MECHANISMS OF SEIZURE-INDUCED DENDRITIC INJURY

癫痫发作引起的树突损伤的机制

• 批准号: 8497045
• 负责人: MICHAEL WONG
• 金额: $ 33.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497045
• 关键词: Actins; Acute; Address; Affect; Animal Model; Attenuated; Behavioral; Brain; Brain Injuries; Brain imaging; Cessation of life; Chronic; Cognitive deficits; Cytoskeleton; Data; Dendrites; Dendritic Spines; Environmental Risk Factor; Enzymes; Epilepsy; Epileptogenesis; Functional disorder; General Population; Grant; High Prevalence; Hippocampus (Brain); Hour; Human; Image; Imaging Techniques; Injury; Lead; Learning; Learning Disabilities; Life; Measures; Mediating; Memory; Mental Retardation; Microfilaments; Molecular; Morbidity - disease rate; Mus; Neurocognitive; Neurologic; Neurons; Neuroprotective Agents; Pathway interactions; Patients; Physiological; Population Research; Problem behavior; Process; Psychosocial Factor; Public Health; Regulation; Research; Research Proposals; Role; Seizures; Sensory Process; Signal Pathway; Signal Transduction; Site; Somatosensory Cortex; Somatosensory Evoked Potentials; Specimen; Spinal Injuries; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Work; cellular imaging; clinically significant; depolymerization; experience; imaging modality; improved; in vivo; inhibitor/antagonist; injured; innovation; insight; kainate; mTOR protein; mortality; neocortical; novel; novel therapeutic intervention; novel therapeutics; polymerization; prevent; psychologic; public health relevance; somatosensory; synaptic function

DESCRIPTION (provided by applicant): Epilepsy patients often experience cognitive deficits, such as memory problems, learning disabilities, and mental retardation. Although environmental and psychosocial factors can also affect brain function, there has been increasing focus on the role of seizures themselves in damaging the brain and thus causing further neurological deficits and decline in epilepsy patients, as well as progressively worsening seizures. Seizures can potentially injure the brain by a variety of mechanisms, including the death of neurons. However, since many people with epilepsy do not have obvious structural evidence of neuronal death on brain imaging or pathological studies, "non-lethal" effects of seizures on the structure and function of synapses and dendrites, the critical sites where neurons communicate, may be equally important in causing brain dysfunction in epilepsy patients. In our previous work, our lab has utilized cutting-edge imaging techniques to directly visualize in living mice injury to dendrits caused by seizures. In this project, we propose to address the hypothesis that a specific cell signaling pathway, called the mammalian target of rapamycin (mTOR) pathway, is involved in causing seizure-induced dendritic injury. First, we will use in vivo multiphoton imaging techniques to visualize whether inhibiting the mTOR pathway can prevent seizure-induced dendritic injury. Next, we will determine whether the mTOR pathway has neuroprotective effects on dendrites by regulating other cellular pathways and molecules related to the actin cytoskeleton of dendrites. Finally, we will investigate the physiological and functional consequences of seizure-induced dendritic injury related to cortical processing of sensory information in mice and test the ability of mTOR inhibitors to preserve normal function. This project should lead to important insights into the detrimental effects of seizures on dendrites and may ultimately lead to novel therapeutic approaches for preventing cognitive deficits and other neurological consequences of epilepsy.

描述（由申请人提供）：癫痫患者通常会出现认知缺陷，如记忆问题、学习障碍和智力迟钝。虽然环境和心理社会因素也会影响大脑功能，但人们越来越关注癫痫发作本身在损害大脑中的作用，从而导致癫痫患者进一步的神经功能缺损和下降，以及癫痫发作的逐渐恶化。癫痫发作可能会通过多种机制损害大脑，包括神经元的死亡。然而，由于许多癫痫患者在脑成像或病理学研究中没有明显的神经元死亡的结构证据，癫痫发作对突触和树突（神经元交流的关键部位）的结构和功能的“非致命”影响可能在导致癫痫患者脑功能障碍方面同样重要。在我们以前的工作中，我们的实验室利用尖端的成像技术直接可视化活体小鼠癫痫发作引起的树突损伤。在这个项目中，我们提出了一个假设，即一个特定的细胞信号通路，称为哺乳动物雷帕霉素（mTOR）通路的目标，参与引起树突状细胞损伤。首先，我们将使用体内多光子成像技术来观察抑制mTOR通路是否可以预防糖尿病诱导的树突状细胞损伤。接下来，我们将确定mTOR通路是否通过调节与树突肌动蛋白细胞骨架相关的其他细胞通路和分子对树突具有神经保护作用。最后，我们将研究与小鼠感觉信息的皮层处理相关的肾上腺素诱导的树突状细胞损伤的生理和功能后果，并测试mTOR抑制剂保持正常功能的能力。这个项目应该导致重要的见解癫痫发作对树突的有害影响， 可能最终导致新的治疗方法，用于预防癫痫的认知缺陷和其他神经学后果。