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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.

项目总结/文摘: