TGF-beta Mediated Inflammatory Signaling: a Critical Role in Epileptogenesis

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DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders. It has long been known that brain injury or ischemia often result in epileptic activity. Post-traumatic epilepsy (PTE) is a recurrent seizure disorder secondary to brain injury following head trauma. PTE accounts for 20% of symptomatic epilepsy in the general population, and up to 50% in the military population due to higher incidence of penetrating head injuries. Mechanisms by which brain injury leads to epileptogenesis are mostly unknown. Traumatic, ischemic, or infectious brain injuries are often associated with vascular injuries, specifically with opening of the blood-brain barrier (BBB). We have identified a novel mechanism for the development of epilepsy following BBB compromise: in the rat neocortex, we have shown that opening of the BBB leads to the development of focal epileptiform activity, similar to that observed following injury, and that serum albumin is a critical factor in subsequent epileptogenesis. Specifically, we have found that albumin interacts with transforming growth factor-beta (TGF-b) receptors in astrocytes, leading to albumin uptake, and that albumin uptake causes induction of the TGF-b signaling pathway. We propose to perform a detailed analysis of the molecular and physiological changes that are induced by albumin activation of the TGF-b pathway. We will then target this pathway to assess the efficacy of TGF-b pathway blockers to therapeutically prevent albumin signal transduction and epileptogenesis in living rats. The following specific aims will be carried out: (1) To characterize albumin uptake into specific cell types and albumin interactions with TGF-bRs; (2) To determine the downstream signaling cascade activated by albumin interaction with TGF-bRs; (3) To characterize the downstream effects of TGF-b signaling on the morphology and biophysical properties of astrocytes; and (4) To demonstrate the potential efficacy of epilepsy prevention using TGF-bR antagonists. In this proposal we combine genomic, molecular, biochemical and electrophysiological techniques to unravel a novel epileptogenic cascade, and demonstrate profound clinical implications of blocking this process. PUBLIC HEALTH RELEVANCE: This project will impact public health in two major ways. Firstly, the project will elucidate the pathways that lead to epileptogenesis following traumatic head injury. Secondly, the project will assess the efficacy of targeting these pathways for therapeutic intervention and prevention of epileptogenesis. Since brain insults are one of the primary causes of disability with no means of prevention as of yet, this proposal represents an important advancement toward resolving this unmet medical need.