Epistatic Regulation of Gene Expression

基因表达的上位调控

• 批准号: 8771072
• 负责人: DAVID A BUCHNER
• 金额: $ 7.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771072
• 关键词: Animal Model; Architecture; Bayesian Method; Biological Models; Cellular biology; Clinical; Comorbidity; Complement; Complex; Consomic Strain; Data; Data Set; Detection; Diabetes Mellitus; Disease; Gene Expression; Gene Expression Regulation; Gene-Modified; Genes; Genetic; Genetic Crosses; Genetic Epistasis; Genetic Techniques; Genome; Genotype; Health; Hepatic; Heritability; Human; Individual; Lead; Light; Linear Models; Mentored Research Scientist Development Award; Mentors; Metabolic Diseases; Methods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pattern; Physiology; Population; Predisposition; Reproducibility; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Testing; Training; Weight Gain; Work; base; disorder risk; genetic risk factor; human disease; improved; insight; mouse model; novel; novel strategies; public health relevance; trait; transcriptome sequencing

DESCRIPTION (provided by applicant): Obesity and its comorbidities such as type 2 diabetes are a common health problem in the U.S. and throughout the developed world. Approximately one-third of the U.S population is currently obese. There is strong evidence that genetic factors contribute to an individual's propensity for weight gain, however identifying these factors has proven difficult. Part of the difficulty is likely due to complex interactions between genes that modify the phenotypic effects of each gene. Identifying interacting genes is difficult in both humans and in model organisms using traditional genetic techniques. We will to take a novel approach based on using mouse chromosome substitutions strains to characterize and identify these interacting genes. These strains have many advantages that facilitate the identification of genes underlying complex traits including improved reproducibility and simplified genetic crosses and data interpretation due to the partitioning of the genome into non-overlapping segments. We propose to study gene expression in pairwise combinations of the chromosome substitution strains. This will allow us to identify genes with expression patterns that are dependent on non-additive interactions between unlinked loci. This data will then be applied to existing human datasets for which gene expression and genotyping data are available. The mouse epistasis data will be used as a guide to improve statistical power in human studies, and therefore better detect epistasis in humans. Dr. Buchner's training prior to his K01 award had focused on the genetics of complex disease. During the K01 award period, he has complemented this training with additional activities in the fields of physiology, cell biology, an metabolic disease. This R03 proposal now seeks to combine Dr. Buchner's expertise in genetics, physiology, and metabolic disease to distinguish his research from that of his current and former mentors. This proposal will provide novel insights into the genetic architecture of complex traits while laying the groundwork for Dr. Buchner's work as an independent investigator.

描述（由申请人提供）：肥胖及其合并症，如2型糖尿病，是美国和整个发达国家普遍存在的健康问题。目前大约有三分之一的美国人肥胖。有强有力的证据表明，遗传因素会导致个人体重增加的倾向，然而，确定这些因素已被证明是困难的。部分困难可能是由于基因之间复杂的相互作用，改变了每个基因的表型效应。使用传统的遗传技术在人类和模式生物中识别相互作用的基因是困难的。我们将采用一种基于小鼠染色体替换菌株的新方法来表征和鉴定这些相互作用的基因。这些菌株具有许多优势，有助于识别复杂性状的基因，包括提高可重复性和简化遗传杂交和数据解释，因为基因组被划分为不重叠的片段。我们建议在染色体替代菌株的成对组合中研究基因表达。这将使我们能够识别具有依赖于非连锁位点之间非加性相互作用的表达模式的基因。然后，这些数据将应用于现有的人类数据集，其中基因表达和基因分型数据是可用的。小鼠鼻衄数据将作为指导，提高人类研究的统计能力，从而更好地检测人类鼻衄。在获得K01奖之前，Buchner博士的培训重点是复杂疾病的遗传学。在K01奖期间，他在生理学、细胞生物学和代谢疾病领域进行了额外的活动，补充了这一培训。这项R03提案现在寻求将Buchner博士在遗传学、生理学和代谢疾病方面的专业知识结合起来，以使他的研究与他现任和前任导师的研究区别开来。这一建议将为复杂性状的遗传结构提供新的见解，同时为Buchner博士作为独立研究者的工作奠定基础。