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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：
7545508
负责人：
DAVID J ROSSI
金额：
$ 33.47万
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/7545508
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 Clinical Development 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

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.

本建议的主要目的是研究可能涉及小脑损伤的机制