscle fibers, including their large size, make them suitable for investigations of particular aspects of cellular biology such as surface membrane production, maintenance and repair. An important protein implicated in muscle surface membrane repair is dysferlin. Mutations in dysferlin are a frequent cause of the recessively inherited limb girdle muscular dystrophies (LGMD), defining the common subtype of LGMD2B. In addition to LGMD2B, dysferlin mutations also cause Miyoshi Myopathy (MM) and distal anterior compartment myopathy, which are both distal forms of muscular dystrophy. No treatment is currently available for these disabling diseases. The design of treatment strategies for dysferlin deficiency requires knowledge about the cellular function of the dysferlin protein and about its interacting partners. This knowledge is currently scarce. Using affinity purification followed by liquid chromatography/mass spectrometry, we identified a number of proteins in skeletal muscle that showed association with dysferlin. Importantly, we were able to identify the few proteins previously shown to interact with dysferlin, thus indicating the validity of our approach. The newly identified proteins fall into categories of surface membrane proteins, proteins involved in cellular trafficking, signal transduction proteins, as well as proteins involved in protein degradation and quality control. In this application, we propose to study the interaction of dysferlin with selected newly identified binding partners in order to gain insight into the membrane repair mechanism, to understand the trafficking of dysferlin and the degradation pathways used by dysferlin and its mutant variants. This knowledge should allow us to identify cellular targets that could be pharmacologically modified to reconstitute dysferlin expression in patients with dysferlin missense mutations, and, in a broader applicability, to enhance membrane resealing in patients with muscular dystrophies in which the loss of sarcolemmal integrity contributes to the disease process. Neuromuscular Research Laboratory Project 1: Biology of Dysferlin Project 2: Myotonic Dystrophy Project 3: Molecular Diagnostics Research Project | 1 Project MembersDie Schweizerische Stiftung zur Erforschung der Muskelkrankheiten (SSEM), die Schweizerische Gesellschaft für Muskelkranke (SGMK) und die Association Suisse Romande et Italienne contre la Myopathie (ASRIM)unterstützen grosszügigerweise unser Neuromuskuläres Forschungslabor. Project 1: Dysferlin ist ein transmembranäres Protein, welches für die Reparatur von Muskelzellmembranen verantwortlich ist. Mutationen im Dysferlin Gen führen zu Muskeldystrophien. Wir untersuchen die molekularen Vorgänge der Muskelzellmembran Reparation mit dem Ziel Therapien für Muskelerkranungen zu entwickeln. Projekt 2: Myotone Dystrophien sind häufige Formen der Muskeldystrophien. Die Erkrankungen werden durch toxische RNA Moleküle verursacht. Wir versuchen klein molekulare Substanzen zu finden, welche dieser Toxizität entgegenwirken, und welche als Medikamente gegen die Myotone Dystrophie eingesetzt werden könnten. Projekt 3: Viele Neuromuskuläre Erkrankungen sind genetisch bedingt. Die Erkennung der genauen genetischen Mutation ist wichtig, da neue Therapien von der Art der Mutation abhängen. Wir möchten eine genetische Untersuchungsmethode entwickeln, die es erlaubt mehrere neuromuskuläre Gene gleichzeitig in einer effizienten und kostengünstigen Art zu analysieren. 1 1 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 5 foundShow per page10 10 20 50 RNA protein interaction of CUG repeats/Muscleblind like-1 protein (MOA) Research Project | 1 Project MembersNo Description available The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies. Therapies for dysferlinopathies Research Project | 1 Project MembersMuskeldystrophien sind genetisch bedingte Erkrankungen, welche zur Zerstörung von Muskelgewebe führen. Dysferlin ist ein Protein des Muskels, welches der Reparatur von Verletzungen der Muskelzellmembranen dient. Mutationen im Dysferlin-Gen führen zum raschen Abbau des veränderten Dysferlin-Proteins, zu mangelnder Reparatur der Muskelzellmembranen und dadurch zu Muskeldystrophien. Der Forschungsgruppe um Prof. Michael Sinnreich gelang es, die Funktionstüchtigkeit des mutierten Dysferlin-Proteins in kultivierten menschlichen Muskelzellen von Patienten mit Muskeldystrophie wiederherzustellen. Die Forschungsgruppe identifizierte den zellulären Mechanismus, der für den Abbau des mutierten Dysferlin-Proteins verantwortlich ist, und konnte durch medikamentöse Hemmung dieses Mechanismus Verletzungen von Muskelzellmembranen reparieren. Die gewonnenen Erkenntnisse könnten in Zukunft neue Behandlungsmöglichkeiten für bestimmte Muskeldystrophien eröffnen. Eine auf diesem Mechanismus basierende klinische Studie, mit einem bereits für andere Indikationen zugelassenen Medikament (Proteasom-Inhibitor), wird nun am Neuromuskulären Zentrum, Abteilung für Neurologie, des Universitätsspitals Basel durchgeführt. Diesem Forschungsprojekt wurde kürzlich ein "Rare Diseases - New Approaches" - Grant der Gebert Rüf Stiftung zugesprochen. Das geförderte Projekt hat zudem das Ziel weitere Dysferlin Mutationen, die dieser Therapie zugänglich wären aufzudecken, sowie den zellulären Abbaumechanismus des mutierten Dysferlin noch näher zu untersuchen. The dysferlin interactome application for therapeutic strategies Research Project | 1 Project MembersFinding treatment for muscular dystrophies is imperative, as these diseases have a high personal and socioeconomic impact. As skeletal muscles become weak, patients become dependent on their family members, partners and friends for displacements, personal hygiene and feeding. We are interested in the cell biology of human diseases affecting skeletal muscle. Certain features of skeletal muscle fibers, including their large size, make them suitable for investigations of particular aspects of cellular biology such as surface membrane production, maintenance and repair. An important protein implicated in muscle surface membrane repair is dysferlin. Mutations in dysferlin are a frequent cause of the recessively inherited limb girdle muscular dystrophies (LGMD), defining the common subtype of LGMD2B. In addition to LGMD2B, dysferlin mutations also cause Miyoshi Myopathy (MM) and distal anterior compartment myopathy, which are both distal forms of muscular dystrophy. No treatment is currently available for these disabling diseases. The design of treatment strategies for dysferlin deficiency requires knowledge about the cellular function of the dysferlin protein and about its interacting partners. This knowledge is currently scarce. Using affinity purification followed by liquid chromatography/mass spectrometry, we identified a number of proteins in skeletal muscle that showed association with dysferlin. Importantly, we were able to identify the few proteins previously shown to interact with dysferlin, thus indicating the validity of our approach. The newly identified proteins fall into categories of surface membrane proteins, proteins involved in cellular trafficking, signal transduction proteins, as well as proteins involved in protein degradation and quality control. In this application, we propose to study the interaction of dysferlin with selected newly identified binding partners in order to gain insight into the membrane repair mechanism, to understand the trafficking of dysferlin and the degradation pathways used by dysferlin and its mutant variants. This knowledge should allow us to identify cellular targets that could be pharmacologically modified to reconstitute dysferlin expression in patients with dysferlin missense mutations, and, in a broader applicability, to enhance membrane resealing in patients with muscular dystrophies in which the loss of sarcolemmal integrity contributes to the disease process. Neuromuscular Research Laboratory Project 1: Biology of Dysferlin Project 2: Myotonic Dystrophy Project 3: Molecular Diagnostics Research Project | 1 Project MembersDie Schweizerische Stiftung zur Erforschung der Muskelkrankheiten (SSEM), die Schweizerische Gesellschaft für Muskelkranke (SGMK) und die Association Suisse Romande et Italienne contre la Myopathie (ASRIM)unterstützen grosszügigerweise unser Neuromuskuläres Forschungslabor. Project 1: Dysferlin ist ein transmembranäres Protein, welches für die Reparatur von Muskelzellmembranen verantwortlich ist. Mutationen im Dysferlin Gen führen zu Muskeldystrophien. Wir untersuchen die molekularen Vorgänge der Muskelzellmembran Reparation mit dem Ziel Therapien für Muskelerkranungen zu entwickeln. Projekt 2: Myotone Dystrophien sind häufige Formen der Muskeldystrophien. Die Erkrankungen werden durch toxische RNA Moleküle verursacht. Wir versuchen klein molekulare Substanzen zu finden, welche dieser Toxizität entgegenwirken, und welche als Medikamente gegen die Myotone Dystrophie eingesetzt werden könnten. Projekt 3: Viele Neuromuskuläre Erkrankungen sind genetisch bedingt. Die Erkennung der genauen genetischen Mutation ist wichtig, da neue Therapien von der Art der Mutation abhängen. Wir möchten eine genetische Untersuchungsmethode entwickeln, die es erlaubt mehrere neuromuskuläre Gene gleichzeitig in einer effizienten und kostengünstigen Art zu analysieren. 1 1
RNA protein interaction of CUG repeats/Muscleblind like-1 protein (MOA) Research Project | 1 Project MembersNo Description available
The Mode of Action of Metformin and L-Citrullin on Muscle Metabolism in Duchenne Muscular Dystrophy. A Biomarker Study. Research Project | 5 Project MembersDuchenne muscular dystrophy (DMD) is the most common inherited muscle disorder leading to relentless muscle wasting and premature death in affected children. The only currently available symptomatic treatment for DMD consists of corticosteroids, resulting in modest beneficial effects but relevant side effects. In DMD dystrophin expression is lost disrupting the normal cytoskeletal structure. To date a lot is known about the structural consequences auf DMD, e.g. destabilization of the dystrophin associated glycoprotein complex resulting in muscles fibres that are more sensitive to mechanical damage and thus degenerate. Still very little is known about the metabolic consequences of dystrophin loss which is associated with a severe reduction of neuronal nitric oxide (NO) synthase (nNOS). NO stimulates the up-regulation of nuclear genes involved in mitochondrial biogenesis and ATP generation. In a small pilot trial with 5 DMD patients we tested if NO precursors as the amino acids L-arginine and the biguanide antidiabetic drug metformin (indirect nNOS activator) can improve muscle function and influence metabolism in DMD. We observed an improved lipid metabolism, improved functional abilities and prolonged walking distances in the 2 min walking distance. Quantitative muscle magnet resonance imaging (MRI) indicated a slowing in muscle degeneration in these patients. Our results thus indicate that there is a potential of treating the disturbed cell metabolism in DMD. To prove these results in a larger cohort, we will start soon an investigator driven double-blind placebo controlled randomized clinical trial (RCT) in DMD. 40 DMD patients will be randomised for a 26 week (1:1) trial. L-citrulline instead of L-arginine will be used, as it was demonstrated that in humans L-citrulline increases the L-arginine and NO concentrations more than L-arginine itself. As the mode of action of L-citrulline and metformin on cell metabolism in DMD is still poorly understood the proposed project forms a sub-project of this trial to examine markers of nitric oxide metabolism, mitochondrial function and energy production, carbohydrate and fatty utilization ratios, and oxidative stress markers in urine and blood samples to better define the pharmacological pathways of the drug combination, and to search for metabolic biomarkers in DMD. Quantitative muscle MRI will be used to observe how close changes in cell metabolism and muscle degeneration are linked. In case of positive results of the main trial a more effective and safer symptomatic treatment will be available in DMD and a better understanding of the cell metabolism in DMD might help to improve or even develop new drugs for DMD and related myopathies.
Therapies for dysferlinopathies Research Project | 1 Project MembersMuskeldystrophien sind genetisch bedingte Erkrankungen, welche zur Zerstörung von Muskelgewebe führen. Dysferlin ist ein Protein des Muskels, welches der Reparatur von Verletzungen der Muskelzellmembranen dient. Mutationen im Dysferlin-Gen führen zum raschen Abbau des veränderten Dysferlin-Proteins, zu mangelnder Reparatur der Muskelzellmembranen und dadurch zu Muskeldystrophien. Der Forschungsgruppe um Prof. Michael Sinnreich gelang es, die Funktionstüchtigkeit des mutierten Dysferlin-Proteins in kultivierten menschlichen Muskelzellen von Patienten mit Muskeldystrophie wiederherzustellen. Die Forschungsgruppe identifizierte den zellulären Mechanismus, der für den Abbau des mutierten Dysferlin-Proteins verantwortlich ist, und konnte durch medikamentöse Hemmung dieses Mechanismus Verletzungen von Muskelzellmembranen reparieren. Die gewonnenen Erkenntnisse könnten in Zukunft neue Behandlungsmöglichkeiten für bestimmte Muskeldystrophien eröffnen. Eine auf diesem Mechanismus basierende klinische Studie, mit einem bereits für andere Indikationen zugelassenen Medikament (Proteasom-Inhibitor), wird nun am Neuromuskulären Zentrum, Abteilung für Neurologie, des Universitätsspitals Basel durchgeführt. Diesem Forschungsprojekt wurde kürzlich ein "Rare Diseases - New Approaches" - Grant der Gebert Rüf Stiftung zugesprochen. Das geförderte Projekt hat zudem das Ziel weitere Dysferlin Mutationen, die dieser Therapie zugänglich wären aufzudecken, sowie den zellulären Abbaumechanismus des mutierten Dysferlin noch näher zu untersuchen.
The dysferlin interactome application for therapeutic strategies Research Project | 1 Project MembersFinding treatment for muscular dystrophies is imperative, as these diseases have a high personal and socioeconomic impact. As skeletal muscles become weak, patients become dependent on their family members, partners and friends for displacements, personal hygiene and feeding. We are interested in the cell biology of human diseases affecting skeletal muscle. Certain features of skeletal muscle fibers, including their large size, make them suitable for investigations of particular aspects of cellular biology such as surface membrane production, maintenance and repair. An important protein implicated in muscle surface membrane repair is dysferlin. Mutations in dysferlin are a frequent cause of the recessively inherited limb girdle muscular dystrophies (LGMD), defining the common subtype of LGMD2B. In addition to LGMD2B, dysferlin mutations also cause Miyoshi Myopathy (MM) and distal anterior compartment myopathy, which are both distal forms of muscular dystrophy. No treatment is currently available for these disabling diseases. The design of treatment strategies for dysferlin deficiency requires knowledge about the cellular function of the dysferlin protein and about its interacting partners. This knowledge is currently scarce. Using affinity purification followed by liquid chromatography/mass spectrometry, we identified a number of proteins in skeletal muscle that showed association with dysferlin. Importantly, we were able to identify the few proteins previously shown to interact with dysferlin, thus indicating the validity of our approach. The newly identified proteins fall into categories of surface membrane proteins, proteins involved in cellular trafficking, signal transduction proteins, as well as proteins involved in protein degradation and quality control. In this application, we propose to study the interaction of dysferlin with selected newly identified binding partners in order to gain insight into the membrane repair mechanism, to understand the trafficking of dysferlin and the degradation pathways used by dysferlin and its mutant variants. This knowledge should allow us to identify cellular targets that could be pharmacologically modified to reconstitute dysferlin expression in patients with dysferlin missense mutations, and, in a broader applicability, to enhance membrane resealing in patients with muscular dystrophies in which the loss of sarcolemmal integrity contributes to the disease process.
Neuromuscular Research Laboratory Project 1: Biology of Dysferlin Project 2: Myotonic Dystrophy Project 3: Molecular Diagnostics Research Project | 1 Project MembersDie Schweizerische Stiftung zur Erforschung der Muskelkrankheiten (SSEM), die Schweizerische Gesellschaft für Muskelkranke (SGMK) und die Association Suisse Romande et Italienne contre la Myopathie (ASRIM)unterstützen grosszügigerweise unser Neuromuskuläres Forschungslabor. Project 1: Dysferlin ist ein transmembranäres Protein, welches für die Reparatur von Muskelzellmembranen verantwortlich ist. Mutationen im Dysferlin Gen führen zu Muskeldystrophien. Wir untersuchen die molekularen Vorgänge der Muskelzellmembran Reparation mit dem Ziel Therapien für Muskelerkranungen zu entwickeln. Projekt 2: Myotone Dystrophien sind häufige Formen der Muskeldystrophien. Die Erkrankungen werden durch toxische RNA Moleküle verursacht. Wir versuchen klein molekulare Substanzen zu finden, welche dieser Toxizität entgegenwirken, und welche als Medikamente gegen die Myotone Dystrophie eingesetzt werden könnten. Projekt 3: Viele Neuromuskuläre Erkrankungen sind genetisch bedingt. Die Erkennung der genauen genetischen Mutation ist wichtig, da neue Therapien von der Art der Mutation abhängen. Wir möchten eine genetische Untersuchungsmethode entwickeln, die es erlaubt mehrere neuromuskuläre Gene gleichzeitig in einer effizienten und kostengünstigen Art zu analysieren.
