Genetic Regulation of Circulating IGF1

描述（由申请人提供）：胰岛素样生长因子1（IGF1）通路在调节衰老和寿命方面起着重要作用。IGF1通路中的单基因突变延长了多种生物体的寿命，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信号与较长的寿命有关。在正常人群中，IGF1水平变化很大，遗传多态性在确定IGF1水平中起重要作用。然而，允许遗传多态性调节IGF1水平的机制尚未被揭示。此外，我们的研究表明，IGF1是由一个复杂的遗传位点网络，包含以前未被识别的基因。我们建议研究IGF1基因调控使用创新的，公正的方法，结合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，以确定候选基因。我们的方法包括：1）确定决定互交群体中IGF1水平的遗传基因座，2）使用组合的杂交和单倍型分析来鉴定调节IGF1的候选基因，不包括IGF1基因座本身，以及3）使用基因测序和表达数据来缩小候选基因的列表。 这项研究中确定的IGF1调节基因将为调节衰老和长寿以及与年龄相关的疾病（如癌症和心脏病）的关键遗传机制提供见解。由于小鼠是了解人类生物学和病理学特征遗传调控的极好模型，因此这些数据将允许在人类群体中进行候选基因分析和关联研究。) 公共卫生相关性：胰岛素样生长因子1（IGF1）是一种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，并与个体遗传密码的差异有关。使用小鼠模型，我们的研究将确定这些遗传变异，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的治疗方法，如心血管疾病和癌症。

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.