Cerebellar malfunction and damage during ischemia

缺血期间的小脑功能障碍和损伤

基本信息

批准号：
7164417
负责人：
DAVID J ROSSI
金额：
$ 33.41万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7164417
关键词：
Affect Anions Apoptosis Apoptotic Area Asphyxia Neonatorum Biological Assay Brain Brain Injuries Brain Ischemia Brain region Cause of Death Cell Death Cell membrane Cells Cerebellar cortex structure Cerebellum Chloride Channels Chromosome Pairing Clinical Development Disruption Event Exocytosis Exposure to Fiber Future Glutamate Receptor Glutamate Transporter Glutamates Goals Heart Arrest Hippocampus (Brain)In Vitro Ischemia Ischemic Brain Injury Lead Measures Mediating Metabotropic Glutamate Receptors Modeling Modification Molecular Necrosis Neurons Osmotic Pressure Output Process Purkinje Cells Receptor Activation Research Personnel Role Signal Transduction Simulate Slice Stroke Swelling Synapses System Testing Therapeutic Therapeutic Intervention Time Tissues Traumatic Brain Injury United States Vertebral column Vesicle brain cell cell injury computerized data processing design disability fluorescence imaging gamma-Aminobutyric Acid granule cell improved in vivo in vivo Model mossy fiber patch clamp postsynaptic prevent programs receptor research study response therapeutic target therapy development tool transmission process uptake voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): ' The primary goal of this proposal is to investigate mechanisms that may be involved in cerebellar damage and malfunction during brain ischemia. Brain ischemia, which occurs during cardiac arrest, stroke and perinatal asphyxia, is a leading cause of death and long term disability. The cerebellum is a frequent target of stroke, and cerebellar Purkinje cells are one of the most susceptible brain cells to ischemic damage. However, relatively little is known about how Purkinje cells respond to and are damaged by ischemia. This lack of information is problematic because many of the ischemic mechanisms operating in other brain regions involve molecular processes that are either not expressed or have an unusual configuration in Purkinje cells. For this proposal, a brain slice model will be used to simulate brain ischemia in vitro and patch-clamp recording, confocal fluorescence imaging and pharmacological manipulations will be used to investigate mechanisms of cerebellar ischemic damage. Simulated ischemia induces a severe depolarization of Purkinje cells which is mediated by activation of non-NMDA ionotropic glutamate receptors (and possibly other glutamate receptors/transporters) but its onset is delayed by activation of GABAA receptors. These electrophysiological responses are associated with extensive tissue swelling and the subsequent development of necrotic and apoptotic cell death very similar to that observed with in vivo models. Simulated ischemia also severely disrupts electrical signal transduction through the cerebellum and the disruption persists for long periods after the ischemic episode is terminated. Determining the mechanisms that underlie both cellular damage and disrupted signal processing should provide useful information for the development of therapies. The specific aims of this proposal are: 1) To determine the mechanisms that lead to glutamate accumulation around Purkinje cells, elucidate which receptors mediate the Purkinje cell response and determine their contribution to cell damage; 2) To determine the mechanisms by which GABAA receptor activation delays the onset of Purkinje cell depolarization and to determine if the delay is beneficial or damaging; and 3) To determine where in the cerebellar circuitry and by what mechanism electrical signal transduction is disrupted.

描述（由申请人提供）：“该提案的主要目标是研究在脑缺血期间可能涉及小脑损伤和故障的机制。在心脏骤停，中风和围产期窒息期间发生的脑缺血是死亡和长期残疾的主要原因。小脑是中风的常见靶标，小脑Purkinje细胞是最易感性脑细胞的缺血性损伤之一。然而，关于浦肯野细胞如何应对和缺血会损害的情况相对较少。缺乏信息是有问题的，因为在其他大脑区域中运行的许多缺血机制都涉及分子过程，这些过程既不表达，否则在Purkinje细胞中具有异常构型。对于此提案，将使用脑切片模型在体外和斑块钳记录中模拟脑缺血，共聚焦荧光成像，并将使用药理学操纵来研究小脑缺血性损害的机制。模拟的缺血诱导了浦肯野细胞的严重去极化，这是由于非NMDA离子型谷氨酸受体的激活而介导的（以及其他可能的其他谷氨酸受体/转运蛋白），但其发作会因激活GABAA受体而延迟。这些电生理反应与广泛的组织肿胀以及随后的坏死和凋亡细胞死亡的发展与体内模型非常相似。模拟的缺血还严重破坏了通过小脑的电信号转导，并且在缺血性发作终止后长期存在破坏。确定基于细胞损伤和破坏信号处理的机制应为疗法的开发提供有用的信息。该提案的具体目的是：1）确定导致Purkinje细胞周围谷氨酸积累的机制，阐明哪些受体介导Purkinje细胞反应并确定其对细胞损伤的贡献； 2）确定GABAA受体激活延迟Purkinje细胞去极化的发作的机制，并确定延迟是有益的还是有益的； 3）确定小脑电路中的位置，以及通过哪种机理电信号转导中断。