Identify genetic mechanisms that regulate female sexual maturation

确定调节女性性成熟的遗传机制

• 批准号: 8700067
• 负责人: Rong Yuan
• 金额: $ 7.38万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700067
• 关键词: Age; Age at Menarche; Aging; Aging-Related Process; Bioinformatics; Biological; Biometry; Candidate Disease Gene; Chromosome Mapping; Code; Complex; Coronary heart disease; DNA; DNA Resequencing; Data; Diabetes Mellitus; Disease; Ensure; Family; Female; Foundations; Future; Genes; Genetic; Genetic Variation; Genotype; Haplotypes; Health; House mice; Human; Human Genome; Inbred Strain; Inbred Strains Mice; Insulin-Like Growth Factor I; Investigation; Life; Longevity; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Measures; Methods; Mouse Strains; Mus; Obesity; Organism; Osteoporosis; Outcome; Pathologic Processes; Plasma; Proprotein Convertases; Quantitative Trait Loci; Regulation; Reproduction; Risk; Sampling; Sexual Maturation; Solid; Stroke; Subtilisins; Surveys; Time; Tissue Inhibitor of Metalloproteinase-3; Vagina; Variant; Woman; age related; base; density; genome sequencing; genome wide association study; human NRIP1 protein; kexin; life history; malignant breast neoplasm; mortality; new therapeutic target; novel; progenitor; programs; public health relevance; success; trait; translational medicine

DESCRIPTION (provided by applicant): Sexual maturation is key to the evolutionary success of an organism. Evolutionary hypotheses predict that slower but fully functional female reproduction indicates slower aging and associates with extended lifespan. In humans, the age at menarche (AAM) is associated with significant health conditions later in life, and at least half the variation in AAM is determined by genetic factors that are not yet fully understood. Recently, we systematically measured age of female sexual maturation (FSM) in 32 mouse strains. The age of FSM varied dramatically among these strains, and delayed FSM correlated with lower circulating insulin like growth factor 1 (IGF1) and extended longevity. Some strains, however, had delayed FSM but higher IGF1, showing that circulating IGF1 dependent and independent mechanisms are involved. To identify the underlying genetic mechanisms, we generated 7 mouse crosses from 15 inbred strains that broadly represent the genetic diversity and variation in age of FSM across the mouse family. We have collected the age of FSM, plasma and DNA samples for 1,962 females of these crosses. And using genetic and bioinformatic methods, we identified a promising candidate gene, proprotein convertase subtilisin/kexin type 2 (Pcsk2). In this project, we propose to identify novel regulatory candidates of female sexual maturation. This project will lay a solid foundation for future investigation of FSM and its related diseases, s well as the aging process itself.

描述（由申请人提供）：性成熟是生物体进化成功的关键。进化假说预测，较慢但功能齐全的女性生殖表明较慢的衰老，并与寿命延长有关。在人类中，月经初潮年龄（AAM）与生命后期的重大健康状况有关，至少有一半