Pre-clinical in-vivo and in-vitro investigations to discover new anti-epileptogenic drugs and their cellular targets

对于我的博士研究，我建议致力于发现新的抗癫痫物质，并有助于我们了解它们是如何工作的。对于癫痫患者来说，下一次癫痫发作的不确定性比癫痫发作本身更能损害他们的生活质量。因此，不仅希望降低癫痫发作频率，而且希望实现无癫痫发作。由于癫痫是无法治愈的今天，不幸的是，这往往只能通过终身药物治疗与抗癫痫药物。因此，开发永久性降低大脑兴奋性而不仅仅是控制癫痫发作的抗癫痫药物（AED）至关重要。但是，目前还没有这种药物。除其他外，这是由于新的抗癫痫物质的临床前研究产出不足。由于抗癫痫是神经科学中一个令人着迷的新兴领域，我想把我的博士学位花在临床前研究中。具体来说，我建议从检查可能参与癫痫发生的细胞成分开始，以揭示新AED的可能靶点。我计划在通过手术或尸检从癫痫患者以及慢性癫痫动物（例如由癫痫持续状态或点燃引起的癫痫）中获得的标本中进行这项研究。此外，我打算在这些动物模型中测试使用相应药剂的治疗结果。因此，我建议在慢性癫痫动物模型中进行随机和盲法试验，在诱导癫痫之前、期间和之后的不同时间点注射不同剂量的潜在AED以及对照溶液（例如生理盐水溶液）。通过长期观察动物及其癫痫发作频率，并通过检查分离的脑切片和单个细胞，例如通过电生理学测量和膜片钳研究，可以确定用相应药剂治疗的结果。一方面，我的目标是找到适合AED靶向的脑细胞中的分子生物学成分。另一方面，我的目标是在动物模型中成功地证明靶向这些结构的药物的抗癫痫潜力，以便它们可以用于临床试验。由于癫痫是一种常见的神经系统疾病（超过1%的人口患有癫痫），我相信抗癫痫药物的开发对许多人的健康至关重要。由于我已经在不同的医学学科的研究经验，并非常热衷于神经科学，特别是癫痫研究，我非常适合在牛津大学攻读博士学位。

For my PhD research I propose to work on the discovery of new antiepileptogenic substances and to contribute to our understanding of how they work. For patients with epilepsy the uncertainty about when the next seizure will occur impairs their quality of life more than the seizure itself. It is therefore desirable to not only lower seizure frequency, but to achieve seizure freedom. As epilepsy is not curable today this can unfortunately often only be reached through life-long medication with anti-seizure drugs. Thus, it is crucial to develop anti-epileptogenic drugs (AEDs) that permanently reduce the cerebral excitability instead of only controlling seizures. However, such drugs are not yet available. Amongst others, this is due to the insufficient output of preclinical research of new antiepileptogenic substances. As antiepileptogenesis is a fascinating emerging field in neuroscience, I want to spent my PhD investigating such AEDs in preclinical research. Specifically, I propose to start with examining cellular components that potentially participate in epileptogenesis in order to unravel possible targets for new AEDs. I plan to do this in specimens obtained from patients with epilepsy by surgery or autopsy, as well as from animals with chronic epilepsy, for example induced by status epilepticus or kindling. Additionally, I intend to test the outcome of treatment with respective agents in such animal models. Therefore, I propose to perform randomized and blind tests in an animal model of chronic epilepsy by injection of different doses of potential AEDs, as well as of a control solution (e.g. physiological saline solution) at various time points prior, duringand after the induction of epilepsy. The outcome of a treatment with respective agents could be determined by observing the animals and their seizure frequency over a long period and by examination of isolated brain slices and singular cells, for example with electrophysiological measurements and patch clamp investigations. On one hand my goal is to find molecular biological components in cerebral cells suitable for targeting with AEDs. On the other hand, I aim to successfully prove the antiepileptogenic potential of agents targeting such structures in animal models so that they then can be used for clinical trials. Since epilepsy is a common neurological condition (over 1% of the population suffer from epilepsy), I believe that the development of antiepileptogenic medication is fundamental for the well-being of many people. As I already have research experience in diverse medical disciplines and am very enthusiastic about neuroscience and specifically epilepsy research, I am well-suited for undertaking a PhD at University of Oxford.