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TGF-beta Mediated Inflammatory Signaling: a critical role in epileptogenesis

TGF-β介导的炎症信号传导：在癫痫发生中的关键作用

基本信息

批准号：
8928881
负责人：
Daniela KAUFER
金额：
$ 53.42万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2016-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928881
关键词：
Accounting Adrenergic beta-Antagonists Albumins Antiepileptic Agents Antiepileptogenic Applications Grants Astrocytes Binding Biological Markers Biological Neural Networks Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Chemicals Clinical Closed head injuries Cognitive Development Diagnosis Disease Early Intervention Effectiveness Epilepsy Epileptogenesis Event Functional disorder Funding Gene Expression Profile General Population Genetic Goals Health Human Image Individual Inflammatory Infusion procedures Injury Intervention Ischemic Brain Injury Knock-out Lead Life Magnetic Resonance Imaging Mediating Mediator of activation protein Medical Messenger RNA Military Personnel Modeling Modification Molecular Genetics Motor Neurons Pathological Staging Pathology Pathway interactions Patients Permeability Pharmaceutical Preparations Physiological Population Populations at Risk Post-Traumatic Epilepsy Prevention Process Public Health Resistance Risk Rodent Role Seizures Serum Albumin Serum Proteins Signal Transduction Staging Synapses Synaptic plasticity TGF Beta Signaling Pathway Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transforming Growth Factor beta Transforming Growth Factor beta Receptors Translating Traumatic Brain Injury Work base clinically relevant disability efficacy testing gliogenesis in vivo innovation nervous system disorder neurogenesis newborn neuron novel prevent programs single molecule synaptogenesis

项目摘要

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.

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，人们一直知道脑损伤（例如创伤性、缺血性和感染性）通常会导致癫痫发作和癫痫（AKA“创伤后癫痫”）。创伤后癫痫（PTE）占一般人群中症状性癫痫的20%，在军事人群中高达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。在这里，我们建议通过探索来寻找能够阻断癫痫发生的治疗药物：1。白蛋白诱导的突触发生和神经发生以及对兴奋性/抑制性失衡的贡献。2.白蛋白暴露对神经网络重组的下游影响。3. BBB成像作为癫痫风险生物标志物和抗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学有关，特别是与血脑屏障（BBB）的开放有关。根据先前的RO 1，我们已经确定了一种新的机制，为癫痫的发展后，血脑屏障妥协：我们已经表明，化学开放的血脑屏障导致局灶性癫痫样活动的延迟发展，血清白蛋白是一个关键因素，在随后的过程中癫痫发生。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，激活TGF β信号通路，诱导癫痫促进转录程序，随后导致星形胶质细胞早期功能障碍和延迟的病理性过度兴奋和癫痫发作。本建议结合细胞，电路，分子/遗传，和MR成像方法来研究网络重组，以下暴露于血清蛋白白蛋白的大脑，促进癫痫。这项工作揭示了一种新的致癫痫级联反应，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。