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。众所周知，脑损伤(如创伤性、缺血性和感染性)通常会导致癫痫发作和癫痫(又名“创伤后癫痫”)。创伤后癫痫(PTE)在一般人群中占症状性癫痫的20%，在军人人群中高达50%。大脑损伤导致癫痫发生的机制大多尚不清楚，因此我们无法识别处于风险中的患者，也无法为他们提供阻止癫痫发展的治疗方法。在这里，我们建议通过探索以下几个方面来寻找能够阻断癫痫发生的治疗药物：1.白蛋白诱导的突触和神经发生及其对兴奋性/抑制性失衡的贡献。2.白蛋白暴露对神经元网络重组的下游影响。3.血脑屏障显像作为癫痫风险的生物标志物和抗转化生长因子β治疗预防颅脑损伤后癫痫发生的可能性。脑损伤通常与血管病理有关，特别是与血脑屏障(BBB)的开放有关。在以前的RO1中，我们发现了BBB妥协后癫痫发生的新机制：我们已经证明，BBB的化学开放导致局灶性癫痫样活动的延迟发展，而血清白蛋白是随后癫痫发生过程中的关键因素。 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，激活转化生长因子-β信号通路，诱导癫痫的转录程序，继而导致星形胶质细胞的早期功能障碍和延迟的病理性高兴奋性和癫痫发作。本提案结合细胞、电路、分子/遗传学和磁共振成像方法，研究大脑暴露于血清蛋白白蛋白后的网络重组，并促进癫痫。这项工作揭示了一种新的致痫级联反应，并对诊断癫痫风险和开发安全有效的抗癫痫药物治疗人类获得性癫痫具有深远的临床意义。

DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders. It has long been known that brain injuries (e.g. traumatic, ischemic, and infectious) often result in seizures and epilepsy (AKA "post traumatic epilepsy"). Post-traumatic epilepsy (PTE) accounts for 20% of symptomatic epilepsy in the general population, and up to 50% in the military population. The mechanisms by which injury to the brain leads to epileptogenesis are mostly unknown, and consequently we are unable to identify patients at risk, or offer them therapies that can bock the development of epilepsy. Here, we propose to identify therapeutic agents able to block epileptogenesis by exploring: 1. Albumin-induced synaptogenesis and neurogenesis and the contribution to excitatory/inhibitory imbalance. 2. Downstream effects of albumin exposure on neuronal network reorganization. 3. The potential of BBB imaging as a biomarker for epilepsy risk and anti-TGF beta therapeutics to prevent epileptogenesis following traumatic brain injury. Brain injuries are often associated with vascular pathology, specifically with opening of the blood-brain barrier (BBB). Under the previous RO1 we have identified a novel mechanism for the development of epilepsy following BBB compromise: we have shown that chemical opening of the BBB leads to the delayed development of focal epileptiform activity, and that serum albumin is a critical factor in the subsequent process of epileptogenesis. Specifically, we have found that albumin interacts with transforming growth factor-beta (TGF beta receptors in astrocytes and activates the TGF beta signaling pathway, induces an epilepsy-promoting transcriptional program, and subsequently leads to the early dysfunction of astrocytes and delayed pathological hyper-excitability and seizures. The present proposal combines cellular, circuit, molecular/genetic, and MR imaging approaches to investigate network reorganization that follows the exposure of the brain to the serum protein albumin and promotes epilepsy. The proposed work unravels a novel epileptogenic cascade and demonstrates profound clinical implications for diagnosing epilepsy risk, and developing a safe/effective anti-epileptogenic drugs for treatment of acquired epilepsies in humans.