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You searched for +publisher:"Vanderbilt University" +contributor:("Jennifer A. Kearney, Ph.D."). Showing records 1 – 2 of 2 total matches.

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Vanderbilt University

1. Kiddie, Elizabeth Ferrick. Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1.

Degree: PhD, Molecular Physiology and Biophysics, 2017, Vanderbilt University

Kv1.1 voltage-gated potassium channels serve as key regulators of neuronal function and mutations in Kv1.1 lead to the human movement and epilepsy-related disorder, Episodic Ataxia type-1 (EA1). Transcripts encoding Kv1.1 may be modified by a site-specific adenosine-to-inosine RNA editing event, leading to the expression of an altered protein with an isoleucine to valine change at amino acid 400 (I400V). The non-edited [Kv1.1(I)] and edited [Kv1.1(V)] channels display altered functions in heterologous expression systems, but their significance in normal physiology and with regard to EA1 have not been characterized. We have developed new mouse models which solely express either the non-edited [Kv1.1(I)] or edited [Kv1.1(V)] isoforms of the channel. Our studies have revealed that both mice display conditional postnatal lethality and that the non-edited [Kv1.1(I)] mice exhibit an EA1-like disorder, stress-induced motor dyscoordination. In addition, we observed that editing altered drug-induced seizure-susceptibility for these mutant mouse models. Mice expressing the non-edited [Kv1.1(I)] channel exhibited a lowered threshold for drug-induced seizures, whereas mutant animals expressing the edited [Kv1.1(V)] channel exhibited an increased threshold. To further characterize the collective effects of Kv1.1 editing in transcripts containing human EA1 mutations, we discovered that three mutations (V404I, I407M, and V408A), in close proximity to the editing site, decreased Kv1.1 RNA editing in vitro. Utilizing the V408A/+ mouse model of EA1, we confirmed that the V408A mutation leads to decreases in Kv1.1 RNA editing in vivo. Electrophysiological characterization of the edited EA1 mutant channels also indicated that these channel isoforms display channel dysfunctions unique to each mutation, as compared to their respective non-edited EA1 channels. Thus, Kv1.1 RNA editing has a substantial impact on normal physiology and may be dysregulated in the EA1 disorder, as well as contribute to the wide variety in symptom severity observed in EA1 patients. Advisors/Committee Members: Ronald B. Emeson, Ph.D. (committee member), Roger J. Colbran, Ph.D. (committee member), Aurelio A. Galli, Ph.D. (committee member), Jennifer A. Kearney, Ph.D. (committee member), Charles E. Cobb, Ph.D. (Committee Chair).

Subjects/Keywords: Kv1.1; RNA editing; RNA; neuroscience; potassium channel; seizure; electrophysiology; episodic ataxia type-1; EA1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Kiddie, E. F. (2017). Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10800

Chicago Manual of Style (16th Edition):

Kiddie, Elizabeth Ferrick. “Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed January 16, 2021. http://hdl.handle.net/1803/10800.

MLA Handbook (7th Edition):

Kiddie, Elizabeth Ferrick. “Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1.” 2017. Web. 16 Jan 2021.

Vancouver:

Kiddie EF. Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1803/10800.

Council of Science Editors:

Kiddie EF. Kv1.1 RNA Editing: Physiological Roles and its Implications for Episodic Ataxia Type-1. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/10800


Vanderbilt University

2. Jorge, Benjamin S. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.

Degree: PhD, Neuroscience, 2014, Vanderbilt University

Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are genetic in origin. Variable expressivity is commonly observed in families with inherited mutations in epilepsy-associated genes, suggesting that variation in genetic modifiers may contribute to epilepsy phenotypes. We previously identified the modulatory voltage-gated potassium channel subunit, Kcnv2, as a candidate modifier gene in a transgenic mouse model of epilepsy. This dissertation outlines: the validation of Kcnv2 as a quantitative modifier of epilepsy in mice; the identification of KCNV2 variants in pediatric epilepsy patients; the determination of Kcnv2 regulatory regions; and the identification of mutations in a delayed-rectifier potassium channel gene, KCNB1, in individuals with epileptic encephalopathy. These studies highlight the importance of delayed-rectifier potassium current in governing neuronal excitability and demonstrate the utility of identifying and characterizing genetic modifiers to elucidate mechanisms of pathogenesis. Advisors/Committee Members: Kevin C. Ess, M.D., Ph.D. (committee member), Jennifer A. Kearney, Ph.D. (committee member), Douglas P. Mortlock, Ph.D. (committee member), Alfred L. George, Jr., M.D. (Committee Chair).

Subjects/Keywords: potassium channel; epileptic encephalopathy; mouse model; genetics; whole-exome sequencing; epilepsy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Jorge, B. S. (2014). Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14387

Chicago Manual of Style (16th Edition):

Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 16, 2021. http://hdl.handle.net/1803/14387.

MLA Handbook (7th Edition):

Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Web. 16 Jan 2021.

Vancouver:

Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1803/14387.

Council of Science Editors:

Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14387

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