Remodeling Ca2+ and K+ Channels in Genetic Epilepsy

点击翻译按钮获取中文摘要

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.