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

模型遗传系统中人类癫痫突变的遗传抑制研究

• 批准号: 8228069
• 负责人: ROBERT A. REENAN
• 金额: $ 32.4万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228069
• 关键词: Address; Alleles; Animals; Award; Behavior; Biological; Biological Markers; Complex; Coupled; Data; Development; Disease; Disease model; Drosophila genome; Drosophila genus; Enhancers; Epilepsy; Epileptogenesis; Frequencies; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Suppression; Genome; Genomics; Human; Laboratories; Literature; Methods; Modeling; Mutate; Mutation; Nature; Pathway interactions; Patients; Phenotype; Physicians; Processed Genes; RNA; Recording of previous events; Seeds; Seizures; Symptoms; System; Temperature; Time; Whole Organism; base; disease-causing mutation; fly; gene conservation; gene interaction; genome-wide; high risk; homologous recombination; human disease; innovation; insight; interest; mutant; novel; response; time use; transcriptomics

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.

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史上已被证明是无价的。产生基因突变，然后抑制或增强突变产生答案，在整个生物体水平上，直接生物相关性的问题。此外，遗传修饰基因和突变的性质可能揭示新的机制见解。我们的实验室率先使用同源重组（HR）将导致人类癫痫的突变引入果蝇基因组，产生强大的癫痫发作表型。这种在复杂动物中精确遗传建模的系统为癫痫发生机制的系统分析和新疗法的途径创造了独特的机会。在这里，我们建议利用果蝇人类癫痫模型在基因组范围内的系统性屏幕转录组的变化，响应癫痫发作，以及正向遗传筛选的基因突变，能够抑制（“遗传治愈”）所赋予的人类癫痫突变的表型。这些基于发现的方法，虽然风险很高，但正如突变表型所证明的那样，是基于基因和过程的保守性。我们的尤里卡提案包含揭示癫痫发展的新见解，抵消扰动兴奋性的补偿机制，以及能够逆转人类癫痫突变影响的基因和过程的改变。