Genetic Suppression studies of human epilepsy mutations in a model genetic system

描述(由申请人提供)：使用模型遗传系统来研究基因相互作用在遗传学历史上已被证明是非常宝贵的。基因突变的产生，然后是抑制子或增强子突变，在整个生物体层面上产生了对直接生物相关问题的答案。此外，遗传修饰基因和突变的性质可能揭示新的机制洞察力。我们的实验室率先使用同源重组(HR)将人类导致癫痫的突变引入果蝇基因组，产生强大的癫痫表型。这种在复杂动物中进行精确遗传建模的系统为系统分析癫痫的发生机制和新疗法的途径创造了独特的机会。在这里，我们建议利用全基因组的人类癫痫模型系统地筛选癫痫发作后的转录改变，以及对能够抑制(“基因治愈”)人类癫痫突变表型的基因突变进行正向遗传筛选。这些基于发现的方法虽然风险很高，但却坚定地基于基因和过程的保守，正如突变表型所表明的那样。我们的尤里卡提案包含了揭示癫痫发展的新见解、抵消受扰兴奋性的代偿机制以及能够逆转人类癫痫突变影响的基因和过程的变化的潜力。

DESCRIPTION (provided by applicant): 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.