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

• 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
• 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

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： 严重的脑损伤后的潜在时期，例如脑损伤或癫痫持续状态，然后 赞助复发性癫痫发作的发作的特征是成年海马神经发生的变化。 深刻的形态学变化，包括希拉尔生态颗粒细胞和树突状发育异常 （例如，肺门基底树突）被观察到，因此提出了癫痫发作的神经发生的问题 是癫痫发作的。我们过去在急性癫痫发作之前或之后消融成人神经发生的工作表明 新神经元的癫痫作用，但是动物模型中现有的消融策略都遭受了 由于细胞，无法破译促进异常出生的颗粒细胞（ABGC）的机制 从电路中删除。在此修订后的R01应用程序中，我们将利用来自 我们的实验室表明，未成熟ABGC中的活性调节Ca2+和基因表达，这是 必要且足够的生产异常ABGC和海马电路的破坏 导致癫痫。我们提出的工作以确定促进异常神经发生的机制 专注于驱动异常ABGC并识别神经元的基因和信号通路 异常ABGC的输入。因为我们过去的工作一直都在Mesial的Pilocarpine模型中 临时叶癫痫 模型，例如在受控皮质冲击损伤后发生的癫痫。在AIM 1中，我们将证明 ABGC中HM4DI调节的基因表达提供了一种操纵潜在异常基因调节的新方法 途径并定义了我们在RNA-中鉴定的前两个候选基因的功能作用 - Timp3和RRM2。 测序分析。在AIM 2中，我们将使用Pilocarpine模型中的HM4DI在AIM 1中完成工作，并且 识别野生型小鼠中与异常ABGC相关的HM3DQ活化基因和神经元输入。在 AIM 3，我们将在受控皮质撞击损伤后消除或沉默ABGC，并评估对该影响的影响 慢性癫痫发作的发展。预计这些研究将提供对 促进异常ABGC成熟的机制，这可能提供新的策略来专门针对 在保留健康的神经元的同时，新的神经元异常。这些研究将在各种 神经系统疾病，包括癫痫。