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Mechanisms by which T-type calcium channels increase seizure susceptibility

T型钙通道增加癫痫易感性的机制

基本信息

批准号：
7776541
负责人：
EDWARD PEREZ-REYES
金额：
$ 38.5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7776541
关键词：
Absence Epilepsy Accounting Action Potentials Address Adverse effects Affect Animal Model Antiepileptic Agents Appearance Biophysics Brain Calcium Calcium Channel Calcium Channel Blockers Cell membrane Cell physiology Cellular biology Clinical Development Electrophysiology (science)Epilepsy Ethosuximide Feedback Fire - disasters Generalized Epilepsy Genes Genetic Goals Grant Hippocampus (Brain)Inherited Ion Channel Lead Membrane Membrane Potentials Microscopy Modeling Molecular Biology Morphology Mutation Neurites Neurons Neurosciences Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Play Population Predisposition Productivity Proteins Quality of life Rattus Research Rest Role Seizures Sodium Sorting - Cell Movement Surface Susceptibility Gene Synapses T-Type Calcium Channels Testing Trees United States Variant channel blockers deletion analysis drug development gain of function insight interest neuron development neuronal excitability novel novel therapeutics painful neuropathy prevent productivity loss tool trafficking

项目摘要

Significance -- Epilepsy affects about 2.5 million people in the United States. If not properly controlled by antiepileptic drugs, seizure disorders can lead to lower quality of life and loss of productivity. One class of epilepsy is called idiopathic generalized epilepsy (IGE), because the cause is not known (idiopathic) and the seizures can alter activity throughout the brain (generalized). Although this type of epilepsy can be inherited, there appear to be many genes involved (polygenic). Mutations in the gene, CACNA1H, which encodes the Cav3.2 channel, have been discovered in IGE patients. Approach -- This study will test the hypothesis that these epilepsy variants lead to a gain of function, either by altering Cav3.2 channel activity, or by altering its expression in neurons. Cav3.2 channels are a special class of calcium channel that can open near the resting membrane potential of neurons. This calcium entry can affect neurons in two important ways, one to depolarize the membrane and cause the neuron to fire sodium action potentials, and two, to increase calcium within the neuron, a 2nd messenger involved in the activation of many cellular processes such as dendritic arborization. Which of these roles is affected by epilepsy variants? To provide insights into this question, the present grant will address the following specific aims: [1] to establish the mechanisms by which Cav3.2 channels are trafficked in neurons; and [2] determine whether epilepsy variants of Cav3.2 increase dendritic arborization and whether this can be reversed by novel T-channel antagonists. The approaches used to address these important issues include molecular biology, cell biology, fluorescent microscopy, electrophysiology, and pharmacology. Impact -- These studies are likely to impact the field of neuroscience by uncovering novel roles of T- channels in dendritic arborization and neuronal excitability, and by validating novel antagonists. The studies will likely have a clinical impact: showing that T-channel antagonists reverse the effects of Cav3.2 variants on dendritic development, thereby providing the rationale for their early use to cure epilepsy.

意义——癫痫在美国影响着大约250万人。如果控制不当