Epilepsy and the Wnt Signaling Pathway

Principal Investigator: DEGREGORI, JAMES
Program: PRMRP
Proposal Number: PR093303
Award Number: W81XWH-10-1-0380
Funding Mechanism: Investigator-Initiated Research Award - Partnering PI Option
Partnering Awards: PR093303P1
Award Amount: $756,982.00


1. What will be the ultimate applicability of the research?

Epilepsy is a common brain abnormality with symptoms of repeated seizures, and mood and learning problems. About 3 million Americans suffer from epilepsy and the estimated cost per year for this condition is 13 billion dollars. Epilepsy may start with an injury [such as a prolonged seizure called status epilepticus (SE), a head injury, or a brain infection]. This is followed by a "latent period" of months to years when a person or animal may not experience any obvious symptoms. Epilepsy is defined by having two or more spontaneous seizures. The process by which a normal person or animal becomes epileptic, is called epileptogenesis. During the latent period, brain cell (neuron) function may be altered, and groups of brain cells (networks) may develop abnormal communication patterns, causing the seizures. The goal of this project is to identify changes in the ways that cells communicate with each other and identify abnormal genes that might turn on after SE. We will examine a cell signaling pathway, called "Wnt", which has been studied in normal development and is abnormal in cancers. We will examine if Wnt inhibitors can prevent epileptogenesis if given during or immediately following the injury. We will use whole animal models of epilepsy, and biochemical and electrophysiological techniques to address our aims.

1a. What types of patients will it help and how? This research will help patients who are at risk to develop epilepsy -- those who have suffered from traumatic brain injury, suffered from a brain infection, stroke, or other causes for "acquired" epilepsies.

1b. What are the potential clinical applications, benefits, and risks? The Wnt signaling pathway is actively being studied in many types of cancers. We will alter this pathway with drugs/compounds/techniques already in use by cancer researchers. There are two drugs that are close to Phase I clinical trials in cancer. Therefore, side effect profiles of these compounds will be evaluated in patients with cancer so that initial safety data will be acquired.

1c. What is the projected time it may take to achieve a consumer-related outcome? We anticipate a 5-10 year time window to move the basic studies into whole animal in-vivo studies, then to Phase I human clinical trials. Side effect profiles of these compounds will be tested in patients with cancer so that initial safety data will be acquired.

2. If the research is too basic for clinical applicability, what are the interim outcomes?

One important interim outcome is to examine and validate the CA3 in-vitro system as a measure of seizure probability. Currently, we have no way of predicting which animals will develop epilepsy. Recent work has suggested that interictal spikes (as modeled by CA3 slice preparation) "drive epileptogenesis" -- or make it progress. We are using this model to see if we can slow down the bursting in CA3 as a way to screen for effective compounds to prevent epilepsy/epileptogenesis.

2a. What types of contributions will this study make to advance research? This proposal adopts techniques from the cancer research arena and applies them to neurological conditions.

2b. How will the research enhance this or other studies being conducted? This proposal may add to the fundamental understanding of brain function by examining how epilepsy changes the brain. Wnt signaling is also known to be abnormal in Alzheimer's disease, a condition in which patients suffer from memory loss and Schizophrenia, a condition in which patients have hallucinations and abnormal behaviors. Wnt signaling is also being examined in normal "synaptic plasticity" the way in which brain cells have stronger or weaker connections to each other after a stimulus.