At the heart of the research carried out by NeuroCure are cerebrovascular diseases, neuroinflammation and disorders of functional network structures [diseases], with focus upon typical neurological diseases such as stroke, multiple sclerosis, epilepsy and other developmental disorders of the brain. These points are dealt with in six subject areas (A-F). Following a translational approach to research, a fundamental researcher and a clinical researcher are jointly responsible for a research area.
B | Endogenous brain protection
C | Regeneration
D | Crosstalk between nervous and immune system
E | Developmental Disturbances
F | Molecular neuropathologies of ion channels and transporters
Protecting brain tissue against destruction is the key challenge in acute and chronic neuro-degeneration. A tremendous overlap exists between deleterious mechanisms of clearly separated brain disease entities. Independent of initiating pathophysiology, damage and death of neurons, glial cells, and vascular elements in the central nervous system (CNS) follow stereotypical mechanisms and conserved signaling events. NeuroCure scientists have already identified and investigated up- and down-stream targets by which the cascade of brain damage can be intercepted: receptor-gated ion channels and transporters, inflammatory proteins, death ligands and receptors, as well as caspases, to name but a few. Based on our previous preclinical and clinical findings, NeuroCure researchers join forces to unravel novel mechanisms of damage, such as aberrant cell cycle activity, epigenetic mechanisms of cell death, as well as the ubiquitin proteasome system and protein misfolding. We apply systematic analysis of protein-protein interaction networks to discover new damage mechanisms and therapeutic targets, and perform clinical proof-of-principle as well as Phase II studies in patients with subarachnoid hemorrhage. Thus, understanding and consequently intercepting mechanisms of damage is a main goal of NeuroCure, which we pursue from preclinical models to clinical trials.
Research on endogenous brain protection along with subsequent therapeutic exploitation of its signaling pathways is highly amenable to a joint effort of NeuroCure scientists focusing on diseases causing damage by the classical danger signals of hypoxia/ischemia, inflammation, and hyperexcitablity. Our strategies will involve HIF-1 and erythropoietin-dependent protective pathways, preconditioning via endothelial nitric oxide synthase, multi-drug transporter targeting, and epigenetic modification. These therapeutic modalities open windows into endogenous neuroprotection and potentially, a window of opportunity to utilize these mechanisms in the clinic to treat patients with stroke and other central nervous system (CNS) disorders.
Following damage of the central nervous system (CNS), the brain has a limited capacity to regenerate. The ultimate goal of our research is to achieve brain repair, and thus to restore neurological function after injury or disease. Our efforts comprise the replacement of dysfunctional or lost neurons, the regeneration of nerve fibres, the replacement of myelin sheaths, and the promotion of functional plasticity. We will exploit the therapeutic potential of adult stem cells derived from bone marrow and brain as well as stem-cell-based gene therapy. Moreover we also attempt to stimulate axon regeneration and synaptogenesis to replace degenerated fibers after insult. As regenerative processes are strongly age dependent and may also be affected by confounders prevalent in patient populations in special need of therapeutic neuroregeneration, we also investigate the impact of these factors on regeneration. We hope to be able to improve brain repair by defining and exploiting the complex interactions between the nervous, immune, and hemangiopoietic systems after CNS injury or disease.
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 non-inflammatory injuries, such as stroke and epilepsy. In any 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 including animal models of acute and chronic neurological disorders. Our aim 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. In joint preclinical experiments as well as in planned clinical trials, our major aim is to advance the understanding of the role of the immune response in CNS pathology as a prelude to developing innovative therapeutic strategies based on immune modulation to combat the devastating CNS diseases forming the focus of NeuroCure research.
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 that can be used for patterning, differentiation, and maturation have been identified. These rapid advances in unravelling the mechanisms of molecular and cellular developmental neurobiology 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.
The long-term outcome following brain lesions depends on developmental, experience-dependent, and homeostatic plasticity. The strategy to understand common mechanisms and molecules for development and after a lesion will be an important and indispensable contribution of basic science to NeuroCure. Indeed, only recently, it has become apparent that transcription factors with a role in pattern formation during development are also involved in lesion-induced reorganization. NeuroCure researchers are conducting a systematic survey of the alterations in gene expression that occur in neurons following physiological and pathophysiological activity. We have identified several activity- and plasticity-regulated genes. We now aim to study the role of these genes in synaptic transmission and plasticity. Furthermore, we study synapse function during and after brain lesions following cerebrovascular diseases, neuroinflammation, and disorders of network formation. Unraveling the underlying mechanisms and identifying the involved signaling cascades will be instrumental for the development of identification of therapies preventing abnormal network formation.
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 exploring 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.