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

描述（由申请人提供）：癫痫是最常见的神经系统疾病之一。长期以来，人们都知道脑损伤或局部缺血往往会导致癫痫活动。创伤后癫痫（PTE）是一种继发于头部外伤后脑损伤的反复发作性疾病。PTE占一般人群中症状性癫痫的20%，由于穿透性头部损伤的发生率较高，在军事人群中高达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相关，特别是与血脑屏障（BBB）开放相关。我们已经确定了一种新的机制，癫痫的发展后，血脑屏障妥协：在大鼠新皮层，我们已经表明，开放的血脑屏障导致局灶性癫痫样活动的发展，类似于观察到的损伤后，血清白蛋白是一个关键因素，在随后的癫痫发生。具体而言，我们发现白蛋白与星形胶质细胞中的转化生长因子-β（TGF-β）受体相互作用，导致白蛋白摄取，并且白蛋白摄取引起TGF-β信号通路的诱导。我们建议进行一个详细的分析的分子和生理的变化，诱导白蛋白活化的TGF-β通路。然后，我们将针对这一途径，以评估TGF-β途径阻断剂的疗效，以治疗性地防止白蛋白信号转导和癫痫发生在活的大鼠。本研究的主要目的是：（1）研究白蛋白在特定细胞中的摄取以及白蛋白与TGF-β R的相互作用;（2）研究白蛋白与TGF-β R相互作用激活的下游信号级联反应;（3）研究TGF-β信号对星形胶质细胞形态和生物物理特性的下游影响;（4）证明TGF-β R拮抗剂预防癫痫的潜在功效。在这个建议中，我们结合联合收割机基因组，分子，生物化学和电生理技术来解开一个新的癫痫级联反应，并展示了深刻的临床意义，阻断这一过程。 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，该项目将阐明创伤性脑损伤后导致癫痫发生的途径。其次，该项目将评估针对这些途径进行治疗干预和预防癫痫发生的有效性。由于脑损伤是残疾的主要原因之一，目前尚无预防手段，因此该提案代表了解决这一未满足的医疗需求的重要进展。

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.