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。人们早就知道，脑损伤（如创伤性、缺血性和感染性）往往导致癫痫发作和癫痫（又称“创伤后癫痫”）。创伤后癫痫（PTE）占一般人群症状性癫痫的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是未知的，因此我们无法识别有风险的患者，或为他们提供可以阻止癫痫发展的治疗方法。在这里，我们建议通过探索来确定能够阻断癫痫发生的治疗药物：1。白蛋白诱导的突触发生和神经发生及其对兴奋/抑制失衡的贡献。2. 白蛋白暴露对神经网络重组的下游影响。3. 血脑屏障成像作为癫痫风险的生物标志物和抗tgf β治疗预防创伤性脑损伤后癫痫发生的潜力脑损伤通常与血管病理有关，特别是与血脑屏障（BBB）打开有关。在先前的RO1中，我们已经确定了血脑屏障受损后癫痫发展的新机制：我们已经表明，血脑屏障的化学开放导致局灶性癫痫样活动的延迟发展，血清白蛋白是癫痫发生的后续过程中的关键因素。

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.