Genetic Regulation of Circulating IGF1

循环 IGF1 的基因调控

• 批准号: 7895157
• 负责人: Rong Yuan
• 金额: $ 18.42万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895157
• 关键词: Age; Aging; Aging-Related Process; Bioinformatics; Biological; Biometry; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular Pathology; Chromosome Mapping; Chromosomes; Code; Collaborations; Complex; Data; Databases; Disease; Down-Regulation; Epidemiologic Studies; Future; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Code; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Heart Diseases; Hormones; Human; Inbred Strain; Inbred Strains Mice; Individual; Insulin-Like Growth Factor I; Link; Liver; Longevity; Malignant Neoplasms; Mammals; Maps; Masks; Measures; Methods; Modeling; Mus; Organism; Pathway interactions; Plasma; Play; Population; Processed Genes; Public Health; Publications; Quantitative Trait Loci; Recombinants; Regulation; Research Personnel; Resources; Rodent; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Testing; Time; Variant; Work; Yeasts; age related; fly; gene function; heart disease risk; innovation; insight; mouse model; novel; novel diagnostics; phenome; progenitor; public health relevance; therapeutic target; trait; tumor

DESCRIPTION (provided by applicant): The insulin-like growth factor 1 (IGF1) pathway plays an important role in regulating aging and longevity. Single gene mutations in the IGF1 pathway extend longevity in a variety of organisms, including yeast, worms, flies and rodents. Epidemiological studies found that lower IGF1 signaling is associated with longer longevity. In the normal human population, IGF1 levels vary dramatically and genetic polymorphisms play an important role in determining IGF1 levels. However, the mechanisms that allow genetic polymorphisms to regulate IGF1 levels have not been revealed. Furthermore, our studies suggest that IGF1 is regulated by a complex network of genetic loci containing previously unrecognized genes. We propose to study IGF1 gene regulation using an innovative, unbiased approach that combines critical mouse resources with traditional QTL analysis and newly developed bioinformatics methods to identify candidate genes. Our method includes: 1) Determining the genetic loci that determine IGF1 levels in an intercross population, 2) Identifying candidate genes that regulate Igf1, excluding the Igf1 locus itself, using combined cross and haplotype analyses, and 3) Narrowing the list of candidate genes using gene sequencing and expression data. The IGF1 regulating genes identified in this study will provide insights into key genetic mechanisms regulating aging and longevity, as well as age-related disorders, such as cancer and heart disease. As the mouse is an excellent model for understanding the genetic regulation of human biological and pathological traits, the data will allow candidate gene analysis and association studies in the human population. ) PUBLIC HEALTH RELEVANCE: Insulin-like growth factor 1 (IGF1) is a vital hormone that regulates human aging. Differences in IGF1 levels are associated with changes in longevity and disease and have been linked with differences in individuals' genetic codes. Using mouse models, our studies will identify these genetic variations and examine their role in controlling IGF1 and aging. Ultimately, our work will reveal factors that regulate the human aging process and identify treatments for age related diseases, such as cardiovascular disease and cancer.

描述（由申请人提供）：胰岛素样生长因子1（IGF1）途径在调节衰老和寿命方面发挥着重要作用。 IGF1 通路中的单基因突变可延长多种生物体的寿命，包括酵母、蠕虫、苍蝇和啮齿动物。流行病学研究发现，较低的 IGF1 信号传导与较长的寿命相关。在正常人群中，IGF1 水平差异很大，遗传多态性在决定 IGF1 水平方面发挥着重要作用。然而，遗传多态性调节 IGF1 水平的机制尚未被揭示。此外，我们的研究表明 IGF1 受到包含以前未识别的基因的复杂基因位点网络的调节。我们建议使用创新、公正的方法来研究 IGF1 基因调控，该方法将关键的小鼠资源与传统的 QTL 分析和新开发的生物信息学方法相结合，以识别候选基因。我们的方法包括：1) 确定在交叉群体中决定 IGF1 水平的基因位点，2) 使用组合的交叉和单倍型分析来识别调节 Igf1 的候选基因，排除 Igf1 基因座本身，以及 3) 使用基因测序和表达数据缩小候选基因列表。 这项研究中确定的 IGF1 调节基因将提供对调节衰老和长寿以及与年龄相关的疾病（例如癌症和心脏病）的关键遗传机制的见解。由于小鼠是了解人类生物学和病理性状的遗传调控的优秀模型，因此这些数据将允许在人群中进行候选基因分析和关联研究。 ） 公共健康相关性：胰岛素样生长因子 1 (IGF1) 是调节人类衰老的重要激素。 IGF1 水平的差异与寿命和疾病的变化有关，并且与个体遗传密码的差异有关。我们的研究将使用小鼠模型来识别这些遗传变异并检查它们在控制 IGF1 和衰老中的作用。最终，我们的工作将揭示调节人类衰老过程的因素，并确定与年龄相关的疾病（例如心血管疾病和癌症）的治疗方法。