Danzer Research Lab
The Danzer laboratory examines changes in the structure and function of brain circuitry that drive epileptogenesis. Our guiding view is that numerous mechanisms can lead to the development of epilepsy and that, in many patients, the disease reflects the accumulation of multiple pro-epileptogenic changes. In this regard, epilepsy is similar to cancer, with a variety of genetic, cellular and signaling changes driving disease. Correspondingly, we predict that eventual preventatives for epilepsy will resemble current treatments for cancer, in which multiple disease-causing mechanisms are targeted simultaneously, and treatments are modulated over time to preempt evolving disease states. The goal of our research, therefore, is to identify common disease-causing mechanisms that are clinically actionable.
The primary research direction of the lab is on pediatric focal epilepsies, such as tuberous sclerosis complex and focal cortical dysplasia type II. The conditions are caused by germline and somatic mutations among mechanistic target of rapamycin (mTOR) signaling pathway genes which occur during brain development. Somatic mutations typically produce localized cortical malformations which are highly epileptogenic. The conditions tend to respond poorly to existing anti-seizure medications, necessitating research into new therapeutic approaches. Tuberous sclerosis is also often comorbid with autism and other neuropsychiatric disorders, raising additional questions about how disrupted mTOR signaling alters brain development and function.
Mutation carrying cells are typically restricted to focal brain malformations, making them difficult to detect and characterize. Furthermore, even within focal malformations, mutation carrying cells can make up less than one percent of the total neuronal population. A fundamental unresolved question in the epileptogenesis field is how this relatively small population of mutation carry cells can cause epilepsy? Ongoing research in the lab is aimed at understanding how disrupted mTOR signaling promotes the aberrant rewiring of the brain, and whether modulating this pathway can be used to prevent and treat epilepsy and associated comorbidities. The lab uses a variety of pre-clinical models including human induced pluripotent stem cells (iPSCs) and cutting-edge approaches, including advanced confocal imaging and lightsheet microscopy, optogenetics, chemogenetics, calcium imaging, transgenic and viral strategies to manipulate the expression of target genes and multi-electrode array recording. Parallel research programs using preclinical models to develop new therapies, and translational studies to move diagnostics and therapies towards clinical application create a vibrant research environment for trainees in the lab.
