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

描述(申请人提供)：癫痫是最常见的神经系统疾病之一。人们早就知道，脑损伤或脑缺血往往会导致癫痫活动。创伤后癫痫(PTE)是一种继发于颅脑损伤后的反复发作的疾病。在一般人群中，PTE占症状性癫痫的20%，在军人人群中，由于穿透性头部损伤的发生率较高，PTE占50%。脑损伤导致癫痫发生的机制大多是未知的。创伤性、缺血性或感染性脑损伤通常与血管损伤有关，特别是与血脑屏障(BBB)的开放有关。我们发现了血脑屏障受损后癫痫发生的新机制：在大鼠大脑皮层，我们发现血脑屏障开放导致局灶性癫痫样活动的发展，类似于损伤后观察到的，血清白蛋白是随后癫痫发生的关键因素。具体地说，我们发现白蛋白与星形胶质细胞中的转化生长因子-β受体相互作用，导致白蛋白摄取，白蛋白摄取导致诱导转化生长因子-β信号通路。我们建议对白蛋白激活转化生长因子-b途径所引起的分子和生理变化进行详细的分析。然后，我们将针对这一途径来评估转化生长因子-b途径阻滞剂在治疗上预防白蛋白信号转导和活体大鼠癫痫发生的效果。本研究的具体目标如下：(1)研究白蛋白进入特定细胞类型以及白蛋白与转化生长因子受体的相互作用；(2)确定白蛋白与转化生长因子受体相互作用所激活的下游信号级联反应；(3)表征转化生长因子-β信号对星形胶质细胞形态和生物物理性质的下游影响；(4)论证转化生长因子受体拮抗剂预防癫痫的潜在效果。在这项建议中，我们结合了基因组、分子、生化和电生理学技术来揭示一种新的致痫级联反应，并展示了阻断这一过程的深刻临床意义。 公共卫生相关性：该项目将在两个主要方面影响公共卫生。首先，该项目将阐明导致创伤性头部损伤后癫痫发生的途径。其次，该项目将评估以这些通路为靶点进行治疗干预和预防癫痫发生的效果。由于脑损伤是导致残疾的主要原因之一，到目前为止还没有预防的手段，这项提案代表着朝着解决这一未得到满足的医疗需求的方向迈出的重要一步。

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.