Neurotrophins and Epileptogenesis

神经营养素和癫痫发生

• 批准号: 10599144
• 负责人: James O. McNamara
• 金额: $ 49.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599144
• 关键词: Amygdaloid structure; Anatomy; Animal Model; Anticonvulsants; Behavior assessment; Biochemical; Brain-Derived Neurotrophic Factor; Cells; Central Nervous System; Clinical; Development; Disease; Disease remission; Drug Targeting; Electroencephalography; Enterobacteria phage P1 Cre recombinase; Epilepsy; Epileptogenesis; Excitatory Synapse; Exhibits; Foundations; Funding; Genetic; Goals; Hippocampus; Human; In Situ Hybridization; Kainic Acid; Locales; Love; LoxP-flanked allele; Measures; Mediating; Medical; Messenger RNA; Mission; Modeling; Molecular; Molecular Abnormality; Mus; National Institute of Neurological Disorders and Stroke; Nervous System; Neurotrophic Tyrosine Kinase Receptor Type 2; Onset of illness; Operative Surgical Procedures; Pathway interactions; Patients; Peptides; Phospholipase; Phosphotransferases; Pilocarpine; Prevention trial; Preventive; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Remission Induction; Resected; Role; Seizures; Signal Induction; Signal Pathway; Signal Transduction; Site; Status Epilepticus; Temporal Lobe Epilepsy; Testing; Work; anxiety-like behavior; brief intervention; common treatment; comorbidity; excitatory neuron; experimental study; insight; mature animal; nervous system disorder; neurotrophic factor; novel; novel strategies; pharmacologic; pre-clinical; symptom treatment; tool

Project Summary Lack of preventive and disease modifying treatments for common disorders of the human nervous system is a glaring unmet medical need critical to the mission of NINDS. The work proposed here represents a novel approach to uncover molecular signaling mechanisms underlying temporal lobe epilepsy (TLE). Work accomplished during the current funding period reveals a pivotal role for the brain-derived neurotrophic factor (BDNF) receptor tyrosine kinase,TrkB, in the development of TLE induced by status epilepticus. TrkB-mediated activation of the effector, phospholipase C1, is the dominant pathway by which TrkB promotes development of TLE. The objective of the current application is to explore the role of TrkB signaling in the persistence of TLE. To accomplish this objective, we will examine the effect of pharmacological and genetic perturbations of TrkB signaling on epilepsy induced in diverse models of TLE. Successful completion of the work proposed may pave the way to preventive and/or disease modifying therapy of TLE, a common disorder of the human central nervous system.

项目摘要 缺乏对人类常见疾病的预防和疾病改善治疗 神经系统是一个明显的未满足的医疗需求，对NINDS的使命至关重要。工作 提出了一种新的方法来揭示分子信号机制 潜在的颞叶癫痫（TLE）。本供资期间完成的工作 揭示了脑源性神经营养因子（BDNF）受体酪氨酸的关键作用， TrkB在癫痫持续状态诱发的TLE发展中的作用TrkB介导的激活 磷脂酶C β 1是TrkB促进细胞凋亡的主要途径。 TLE的发展。本申请的目的是探索TrkB在细胞内的作用。 信号在TLE的持续性中。为了达到这个目标，我们将研究 TrkB信号转导对不同癫痫患者诱导的癫痫的药理学和遗传学干扰 TLE模型成功完成拟议的工作可能会为预防性 和/或改善TLE（一种常见的人类中枢神经系统疾病）的疾病治疗 系统

项目成果

Long-Term Potentiation of Mossy Fiber Feedforward Inhibition of CA3 Pyramidal Cells Maintains E/I Balance in Epilepsy Model.

CA3 锥体细胞苔藓纤维前馈抑制的长期增强维持癫痫模型中的 E/I 平衡。

• DOI: 10.1523/eneuro.0375-21.2021
• 发表时间: 2022
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Pan,Enhui;Puranam,RamS;McNamara,JamesO
• 通讯作者: McNamara,JamesO

A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.

• DOI: 10.1016/j.neuron.2015.09.032
• 发表时间: 2015-11-04
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Gu B;Huang YZ;He XP;Joshi RB;Jang W;McNamara JO
• 通讯作者: McNamara JO

Molecular signaling mechanisms underlying epileptogenesis.

• DOI: 10.1126/stke.3562006re12
• 发表时间: 2006-10-10
• 期刊: Science's STKE : signal transduction knowledge environment
• 作者: McNamara, James O;Huang, Yang Zhong;Leonard, A Soren
• 通讯作者: Leonard, A Soren

Vesicular zinc promotes presynaptic and inhibits postsynaptic long-term potentiation of mossy fiber-CA3 synapse.

• DOI: 10.1016/j.neuron.2011.07.019
• 发表时间: 2011-09-22
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Pan E;Zhang XA;Huang Z;Krezel A;Zhao M;Tinberg CE;Lippard SJ;McNamara JO
• 通讯作者: McNamara JO

Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis.

• DOI: 10.1002/hipo.22169
• 发表时间: 2013-12
• 期刊: HIPPOCAMPUS
• 影响因子: 3.5
• 作者: Singh, Shatrunjai P.;He, Xiaoping;McNamara, James O.;Danzer, Steve C.
• 通讯作者: Danzer, Steve C.