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The Role of Raptor in Temporal Lobe Eplieptogenesis

猛禽在颞叶表皮发生中的作用

基本信息

批准号：
10058212
负责人：
Christin Margaret Godale
金额：
$ 3.87万
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：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058212
关键词：
Adaptor Signaling Protein Advocate Affect Animal Model Animals Antiepileptic Agents Antiepileptogenic Axon Brain Cell physiology Cells Cellular Metabolic Process Cellular Morphology Complex Development Disease Doctor of Philosophy Electrodes Epilepsy Epileptogenesis Exhibits FRAP1 gene Foundations Frequencies Genetic Genetic Recombination Growth Hippocampus (Brain)Homeostasis Hypertrophy Implant Incidence Individual Injections Intractable Epilepsy Lead Measurable Mediating Medical Mentors Metabolic Methodology Modeling Morphology Mus Neuronal Plasticity Neurons Newborn Infant PTEN gene Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmacology Pilocarpine Play Positioning Attribute Raptors Recurrence Research Risk Rodent Role Seizures Severities Signal Pathway Signal Transduction Sirolimus Status Epilepticus Temporal Lobe Temporal Lobe Epilepsy Testing Training Transgenic Animals United States Viral Virus calmodulin-dependent protein kinase II career cellular targeting dentate gyrus effective therapy entorhinal cortex experience granule cell improved inhibitor/antagonist innovation internal control molecular drug target mossy fiber nervous system disorder neuronal cell body neuronal growth novel prevent

项目摘要

Project Summary Despite availability of anti-epileptic drugs, one-third of the 3.4 million US patients with epilepsy have medically intractable epilepsy and still experience seizures despite treatment. There are no effective treatments to prevent the development of this debilitating condition (antiepileptogenic) in at-risk patients. The mechanistic target of rapamycin (mTOR) pathway, which regulates neuronal plasticity and growth, has emerged as a promising candidate for the development of anti-epileptogenic therapies. Pharmacological antagonists of the mTOR pathway have shown efficacy at preventing seizure occurrence in animal models of epilepsy, however, the cellular targets and signaling complexes mediating these effects are unclear. Hippocampal dentate granule cells (DGCs) may be prime targets of mTOR mediated pathological changes seen in temporal lobe epilepsy (TLE). mTOR signaling is increased among DGCs during the development of TLE, and treatment with rapamycin can block the formation of atypical DGC morphology. Our lab has shown that deletion of mTOR inhibitor, phosphatase and tensin homolog (PTEN) from newborn hippocampal dentate granule cells (DGCs) resulted in the mossy fiber sprouting and soma hypertrophy associated with epilepsy. These abnormalities exhibited in DGCs are thought to be associated with breakdown of the dentate gyrus’ ability to filter incoming information from the entorhinal cortex, creating hyper-excitable hippocampal circuits, resulting in spontaneous recurrent seizures. We hypothesize that rapamycin produces its diseasing modifying effects by blocking mTOR signaling in DGCs. To test this hypothesis, we will genetically delete the essential mTORC1 adaptor protein raptor from granule cells in a mouse TLE model and determine whether the treatment reduces seizure incidence and prevents dysmorphogenesis in DGCs (Aim 1). To assess the role of raptor in epileptogenesis, we have developed a viral strategy in which LoxP-flanked raptor can be deleted after pilocarpine-induced status epilepticus by injecting transgenic animals with AAV9.CamKII.HI.eGFP-Cre. Cre- mediated recombination in hippocampal neurons will lead to the deletion of raptor, preventing mTORC1 activity in these cells. (Aim 2) We predict that blocking hippocampal DGCs plays a role in the pathogenesis of TLE. Our proposal leverages collaborative, conceptual, and methodological innovation to make meaningful progress towards delineating the roles of mTORC1 and mTORC2 in the pathogenesis of epilepsy. The results, together with mentored training, will provide a foundation for working toward new solutions for epilepsy and other neurological disorders.

项目总结