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: 8130046
• 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/8130046
• 关键词: Acceleration; Accounting; Address; Alleles; Animals; Applications Grants; Area; Award; Behavior; Biological; Biological Markers; Complex; Coupled; Critiques; Data; Development; Disease; Disease model; Drosophila genome; Drosophila genus; Enhancers; Epilepsy; Epileptogenesis; Evaluation; Fostering; Frequencies; Funding; Funding Opportunities; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Suppression; Genome; Genomics; Human; Individual; Institutes; Instruction; Investigation; Knowledge; Laboratories; Literature; Methodology; Methods; Mission; Modeling; Mutate; Mutation; Nature; Pathway interactions; Patients; Phenotype; Physicians; Pilot Projects; Probability; Processed Genes; RNA; Recording of previous events; Research; Risk; Science; Seeds; Seizures; Study Section; Symptoms; System; Temperature; United States National Institutes of Health; Update; Whole Organism; Writing; base; design; disease-causing mutation; fly; gene conservation; gene interaction; genome-wide; high risk; homologous recombination; human disease; innovation; insight; interest; meetings; 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历史上被证明是无价的。基因突变的产生，然后抑制或增强突变产生了答案，在整个生物体水平上，直接与生物学相关的问题。此外，基因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）将人类癫痫引起的突变引入果蝇基因组，产生强大的癫痫表型。这种复杂动物的精确遗传建模系统为系统分析癫痫发生机制和新疗法的途径创造了独特的机会。在这里，我们建议利用果蝇人类癫痫模型在全基因组范围内系统筛选癫痫发作反应的转录组变化，以及能够抑制（“遗传治愈”）人类癫痫突变所赋予的表型的基因突变的前向遗传筛选。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护。我们的EUREKA提案包含揭示癫痫发展的新见解，补偿机制以抵消兴奋性紊乱，以及能够逆转人类癫痫突变影响的基因和过程的改变的潜力。