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Exploring the function of the central control of breathing in mice with sodium-channel mutations causing epilepsy, implication for the sudden unexpected death in epilepsy (SUDEP).

探索导致癫痫的钠通道突变小鼠的呼吸中枢控制功能，这对癫痫突然意外死亡（SUDEP）的影响。

基本信息

批准号：
263938822
负责人：
Dr. Henner Koch, Ph.D.
金额：
--
依托单位：
Klinik für Neurologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/263938822?language=en
关键词：
Exploring function central control breathing

项目摘要

Breathing is essential for life and a dysfunction of the neuronal network that controls this behaviour is suspected to be involved in several neurological diseases. The PreBötzinger Complex (PreBötC) is the central generator of the inspiratory breathing activity located in the brainstem. This research proposal is designed to unravel the consequences, of known epilepsy-causing mutations in genes encoding voltage gated sodium-channels, on the function of the PreBötC. The project aims to investigate the breathing activity in vivo and in vitro in mice with targeted knock-out and knock-in mutations in these genes and their possible consequences for SUDEP. Sudden unexpected death in epilepsy (SUDEP) is the most common direct cause of death in people suffering from epilepsy. Specifically, mice with mutations in the genes SCN1A and SCN2A will be examined. First, breathing will be characterized in great detail in the mutant mice and compared to the wildtype (WT) littermates. I propose to use in vivo whole body plethysmography recordings of freely moving mice to characterize the breathing parameters (objective1). Second, I will utilize in vitro electrophysiology and histology, obtained from brainstem slices containing the PreBötC, to dissect the possible pathological mechanisms at the network and cellular level caused by these mutations (objective 2). In my previous work, I have already shown how monogenic mutations (CACNA1A and NDUFS4, preliminary work) can lead to severe and potential lethal dysfunction of the central control of breathing. The results of objective 1 and 2 will provide, not only, an understanding how mutations in these genes might cause the pathology, but will enhance our knowledge of the fundamental function of the central control of breathing. Furthermore, in a third set of experiments, I propose to investigate the effects of Antiepileptic drugs (AED) on the function of the PreBötC in vitro and in vivo (objective 3) in wildtype and mutant mice to understand how these drugs might affect the function of the PreBötC. The exact pathophysiology leading to SUDEP is not well understood. A dysfunction of the autonomic control of heart beat and breathing are suspected to be involved in SUDEP. The function of the PreBötC might therefore play a crucial role in the fatal cascade leading to the death in these patients. The results of the first, second and third series of experiments will be correlated and combined to unravel if and how a dysregulation of the PreBötC could be involved in these events.

呼吸对生命至关重要，控制这种行为的神经网络功能障碍被怀疑与几种神经系统疾病有关。PreBötzinger复合体（PreBötC）是位于脑干的吸气式呼吸活动的中心发生器。这项研究计划旨在揭示编码电压门控钠通道的基因中已知的导致癫痫的突变对PreBötC功能的影响。该项目旨在研究这些基因靶向敲除和敲入突变小鼠体内和体外的呼吸活动及其对SUDEP的可能后果。癫痫猝死（SUDEP）是癫痫患者最常见的直接死亡原因。具体来说，将对SCN1A和SCN2A基因突变的小鼠进行检查。首先，突变小鼠的呼吸将被详细描述，并与野生型（WT）幼崽进行比较。我建议使用自由运动小鼠的体内全身体积脉搏波记录来表征呼吸参数（目标1）。其次，我将利用体外电生理学和组织学，从含有PreBötC的脑干切片中获得，在网络和细胞水平上剖析这些突变引起的可能的病理机制（目标2）。在我之前的工作中，我已经展示了单基因突变（CACNA1A和NDUFS4，初步工作）如何导致呼吸中枢控制严重和潜在致命的功能障碍。目标1和目标2的结果将不仅提供对这些基因突变如何导致病理的理解，而且将增强我们对呼吸中枢控制基本功能的认识。此外，在第三组实验中，我建议研究抗癫痫药物（AED）对野生型和突变小鼠体内和体外PreBötC功能的影响（目标3），以了解这些药物如何影响PreBötC的功能。导致猝死的确切病理生理机制尚不清楚。心跳和呼吸自主控制功能障碍被怀疑与猝死有关。因此，PreBötC的功能可能在导致这些患者死亡的致命级联反应中发挥关键作用。第一、第二和第三系列实验的结果将相互关联并结合起来，以揭示PreBötC的失调是否以及如何参与这些事件。