Molecular control of aberrant adult-born granule cells in epilepsy

癫痫中异常成年颗粒细胞的分子控制

基本信息

批准号：
10737298
负责人：
Jenny Hsieh
金额：
$ 42.45万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737298
关键词：
Ablation Acute Address Adult Animal Model Animals Brain Brain Injuries Candidate Disease Gene Cell Cycle Cell Maturation Cells Chronic Clozapine Complement Dendrites Development Disease Elderly Epilepsy Epileptogenesis Extracellular Matrix Frequencies Functional Regeneration G-Protein-Coupled Receptors Gene Expression Gene Expression Regulation Generations Genes Hilar Hippocampus Hypertrophy Immunohistochemistry Injury Laboratories Ligands Maps Mediating Modeling Molecular Morphology Motion Mus Nerve Tissue Nervous System Trauma Neurons Oxides Pathway interactions Pilocarpine Post-Traumatic Epilepsy Process Production Public Health Publishing Receptor Activation Recurrence Regulation Regulator Genes Regulatory Pathway Research Retroviridae Role Seizures Signal Pathway Signaling Molecule Status Epilepticus TIMP3 gene Temporal Lobe Epilepsy Testing Thymidine Kinase Transgenic Mice Transgenic Organisms Translating Traumatic Brain Injury Traumatic injury United States Wild Type Mouse Work adult neurogenesis cell motility clinically relevant comparison control controlled cortical impact designer receptors exclusively activated by designer drugs digital experimental study granule cell improved loss of function migration mossy fiber mouse model nerve stem cell nervous system disorder nestin protein neurogenesis novel pharmacologic programs therapeutic target transcriptome sequencing

项目摘要

Project Summary/Abstract: The latent period after a severe brain insult such as traumatic brain injury or status epilepticus, and before the onset of spontaneous recurrent seizures, is characterized by changes in adult hippocampal neurogenesis. Profound morphological changes, including hilar ectopic granule cells and abnormal dendritic development (e.g., hilar basal dendrites) is observed, therefore raising the question whether seizure- induced neurogenesis is epileptogenic. Our past work of ablating adult neurogenesis before or after acute seizures has shown a pro- epileptic role of new neurons, however existing ablation strategies in animal models have all suffered from an inability to decipher the mechanisms that promote aberrant adult-born granule cells (abGCs) because the cells are removed from the circuit. In this revised R01 application, we will capitalize on recently published work from our laboratory demonstrating that activity in immature abGCs regulates Ca2+ and gene expression which is necessary and sufficient for the production of aberrant abGCs and disruption of the hippocampal circuitry leading to epilepsy. We propose work to determine the mechanisms that promote aberrant neurogenesis, focusing on the genes and signaling pathways that drive aberrant abGCs as well as identifying the neuronal inputs to the aberrant abGCs. Because our past work has always been in the pilocarpine model of mesial temporal lobe epilepsy, we will expand these studies to address the role of aberrant abGCs in a non-status model, such as epilepsy that occurs after controlled cortical impact injury. In Aim 1, we will demonstrate that hM4Di-regulated gene expression in abGCs offers a new way to manipulate potential aberrant gene regulatory pathways and define the functional role of our top 2 candidate genes – Timp3 and Rrm2 - identified in RNA- sequencing analysis. In Aim 2, we will complement the work in Aim 1 using hM4Di in the pilocarpine model and identify the hM3Dq activated genes and neuronal inputs associated with aberrant abGCs in wild-type mice. In Aim 3, we will ablate or silence abGCs after controlled cortical impact injury and evaluate the impact on the development of chronic seizures. Together these studies are expected to provide a greater understanding of the mechanisms that promote aberrant abGC maturation, which may offer new strategies to specifically target abnormal new neurons while sparing healthy neurons. These studies would be broadly impactful in a variety of neurological disorders including epilepsy.

项目摘要/摘要：严重脑损伤（例如创伤性脑损伤或癫痫持续状态）后和发生之前的潜伏期自发性复发性癫痫发作的特征是成人海马神经发生的变化。深刻的形态学变化，包括肺门异位颗粒细胞和异常树突发育观察到（例如，肺门基底树突），因此提出了癫痫发作是否诱导神经发生的问题我们过去在急性癫痫发作之前或之后消除成人神经发生的研究表明，它具有致癫痫性。新神经元的癫痫作用，然而动物模型中现有的消融策略都受到了无法破译促进异常成年颗粒细胞（abGC）的机制，因为细胞在这个修订后的 R01 应用程序中，我们将利用最近发表的工作。我们的实验室证明，未成熟的 abGC 的活性可调节 Ca2+ 和基因表达，这是对于异常 abGC 的产生和海马回路的破坏是必要且充分的我们建议开展工作以确定促进异常神经发生的机制，专注于驱动异常 abGC 的基因和信号通路以及识别神经元因为我们过去的工作一直是在中间的毛果芸香碱模型中。颞叶癫痫，我们将扩展这些研究以解决异常 abGC 在非状态中的作用模型，例如受控皮质撞击损伤后发生的癫痫，在目标 1 中，我们将证明这一点。 abGC 中 hM4Di 调控的基因表达提供了一种操纵潜在异常基因调控的新方法途径并定义我们在 RNA 中鉴定的前 2 个候选基因 – Timp3 和 Rrm2 的功能作用在目标 2 中，我们将在毛果芸香碱模型中使用 hM4Di 来补充目标 1 中的工作。鉴定与野生型小鼠中异常 abGC 相关的 hM3Dq 激活基因和神经输入。目标 3，我们将在受控皮质撞击损伤后消融或沉默 abGC，并评估对这些研究一起有望提供对慢性癫痫发作的更深入的了解。促进异常 abGC 成熟的机制，这可能提供新的策略来专门针对异常的新神经元，同时保留健康的神经元，这些研究将对各种广泛的影响。神经系统疾病，包括癫痫。