Contributions of aberrant granule cell integration to the development of epilepsy

异常的颗粒细胞整合对癫痫发展的贡献

基本信息

批准号：
7652026
负责人：
Steve C Danzer
金额：
$ 32.81万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2009-08-05 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7652026
关键词：
Ablation Abnormal Cell Acute Address Adult Adverse effects Aftercare Animals Apical Biological Models Brain Bromodeoxyuridine Calcium Cell Aging Cell Death Cell Nucleus Cells Cellular Morphology Child Chimeric Proteins Confocal Microscopy Craniocerebral Trauma Dendrites Development Diphtheria Toxin Disease DsRed Employee Strikes Epilepsy Epileptogenesis Exhibits Frequencies Generations Genetic Recombination Hippocampus (Brain)Human Hypoxia Image Immediate-Early Genes Impact Seizures In Vitro Injury Label Life Maintenance Mediating Monitor Morphology Mus Nervous System Trauma Neurons Neurosciences Newborn Infant Outcome Study Pathology Patients Pharmaceutical Preparations Pharmacotherapy Plastics Play Population Presynaptic Terminals Process Recording of previous events Recurrence Reporter Role Seizures Slice Status Epilepticus Structure Tamoxifen Temporal Lobe Epilepsy Testing Time Transgenes Transgenic Animals Transgenic Mice Vertebral column adult neurogenesis axonal sprouting base brain cell cell age density diphtheria toxin receptor effective therapy granule cell in vivo killings mouse model neuronal patterning progenitor promoter public health relevance recombinase relating to nervous system research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is a serious disease for which there is no preventative and no cure. Moreover, available therapies are often ineffective, and medication side effects can be severe, particularly in children. In an effort to develop better treatments for the disease, we seek to understand how normal brains become epileptic. Elucidating the mechanisms of epileptogenesis will prove critical for treating, and ultimately curing, the disease. Recent advances in neuroscience have revealed that new brain cells are generated in adults. While these new brain cells likely play important roles in healthy humans, we believe that abnormal development and integration of these new cells contributes to the development of epilepsy. To determine whether adult-generated brain cells should be targeted for developing new treatments for epilepsy, we have developed a mouse model system which allows us to compare the structure of existing and newly-generated brain cells during the development of epilepsy. These studies will establish whether the new cells are selectively vulnerable to developing changes likely to promote epilepsy. Initial studies confirm the newborn cells develop hallmark pathologies of the epileptic brain, while mature cells appear unaffected. In a second set of experiments, we will examine the impact of seizures on the integration of new brain cells. Epilepsy frequently develops following neurological injuries such as head trauma, hypoxia or status epilepticus. Abnormal integration of new brain cells may result as a direct consequence of this initial injury. Alternatively, the initial injury may result in the occurrence of spontaneous seizures, and these seizures, in turn, may disrupt new cell integration. To distinguish between these possibilities, seizure frequency will be assessed in mice for several months following an epileptogenic brain insult. The morphology of cells born after the insult will be correlated with the presence and frequency of seizures in these animals. Importantly, the outcome of this study will determine whether seizure control might be an effective target for promoting the correct integration of newborn brain cells. Finally, to determine whether abnormally integrated newborn brain cells can be targeted to cure epilepsy, we will utilize a transgenic mouse model which will allow us to selective ablate newborn cells from the epileptic brain. These studies will be the first to examine the impact of selectively ablating any abnormal cell population from the epileptic brain, and it is our hope that our findings will provide the basis for developing new and more effective treatments for epilepsy. PUBLIC HEALTH RELEVANCE: In adults, new brain cells are born daily in the hippocampus, a region pivotal to the development of common forms of epilepsy. Abnormal incorporation of these new cells into the brain may promote the development of the disease. This proposal will elucidate the contribution of these new neurons to pathology, development and maintenance of epilepsy. By determining how normal brains become epileptic, we can begin to develop therapies to delay, halt and ultimately reverse the process.

描述（由申请人提供）：颞叶癫痫是一种严重的疾病，无法预防，也无法治愈。此外，现有的疗法通常无效，并且药物副作用可能很严重，尤其是对于儿童。为了开发更好的治疗方法，我们试图了解正常的大脑如何变得癫痫。阐明癫痫发生的机制对于治疗并最终治愈该疾病至关重要。神经科学的最新进展表明，成年人会产生新的脑细胞。虽然这些新脑细胞可能在健康人类中发挥重要作用，但我们相信这些新细胞的异常发育和整合会导致癫痫的发生。为了确定成人生成的脑细胞是否应该成为开发癫痫新疗法的目标，我们开发了一种小鼠模型系统，该系统使我们能够比较癫痫发展过程中现有脑细胞和新生脑细胞的结构。这些研究将确定新细胞是否选择性地容易受到可能促进癫痫的发展变化的影响。初步研究证实，新生细胞会出现癫痫脑部的标志性病变，而成熟细胞似乎不受影响。在第二组实验中，我们将检查癫痫发作对新脑细胞整合的影响。癫痫经常在神经损伤后发生，例如头部外伤、缺氧或癫痫持续状态。新脑细胞的异常整合可能是这种最初损伤的直接后果。或者，最初的损伤可能导致自发性癫痫发作的发生，而这些癫痫发作反过来可能会破坏新的细胞整合。为了区分这些可能性，将在致癫痫性脑损伤后的几个月内评估小鼠的癫痫发作频率。损伤后产生的细胞形态将与这些动物癫痫发作的存在和频率相关。重要的是，这项研究的结果将决定癫痫控制是否可能成为促进新生儿脑细胞正确整合的有效目标。最后，为了确定是否可以针对异常整合的新生脑细胞来治疗癫痫，我们将利用转基因小鼠模型，该模型将使我们能够选择性地消除癫痫脑中的新生细胞。这些研究将首次检验选择性消融癫痫大脑中任何异常细胞群的影响，我们希望我们的研究结果将为开发新的、更有效的癫痫治疗方法提供基础。公共卫生相关性：在成年人中，海马体每天都会产生新的脑细胞，海马体是常见癫痫形式发展的关键区域。这些新细胞异常融入大脑可能会促进疾病的发展。该提案将阐明这些新神经元对癫痫病理、发展和维持的贡献。通过确定正常大脑如何变得癫痫，我们可以开始开发延迟、停止并最终逆转这一过程的疗法。