Modeling genetic risk for epilepsy using IPSC and animal models.

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Project Abstract This proposal describes a mentored career development plan and research proposal that is designed to facilitate my transition to becoming an independent clinician scientist with specialization in the genetic determinants of epilepsy and underlying molecular mechanisms of epileptogenesis. Epilepsy affects 1% of the population and results in significant morbidity. Despite increasing discoveries of genetic etiologies that increase epilepsy susceptibility, this information has not led to disease modifying treatments. A better understanding of the mechanisms of epileptogenesis as a result of genetic changes may bring us closer to developing disease modifying treatments. Alterations in intrinsic cell excitability, neuronal organization and synaptic function are potential mechanisms leading to increased network excitability seen in epilepsy. Deletion of the 15q11.2 locus is found in 1.4% of genetic epilepsies, making it one of the most common susceptibility loci identified to date and it results in haplo-insufficiency of the CYFIP1 gene. The CYFIP1 gene regulates activity dependent translation at excitatory synapses as well as dynamic actin rearrangements required for normal neurogenesis and synaptic development. I hypothesize that increased seizure susceptibility and neuropsychiatric disorders in patients with 15q11.2 CNV results from alterations in CYFIP1 expression. In this application, I propose a research plan that will evaluate the functional consequences and underlying mechanisms of CYFIP1-mediated changes using a combination of in vitro human iPSC and in vivo mouse models. My mentorship team includes Nicholas Maragakis, Dwight Bergles, and Carl Stafstrom at Johns Hopkins University and Hongjun Song at the University of Pennsylvania. I have identified 4 short term training goals and 2 long term goals for this funding period. My short term goals are to (1) develop in vitro humanized models to validate molecular mechanisms of epilepsy and excitation / inhibition (E/I) imbalance in the context of human genetic backgrounds; (2) develop and manipulate animal models to probe epilepsy susceptibility and E/I imbalance (3) receive training in advanced electrophysiological techniques, and (4) improve my skills in statistically sound experimental design and analysis. My long term goals are to (1) develop an independent research career investigating the mechanisms of epilepsy in the wider context of neurodevelopmental disabilities and (2) further develop a clinical niche in the care of patients with genetically determined epilepsy. My career development plan and mentorship team will allow me to achieve these goals. The research plan will establish complementary in vitro and in vivo model systems to investigate underlying mechanisms, screen for therapeutic interventions and develop a platform that is generalizable to the investigation of other genetic risk factors for epilepsy. These studies will provide a foundation for my R01 submission in which I will examine genotype dependent changes in E/I balance to screen for new drug targets and predict drug response in vivo and in vitro and the mentorship and training that I receive will facilitate my transition to independent research in my own laboratory.