Genetic Regulation of Circulating IGF1

描述（申请人提供）：胰岛素样生长因子1 （IGF1）通路在调节衰老和长寿中起重要作用。IGF1通路中的单基因突变可以延长多种生物的寿命，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水平变化巨大，遗传多态性在决定IGF1水平方面起着重要作用。然而，基因多态性调控IGF1水平的机制尚未被揭示。此外，我们的研究表明，IGF1是由一个复杂的基因位点网络调控的，其中包含以前未被识别的基因。我们建议使用一种创新的、无偏倚的方法来研究IGF1基因调控，该方法将关键小鼠资源与传统的QTL分析和新开发的生物信息学方法相结合，以确定候选基因。我们的方法包括：1)确定决定杂交群体中IGF1水平的遗传位点；2)使用组合杂交和单倍型分析确定调节IGF1的候选基因（不包括IGF1位点本身）；3)使用基因测序和表达数据缩小候选基因列表。在这项研究中发现的IGF1调节基因将为了解调节衰老和寿命的关键遗传机制，以及与年龄相关的疾病，如癌症和心脏病提供见解。由于小鼠是理解人类生物学和病理性状的遗传调控的极好模型，这些数据将允许候选基因分析和人类群体的关联研究。

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.