The use of model genetic systems to study gene interactions has proven invaluable in the history of genetics. Generation of genetic mutations and then suppressor or enhancer mutations produce answers, at the whole organism level, to questions of immediate biological relevance. In addition, the nature of genetic modifier genes and mutations may reveal novel mechanistic insights. Our laboratory has pioneered the use of homologous recombination (HR) to introduce human epilepsy-causing mutations into the Drosophila genome, generating robust seizure phenotypes. Such a system of accurate genetic modeling in a complex animal creates unique opportunities for systematic analyses of mechanisms of epileptogenesis and avenues to novel therapies. Here, we propose to utilize Drosophila human epilepsy models in genome wide systematic screens for transcriptomic changes in response to seizure, as well as forward genetic screens for mutations in genes that are capable of suppressing (""""""""genetically curing"""""""") the phenotype conferred by human epilepsy mutations. These discovery-based approaches, while high risk, are based solidly on the conservation of genes and processes, as the mutant phenotypes demonstrate. Our EUREKA proposal contains the potential to reveal new insights into the development of epilepsy, compensatory mechanisms to offset perturbed excitability, and alterations in genes and processes capable of reversing the effects of human epilepsy mutations.
Our laboratory has innovated a method to introduce human epilepsy-causing mutations directly into the fruit fly genome. Such mutant animals display symptoms remarkably like human epilepsy. We propose utilize this system along with whole-genome and genetic approaches to identify genes involved with seizure, and those capable of reversing the effects of epilepsy. ****Please note that reviewers were given the following special instructions for the review of these Exceptional Unconventional Research Enabling Knowledge Accelerations (EUREKA) grant applications: The purpose of the EUREKA initiative is to foster exceptionally innovative research that, if successful, will have an unusually high impact on the areas of science that are germane to the mission of one or more of the participating NIH institutes. EUREKA is for new projects. EUREKA is not for the continuation of existing projects. EUREKA is not for support of pilot projects (i.e., projects of limited scope that are designed primarily to generate data that will enable the PI to seek other funding opportunities). Rather, it is anticipated that EUREKA projects will begin and be completed during the funding period. Please provide an opinion and assessment of the likelihood the project will exert a sustained, powerful influence on the research field(s) involved. Significance and innovation should be the major determinants of your overall impact score. The approach should be evaluated for general feasibility. An application should score poorly if it is clear to the reviewers that the proposed methodology has no probability at all of being successful, either because it is inherently illogical or because the same approach has already been attempted and shown not to be feasible. Remember that unavoidable risk, which is intrinsic to novel and innovative approaches, is expected for these applications and reviewers are instructed that the presence or absence of preliminary data should not be taken into account when determining the score. Applications that are good science for standard research type investigation, but not likely to exert a sustained and powerful influence on the field, should be scored down.**** Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
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