Remodeling Ca2+ and K+ Channels in Genetic Epilepsy

重塑遗传性癫痫中的 Ca2 和 K 通道

基本信息

批准号：
7615575
负责人：
Prosper N'Gouemo
金额：
$ 17.24万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-18 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615575
关键词：
Accounting Acetylcholine Action Potentials Calcium Calcium Channel Calcium-Activated Potassium Channel Cells Cyclic AMP-Dependent Protein Kinases Data Doctor of Philosophy Down-Regulation Electrophysiology (science)Epilepsy Epileptogenesis Exhibits Fluorescence Genetic Glutamates Goals Image Imaging Techniques Inferior Colliculus Inherited Ion Channel K-Series Research Career Programs Lead Light Mediating Mentors Messenger RNA Minority Modeling Molecular Molecular Biology Molecular Target Neurons Neurosciences Patch-Clamp Techniques Permeability Pharmacology Phosphorylation Potassium Potassium Channel Predisposition Protein Subunits Proteins RNA amplification Rattus Research Personnel Research Project Grants Role Seizures Source Techniques Testing Tonic-Clonic Epilepsy Training Universities Up-Regulation Western Blotting audiogenic seizure base career development density gamma-Aminobutyric Acid improved mRNA Expression medical schools molecular imaging novel professor skills voltage

项目摘要

DESCRIPTION (provided by applicant): The applicant for this K01, "Career Development Award for Minority Scholars in Neuroscience" is Prosper N'Gouemo, Ph.D., an Assistant Professor in the Department of Pharmacology, Georgetown University Medical School. The applicant's short-term goals are to obtain additional training in calcium (Ca) imaging, single cell RNA amplification, electrophysiology of glutamate- and acetylcholine nicotinic-evoked currents, while increasing his training in Ca and potassium (K) channels, and epilepsy. The applicant's long-term objectives are to acquire additional skills as to make him an effective and independent investigator in neurosciences. Dr. M. Morad, a well known researcher in the field of ion channels, will serve as mentor. Additional specialized co-mentors, consultants, and collaborator in electrophysiology, molecular biology, and epilepsy will actively participate in the applicant's career development. The overall objective of this research project is to identify potential mechanisms that account for the upregulation of high threshold voltage activated Ca and downregulation of Ca-activated K current density in inferior colliculus (IC) neurons of genetically epilepsy-prone rat (GEPR), an inherited model of generalized tonic/clonic epilepsy. The central hypothesis to be tested is that upregulation of Ca and downregulation of K currents contribute to IC neuronal hyperexcitability that predisposes the GEPR to seizures. To test this hypothesis, the following specific aims are proposed: 1) Determine which Ca channel type accounts for the upregulation of Ca currents; 2) Determine whether changes in current activation/inactivation parameters and phosphorylation state of Ca channel via protein kinase A and C account for increases in Ca currents; 3) Determine whether Ca release from internal sources is altered in the GEPR; 4) Determine which component of Ca-activated K channels accounts for downregulation of Ca-activated K currents; 5) Determine whether the sensitivity of K channels to Ca is altered in the GEPR; 6) Determine whether changes in the levels of expression of Ca and Ca activated K channel mRNA and proteins occur in IC neurons of the GEPR. The results of these studies may lead to an improved understanding of the role of Ca and Ca-activated K channels in neuronal hyperexcitability that leads to seizure susceptibility and epilepsy as well as shed light to identify potentially novel molecular target for the therapy of generalized tonic/clonic epilepsy.

描述（由申请人提供）：乔治敦大学医学院药理学系助理教授，这项K01的“神经科学少数学者职业发展奖”的申请人是Prosper N'Gouemo博士。申请人的短期目标是获得钙（CA）成像，单细胞RNA扩增，谷氨酸和乙酰胆碱烟碱诱发电流的电生理学的额外训练，同时增加了他在CA和钾（K）通道（K）通道的训练以及癫痫病。申请人的长期目标是获得额外的技能，以使他成为神经科学领域的有效独立研究者。 M. Morad博士是离子渠道领域的著名研究人员，将担任导师。电生理学，分子生物学和癫痫病的其他专业联席会员，顾问和合作者将积极参与申请人的职业发展。该研究项目的总体目的是确定潜在的机制，这些机制解释了高阈值电压激活的Ca的上调，并下调了CA激活的K电流密度在遗传性癫痫症状大鼠（GEPR）的下丘（IC）神经元中的下调，A遗传的广义滋补/克隆癫痫的模型。要测试的中心假设是，k电流的CA上调和下调有助于IC神经元过度刺激性，使GEPR易于癫痫发作。为了检验该假设，提出了以下特定目的：1）确定哪种CA通道类型解释了CA电流的上调； 2）确定通过蛋白激酶A和C的CA通道的电流激活/灭活参数的变化和CA通道的磷酸化状态是否占Ca电流的增加； 3）确定GEPR中的CA是否从内部来源释放； 4）确定CA激活的K通道的哪些组成部分是CA激活K电流的下调； 5）确定GEPR中K通道对CA的敏感性是否改变； 6）确定在GEPR的IC神经元中，CA和CA激活的K通道mRNA和蛋白的表达水平的变化是否发生。这些研究的结果可能会导致人们对CA和CA激活K通道在神经元过度兴奋性中的作用的了解，从而导致癫痫发作和癫痫病，以及散发光明，以识别潜在的新型分子靶标，用于治疗普遍性滋补的普遍性滋补/克隆癫痫。