Approximately 30% of all epilepsies are symptomatic and traumatic brain injury (TBI) is estimated to cause 20% of all symptomatic epilepsies. Thus, it is estimated that in the United States, at least 0.5 million surviving individuals live with posttraumatic epilepsy (PTE). Increased extracellular adenosine as an acute response to brain injury is known to provide seizure suppression and neuroprotection. However, astrogliosis associated with acute injury results in increased adenosine kinase (ADK), the key regulator of ambient adenosine levels. Upregulation of the astroglial based kinase ADK leads to deficits in the adenosinergic inhibitory feedback-system and thus promotes seizures. Astrogliosis is not only a hallmark of many types of epilepsy, but also a consequence of TBI. Since TBI can lead to subsequent epileptogenesis, it is important to understand how astrogliosis may contribute to epileptogenesis.
We aim to investigate how ADK is regulated in response to TBI and how these findings can be translated into applications to prevent epileptogenesis. The rationale for these studies is derived from the following previous findings from our lab: (1) Deficits of the adenosinergic system, in particular upregulation of ADK during astrogliosis, contribute to epileptogenesis and seizures. (2) Pharmacological blockade or RNAi-mediated downregulation of ADK effectively suppress seizures. Our CENTRAL HYPOTHESIS is that, as an astrogliotic response to injury, upregulation of ADK occurs as a general phenomenon and is a cause for epileptogenesis after TBI. Consequently, local therapeutic downregulation of ADK after TBI is expected to prevent subsequent epileptogenesis. We will therefore monitor astrogliosis, upregulation of ADK and the development of seizures in a novel rat model of TBI. In a therapeutic approach, downregulation of ADK expression with lentiviral RNAi is expected to prevent epileptogenesis after TBI.
The SPECIFIC AIMS of this project are:
Aim 1. Investigate astrogliosis, ADK-expression, and seizures in TBI-model of PTE.
Aim 2. Prevent PTE by local therapeutic intervention.
We plan to interfere with a response of the injured brain to reduce the abundance of the endogenous neuroprotective modulator adenosine. A gene therapy approach will be used to prevent the local reduction of adenosine after injury. Thus, new therapeutic strategies to prevent epileptogenesis after traumatic brain injury become feasible.
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