Epilepsy is a common and disabling disease for which current treatments remain inadequate. Epilepsy is known to have a major genetic contribution, but a small proportion of epilepsy overall is explained by known genes and mechanisms. Thus, there is a critical need to identify the molecules and pathways that underlie epilepsy pathophysiology and to find novel therapeutic strategies. Focusing on pathways which lead to epilepsy-related phenotypes in diverse species and model systems may help accelerate the discovery process. Recently we found mutations in the Prickle genes can contribute to seizures in multiple species ranging from flies to humans. This system can provide a basis for the development of safer and more effective drug regimens for treating epilepsy. Our preliminary findings led us to the hypothesis that mutations in the PRICKLE pathway are associated with epilepsy and that Prickle-modulating reagents can be used to treat epilepsy or seizures. The objective of this R01 application is to identify the molecules involved in Prickle signaling and to determine whether Prickle pathway-modulating reagents alleviate seizures in our multiple model systems. The studies proposed here should both further our understanding of the biology of the Prickles and their connection to epilepsy, and lead to new therapeutic modalities.
Our specific aims are: to 1) Test Prickle-pathway molecules as anti-epilepsy drug targets and 2) Test Wnt5a and related molecules as anti-epileptics in Prickle mutant mice. These experiments should provide insight into the biology of Prickle signaling, how it and whether Prickle-modulating reagents offer new epilepsy treatments.

Public Health Relevance

/Relevant to Public Health Epilepsy is a disabling disease that affects ~1% of the general population and requires long-term treatment. Most forms of epilepsy are inheritable, but for over 70% of patients, the underlying genetic basis for their condition remains unknown, impeding effective diagnosis and treatment. To develop new ways to diagnose and treat epilepsy, we aim to characterize genes and pathways not yet known to be involved, and to explore how these pathways might lead to new drug targets for epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS098590-02
Application #
9272457
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Whittemore, Vicky R
Project Start
2016-05-15
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Todd, Brittany P; Bassuk, Alexander G (2018) A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder. J Neurogenet 32:313-315
Wu, Wen-Hsuan; Tsai, Yi-Ting; Justus, Sally et al. (2018) CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa: A Brief Methodology. Methods Mol Biol 1715:191-205
Yang, Jin; Bassuk, Alexander G; Merl-Pham, Juliane et al. (2016) Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors. Hum Mol Genet 25:4201-4210
Zhang, Lijuan; Justus, Sally; Xu, Yu et al. (2016) Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa. Hum Mol Genet 25:4244-4255
Ehaideb, Salleh N; Wignall, Elizabeth A; Kasuya, Junko et al. (2016) Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans. Ann Clin Transl Neurol 3:695-707