Remodeling Ca2+ and K+ Channels in Genetic Epilepsy

描述（由申请人提供）： 这个K 01的申请人，“神经科学少数民族学者职业发展奖”是Prophyll N 'Gouemo博士，乔治敦大学医学院药理学系助理教授。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方面的额外培训，同时增加他在Ca和钾（K）通道和癫痫方面的培训。申请人的长期目标是获得额外的技能，使他成为神经科学的有效和独立的研究者。M博士莫拉德，一个著名的研究人员在离子通道领域，将担任导师。在电生理学，分子生物学和癫痫方面的其他专业共同导师，顾问和合作者将积极参与申请人的职业发展。本研究项目的总体目标是确定潜在的机制，占高阈值电压激活钙和钙激活钾电流密度下调下丘（IC）神经元的遗传性癫痫易感大鼠（GEPR），遗传模型的全身强直/阵挛性癫痫。要测试的中心假设是，上调的Ca和下调的K电流有助于IC神经元的过度兴奋，使GEPR癫痫发作。为了验证这一假设，提出了以下具体目标：1）确定哪种Ca通道类型解释了Ca电流的上调; 2）确定电流激活/失活参数和Ca通道通过蛋白激酶A和C的磷酸化状态的变化是否解释了Ca电流的增加; 3）确定GEPR中来自内部来源的Ca释放是否改变; 4）确定Ca激活的K通道的哪种组分导致Ca激活的K电流的下调; 5）确定在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和蛋白的表达水平是否发生变化。这些研究的结果可能会导致更好地理解的作用，钙和钙激活的K通道的神经元过度兴奋，导致癫痫发作的易感性和癫痫，以及阐明，以确定潜在的新的分子靶点治疗全身强直/阵挛性癫痫。

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.