The Kalume Laboratory's current research includes:
Investigating How Epilepsy Leads to Sudden Unexpected Death
A small portion of people with epilepsy (especially those with severe and treatment-resistant epilepsy) can die abruptly, without warning or clear medical cause. The Kalume Laboratory is unraveling what causes this phenomenon, known as sudden unexpected death in epilepsy (SUDEP), and paving the way toward new therapies to prevent these deaths.
We recently found that, in mouse models of Dravet syndrome, a severe type of seizure – called a generalized tonic-clonic seizure – can cause sudden death by triggering excessive activity in the vagus nerve. This, in turn, causes a dramatic slowing of the heart. Now we are investigating new treatments that could prevent this fatal cascade of events, such as pacemakers that prevent the heart from slowing during seizure and therapies that stop the vagus nerve from becoming overactive.
Studying How the Ketogenic Diet Reduces Seizures
Despite the emergence of several new antiepileptic drugs in recent decades, seizures remain mostly unmanageable in Dravet syndrome and many other types of epilepsies. But a dietary regimen called the ketogenic diet can help control seizures in some patients with these epilepsies. The ketogenic diet is a low-calorie, high-fat diet that provides at least a 4:1 ratio of fat to carbohydrate or protein. However, it is not completely understood how or why this diet suppresses seizure activity.
Our lab is using a mouse model of Dravet syndrome to study the cellular and molecular mechanisms underlying the diet's therapeutic effects. Our previous results show that heterozygous deletion of NaV 1.1 channels causes a selective loss of sodium current and excitability in hippocampal GABAergic inhibitory neurons of Dravet syndrome mice, which may subsequently cause or exacerbate their seizure phenotype. We hypothesized that the therapeutic effects of ketogenic diet may be due to the diet ability to reduce or reverse the impacts of the NaV 1.1 channel deletion in our mouse model of Dravet syndrome.
Unraveling Why Epilepsy Triggers Sleep Disturbances
We are working to understand the mechanisms that cause sleep disturbances in patients with Dravet syndrome and other epilepsies. Sleep disturbances are common in people with epilepsy and are associated with poor seizure control and poor quality of life. NaV 1.1 channels are expressed neurons of ventrobasal (VB) nucleus of the thalamus and the reticular nucleus of the thalamus (RNT). These two nuclei play an important role in generating the rhythmic electrical brain waves that characterize sleep. We are investigating whether gene mutations that cause epilepsy may concurrently impair sleep quality in a mouse model of Dravet syndrome.