Research

At the heart of the research carried out by NeuroCure are cerebrovascular diseases, neuroinflammation and disorders of functional network structures, with a focus on typical neurological diseases such as stroke, multiple sclerosis, epilepsy and other developmental disorders of the brain. These topics are investigated in seven research areas (A-G). Consistent with a translational research approach, a basic scientist and a clinical researcher are jointly responsible for each research area.
 
 
Research area A:
Mechanisms of damage
 
Coordinators: Endres, Kloetzel

Principal Investigators: Dirnagl, Geiger, Heinemann, Heppner, Kettenmann, Kühn, Meisel, Paul, Priller, Schroeder, Schülke-Gerstenfeld, Vajkoczy, Villringer, Wanker

Protecting brain tissue against destruction is one of the key challenges in acute and chronic neurodegenerative diseases. New findings show that a significant overlap exists between cell death mechanisms of clearly different brain diseases. Independent of the initiating pathophysiology, damage and death of neurons, glial cells, and vascular cells follow stereotypical mechanisms and conserved signaling events. NeuroCure scientists have already identified and characterized a series of these mechanisms and, in the process, discovered new therapeutic principles, some of which are currently being tested in clinical trials. Based on these initial findings, the research groups will jointly look for further mechanisms of damage and new therapeutic approaches. The initial focus will be on, among other things, aberrant cell cycle activity, epigenetic mechanisms, the ubiquitin-proteasome system and protein misfolding, protein-protein interaction networks, but also Phase II clinical studies in patients with subarachnoid hemorrhage. Thus, understanding and consequently interrupting the damage cascade in diseases of the central nervous system (CNS) is a main goal of NeuroCure, which we pursue from preclinical models to clinical trials.
 
Research area B:
Endogenous neuroprotection
 
Coordinators: Dirnagl, Flöel
Principal Investigators: Endres, Heinz, Heppner, Kettenmann, Meisel, Priller, Vajkoczy
 
Understanding endogenous brain protection and exploiting the underlying signaling pathways for therapeutic purposes is the joint aim of NeuroCure researchers in order to develop innovative forms of treatment for stroke, multiple sclerosis and epilepsy. Our strategies involve, among other things, the protective effects of HIF-1 and erythropoietine, preconditioning through upregulation of endothelial nitric oxide synthase, protective effects of multi-drug-transporters in disturbances of blood-brain barrier function, and epigenetic modulation. These innovative therapeutic approaches to utilizing endogenous repair mechanisms may soon also be of clinical value to stroke patients and patients with other brain disorders. 
 
Research area C:
Regeneration
 
Coordinators: Eickholt, Priller
Principal Investigators: Birchmeier, Dirnagl, Endres, Esplugues, Flöel, Heppner, Kettenmann, Lehnardt, Meisel, Scharff, Vajkoczy, Villringer, Wanker
 
The central nervous system (CNS) has a limited capacity to regenerate following damage. NeuroCure scientists have therefore set themseles the long-term goal of achieving brain repair, and thus of restoring neurological function after injury or disease. For this, dysfunctional or lost neurons and myelin sheaths must be replaced, nerve fiber regeneration stimulated and plasticity promoted. To this end, the research groups are using the therapeutic potential of adult bone marrow and CNS stem cells, as well as stem cell-based methods of gene therapy. In addition, they are working on stimulating axon regeneration aned synaptogenesis to replace degenerated fibers after insult. The hope is to be able to improve brain repair by better understanding and exploiting the complex interactions between the nervous, immune and hemoangiopoetic systems following CNS injury or disease.
 
Research area D:
Crosstalk between nervous and immune system
 
Coordinators: Heppner, Meisel
Principal Investigators: Dirnagl, Esplugues, Kettenmann, Kloetzel, Lehnardt, Paul, Priller, Radbruch, Vajkoczy
 
There is increasing evidence that immunological processes are not only involved in the classical inflammatory disorders of the nervous system such as multiple sclerosis but also in primarily noninflammatory injuries such as stroke and epilepsy. In all of these conditions or disorders, immune cells interact with cells of the nervous system. Although the initiating events differ considerably, we hypothesize that there are common pathways in the crosstalk between the immune and nervous systems. We intend to study this crosstalk by combining modern methods of molecular and cellular biology with imaging techniques. We will employ both in vivo and in vitro approaches in conjunction with animal models of acute and chronic neurological disorders. The aim of the research groups is to elucidate the influence of both proinflammatory and regulatory immune cells, via contact or soluble mediators, on neural cells. We also want to unravel the nervous system's capacity to regulate the immune system in the course of central nervous system (CNS) diseases. The researchers' focus is on developing innovative, immune modulation-based therapeutic strategies to combat these devastating CNS diseases. 
 
Research area E:
Developmental disturbances
 
Coordinators: Grüters-Kieslich, Sigrist
Principal Investigators: Birchmeier, Brecht, Eickholt, Geiger, Grantyn, Haucke, Haynes, Heim, Heinemann, Heinz, Jentsch, Kloetzel, Larkum, Lewin, Poulet, Rosenmund, Scharff, Schmitz, Shoichet, Schülke-Gerstenfeld, Tarabykin, Treier, Vida, Winter
 
Over the last two decades, there has been a new understanding of the processes controlling the development of the nervous system. In particular, genes, genetic pathways, and molecular mechanisms important for patterning, differentiation and maturation have been identified. The rapid advances made by molecular and cellular developmental neurobiology in unravelling these mechanisms offer the opportunity to transfer these results into the clinical disciplines of neonatology, pediatric neurology, and pediatric neuroendocrinology to enable precise diagnostic procedures, genetic counselling, and potentially new therapeutic perspectives. 
 
Research area F:
Molecular neuropathology of ion channels and transporters
 
Coordinators: Plested, Schülke-Gerstenfeld
Principal Investigators: Brecht, Geiger, Grantyn, Haucke, Heinemann, Jentsch, Larkum, Lewin, Poulet, Rosenmund, Schmitz, Schroeder, Sigrist, Spahn, Vida
 
Ion channels and transporters are found on every cell of the nervous system. Numerous diseases are based on hereditary defects in these channels. Such defects interfere with normal protein function and disrupt both cellular processes as well as rapid signal transmission between nerve cells. NeuroCure scientists use state-of-the-art technologies in genetics, cytochemistry, biophysics and imaging to investigate the role of these ion channels and transporters in healthy and diseased brain. NeuroCure's particular strength lies in its analysis of ion channels and their operation in the organism as a whole. In vivo studies are supplemented with investigations into the biophysical and biochemical mechanisms of the channel receptor complex and its composition. High throughput screening methods available to the Cluster are used to find new pharmacological substances affecting ion channels. Finally, extensive patient studies and access to patients with ion channel diseases facilitate synergies between molecular and cellular biology as well as neuropathology. This in turn enables fundamental insights into ion channel pathophysiology and the development of new treatment concepts.  
 
Research area G:
Plasticity
 
Coordinators: Heinz, Rosenmund
Principal Investigators: Birchemeier, Brecht, Eickholt, Flöel, Geiger, Grüters-Kieslich, Haucke, Haynes, Heinemann, Jentsch, Kloetzel, Kühn, Larkum, Otte, Poulet, Scharff, Schmitz, Schülke-Gerstenfeld, Shoichet, Sigrist, Spahn, Tarabykin, Treier, Vida, Winter
 
Synapses undergo transient and permanent changes in strength. This plasticity is instrumental in forming properly functioning neural circuits and is also essential for learning and memory. Synaptic plasticity alters circuit properties by changing input-output functions as well as internal processing, and plays a key role in various dysfunctions of the nervous system. Damaging events or genetic mutations often disrupt the balance of excitation and inhibition, which in turn causes major symptoms such as epilepsy, neuropsychiatric disorders and mental retardation. The analysis of synaptic plasticity and circuitry function and dysfunction is a core competence of NeuroCure.
We perform highly integrative, collaborative investigations ranging from molecular manipulations to analysis of networks and behavior. We combine in vitro and in vivo electrophysiological recordings from rodent cortices to examine principles of circuits. Further, we study several aspects of circuitry plasticity mediated by and/or within GABAergic interneuron networks, as they have a commanding role in the development, function and dysfunction of circuits and are also well studied in sensory cortical circuitries.
Finally, we investigate pathophysiological mechanisms of mental disorders such as autism spectrum disorders with a special emphasis on inhibitory neurons, and of patients with movement disorders undergoing deep brain stimulation (DBS). The latter allows exploration of changes in subcortico-cortical circuits in parallel with clinical improvement of motor symptoms during DBS. We expect that our analysis of circuit function and dysfunction will improve our understanding of human behavior and disease.